Tratamiento dirigido para el carcinoma metastásico de células renales
Resumen
Antecedentes
Desde la publicación de una revisión Cochrane sobre el tratamiento dirigido para el carcinoma metastásico de células renales (CMCR) en 2008 se han realizado varios ensayos controlados aleatorizados (ECA) comparativos, que incluyen combinaciones de inhibidores de la tirosina cinasa (ITC) e inhibidores de los puntos de control inmunitarios. Esta revisión representa una actualización de la revisión original.
Objetivos
Evaluar los efectos de los tratamientos dirigidos para el CMCR de células claras en pacientes que no habían recibido tratamiento sistémico.
Métodos de búsqueda
Se realizó una búsqueda exhaustiva sin restricciones en cuanto al idioma o el estado de publicación. La fecha de la última búsqueda fue el 18 de junio de 2020.
Criterios de selección
Se incluyeron los ensayos controlados aleatorizados que reclutaron pacientes con CMCR de células claras que no habían recibido tratamiento sistémico previo. La intervención índice fue cualquier tratamiento dirigido con ITC.
Obtención y análisis de los datos
Dos autores de la revisión evaluaron de forma independiente los estudios incluidos y extrajeron los datos de los desenlaces principales: supervivencia sin progresión (SSP), supervivencia general (SG) y episodios adversos graves (EAG); y de los desenlaces secundarios: calidad de vida relacionada con la salud (CdVRS), tasa de respuesta y episodios adversos (EA) leves. Los análisis estadísticos se realizaron con un modelo de efectos aleatorios y la certeza de la evidencia se calificó según los criterios GRADE.
Resultados principales
Se incluyeron 18 ECA que informaron sobre 11 590 participantes asignados al azar en 18 comparaciones. Este resumen se centra en los desenlaces principales de comparaciones seleccionadas.
1. Pazopanib versus sunitinib
El pazopanib puede dar lugar a poca o ninguna diferencia en la SSP, en comparación con el sunitinib (cociente de riesgos instantáneos [CRI] 1,05; intervalo de confianza [IC] del 95%: 0,90 a 1,23; un estudio, 1110 participantes; evidencia de certeza baja). Según un riesgo de episodios control de 420 por 1000 en este ensayo a los 12 meses, lo anterior se corresponde con 18 participantes menos con SSP (IC del 95%: 76 menos a 38 más) por cada 1000 participantes. El pazopanib puede dar lugar a poca o ninguna diferencia en la SG, en comparación con el sunitinib (CRI 0,92; IC del 95%: 0,80 a 1,06; un estudio, 1110 participantes; evidencia de certeza baja). Según un riesgo de episodios control de 550 por 1000 en este ensayo a los 12 meses, lo anterior se corresponde con 27 SG más (IC del 95%: 19 menos a 70 más) por cada 1000 participantes. El pazopanib puede dar lugar a poca o ninguna diferencia en los EAG, en comparación con el sunitinib (riesgo relativo [RR] 1,01; IC del 95%: 0,94 a 1,09; un estudio, 1102 participantes; evidencia de certeza baja). Según un riesgo de episodios control de 734 por 1000 en este ensayo, lo anterior se corresponde con siete participantes más que presentan EAG (IC del 95%: 44 menos a 66 más) por cada 1000 participantes.
2. Sunitinib versus avelumab y axitinib
El sunitinib probablemente reduce la SSP en comparación con avelumab más axitinib (CRI 1,45; IC del 95%: 1,17 a 1,80; un estudio, 886 participantes; evidencia de certeza moderada). Según un riesgo de episodios control de 550 por 1000 en este ensayo a los 12 meses, lo anterior se corresponde con 130 participantes menos con SSP (IC del 95%: 209 menos a 53 menos) por cada 1000 participantes. El sunitinib puede dar lugar a poca o ninguna diferencia en cuanto a la SG (CRI 1,28; IC del 95%: 0,92 a 1,79; un estudio, 886 participantes; evidencia de certeza baja). Según un riesgo de episodios control de 890 por 1000 en este ensayo a los 12 meses, lo anterior daría lugar a 29 SG menos (IC del 95%: 78 menos a 8 más) por cada 1000 participantes. El sunitinib puede dar lugar a poca o ninguna diferencia en cuanto a los EAG (RR 1,01; IC del 95%: 0,93 a 1,10; un estudio, 873 participantes; evidencia de certeza baja). Según un riesgo de episodios control de 705 por cada 1000 en este ensayo, lo anterior se corresponde con siete EAG más (IC del 95%: 49 menos a 71 más) por cada 1000 participantes.
3. Sunitinib versus pembrolizumab y axitinib
El sunitinib probablemente reduce la SSP en comparación con pembrolizumab más axitinib (CRI 1,45; IC del 95%: 1,19 a 1,76; un estudio, 861 participantes; evidencia de certeza moderada). Según un riesgo de episodios control de 590 por 1000 en este ensayo a los 12 meses, lo anterior se corresponde con 125 participantes menos con SSP (IC del 95%: 195 menos a 56 menos) por cada 1000 participantes. El sunitinib probablemente reduce la SG (CRI 1,90; IC del 95%: 1,36 a 2,65; un estudio, 861 participantes; evidencia de certeza moderada). Según un riesgo de episodios control de 880 por 1000 en este ensayo a los 12 meses, lo anterior daría lugar a 96 SG menos (IC del 95%: 167 menos a 40 menos) por cada 1000 participantes. El sunitinib puede reducir los EAG en comparación con pembrolizumab más axitinib (RR 0,90; IC del 95%: 0,81 a 1,02; un estudio, 854 participantes; evidencia de certeza baja), aunque el IC incluye la posibilidad de ningún efecto. Según un riesgo de episodios control de 604 por 1000 en este ensayo, lo anterior se corresponde con 60 EAG menos (IC del 95%: 115 menos a 12 más) por cada 1000 participantes.
4. Sunitinib versus nivolumab e ipilimumab
El sunitinib puede reducir la SSP en comparación con nivolumab más ipilimumab (CRI 1,30; IC del 95%: 1,11 a 1,52; un estudio, 847 participantes; evidencia de certeza baja). Según un riesgo de episodios control de 280 por 1000 en este ensayo a los 30 meses de seguimiento, lo anterior se corresponde con 89 SSP menos (IC del 95%: 136 menos a 37 menos) por cada 1000 participantes. El sunitinib reduce la SG (CRI 1,52; IC del 95%: 1,23 a 1,89; un estudio, 847 participantes; evidencia de certeza alta). Según un riesgo de episodios control de 600 por 1000 en este ensayo a los 30 meses, lo anterior daría lugar a 140 SG menos (IC del 95%: 219 menos a 67 menos) por cada 1000 participantes. El sunitinib probablemente aumenta los EAG (RR 1,37; IC del 95%: 1,22 a 1,53; un estudio, 1082 participantes; evidencia de certeza moderada). Según un riesgo de episodios control de 457 por 1000 en este ensayo, lo anterior se corresponde con 169 EAG más (IC del 95%: 101 más a 242 más) por cada 1000 participantes.
Conclusiones de los autores
Sobre la base de evidencia de certeza baja a alta, varias combinaciones de inhibidores del punto de control inmunitario parecen ser superiores a los tratamientos dirigidos con un solo agente en cuanto a la SSP y la SG, y con un perfil favorable de EA. Algunos tratamientos dirigidos con un solo agente demostraron un resultado oncológico similar o mejor que otros; se observaron diferencias menores en los EA dentro de este grupo. La certeza de la evidencia fue variable y osciló de alta a muy baja, y todas las comparaciones se basaron en ensayos individuales.
PICO
Resumen en términos sencillos
Tratamiento farmacológico dirigido para el cáncer de riñón que se ha extendido
Pregunta de la revisión
¿Qué tan efectivo es el tratamiento farmacológico dirigido para los pacientes con cáncer de riñón que se ha extendido, en comparación con otros tratamientos farmacológicos dirigidos?
Antecedentes
En la última década, el cáncer de riñón que se ha extendido se ha tratado con un grupo de fármacos, llamados tratamientos dirigidos, que actúan específicamente en las vías moleculares. Sin embargo, en los últimos años ha surgido un nuevo y prometedor grupo de medicamentos llamados inhibidores de los puntos de control inmunitarios que explotan el sistema inmunológico (de ahí que se les llame inmunoterapia). Actualmente algunos de estos fármacos se utilizan en combinaciones. Esta revisión evalúa la eficacia de los tratamientos dirigidos en comparación con otros tratamientos dirigidos, inhibidores de los puntos de control inmunitario o diferentes combinaciones de estos fármacos.
Características de los estudios
Solo se incluyeron los estudios en los que el azar determinó si las personas recibieron un fármaco dirigido u otro fármaco dirigido, y que se informaron en la literatura médica hasta el 18 de junio de 2020. La mayoría de los estudios examinaron los efectos sobre el crecimiento del cáncer de riñón (llamado progresión), la supervivencia (esperanza de vida) y los efectos no deseados graves.
Resultados clave
Se encontraron 18 estudios que respondieron la pregunta de revisión. Los participantes incluidos en estos ensayos tenían cáncer metastásico (cáncer que se ha extendido a otras partes del cuerpo), o cáncer avanzado que no podía ser extirpado mediante cirugía. En esta revisión se analizaron las comparaciones actualizadas más importantes para los médicos y los participantes.
1. Pazopanib versus sunitinib (tratamiento dirigido versus tratamiento dirigido)
El pazopanib puede dar lugar a poca o ninguna diferencia en la progresión, la supervivencia y los efectos no deseados graves, en comparación con el sunitinib.
2. Sunitinib versus avelumab y axitinib (agente dirigido versus inmunoterapia + agente dirigido)
El sunitinib probablemente provoca una mayor progresión, pero puede dar lugar poca o ninguna diferencia en cuanto a la muerte y los efectos no deseados graves, en comparación con el avelumab y el axitinib.
3. Sunitinib versus pembrolizumab y axitinib (agente dirigido versus inmunoterapia + agente dirigido)
El sunitinib probablemente provoca una mayor progresión y a más muertes, pero puede reducir ligeramente los efectos no deseados graves, en comparación con el pembrolizumab y el axitinib.
4. Sunitinib versus nivolumab e ipilimumab (tratamiento dirigido versus combinaciones de inmunoterapia)
El sunitinib puede dar lugar a una mayor progresión y a efectos no deseados graves, en comparación con el nivolumab y el ipilimumab. El sunitinib provoca más muertes, en comparación con las combinaciones.
Certeza de la evidencia
La certeza de la evidencia para la mayoría de los desenlaces fue baja a alta, lo que significa que hay cierta incertidumbre en cuanto a los hallazgos. No obstante, hay datos suficientes para poder establecer conclusiones definitivas sobre la forma en la que estos medicamentos se deben utilizar en el tratamiento de los pacientes con cáncer de riñón que se ha extendido.
Authors' conclusions
Summary of findings
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sunitinib | Risk difference with Sorafenib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 10 months) | 365 | ⊕⊕⊝⊝ | HR 1.19 | Study population | |
| 340 per 1000 | 63 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 365 | ⊕⊝⊝⊝ | HR 0.99 | Study population | |
| 550 per 1000 | 3 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 353 | ⊕⊝⊝⊝ | RR 0.99 | Study population | |
| 670 per 1000 | 7 fewer per 1000 | ||||
| Health‐related quality of life5 | not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of other bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 3 Downgraded by 1 level for study limitations; unclear risk of other bias 4 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 5 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sunitinib | Risk difference with Pazopanib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 1110 | ⊕⊕⊝⊝ | HR 1.05 | Study population | |
| 420 per 1000 | 18 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 1110 | ⊕⊕⊝⊝ | HR 0.92 | Study population | |
| 550 per 1000 | 27 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1102 | ⊕⊕⊝⊝ | RR 1.01 | Study population | |
| 734 per 1000 | 7 more per 1000 | ||||
| Health‐related quality of life (mean change value) follow‐up: after 4 cycle | 467 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life (mean change value) was ‐6.5 | MD 3.6 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;FACIT‐F: Functional Assessment of Chronic Illness Therapy–Fatigue scale; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of other bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 3 Downgraded by 1 level for study limitations; unclear risk of other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included no benefit and benefit) 5 Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias and unclear risk of other bias 6 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (3 points, included benefit and little benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sorafenib | Risk difference with Tivozanib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 517 | ⊕⊕⊝⊝ | HR 0.79 | Study population | |
| 360 per 1000 | 86 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 517 | ⊕⊕⊝⊝ | HR 1.25 | Study population | |
| 620 per 1000 | 70 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 516 | ⊕⊕⊝⊝ | RR 0.85 | Study population | |
| 689 per 1000 | 103 fewer per 1000 | ||||
| Health‐related quality of life | 506 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was ‐0.06 | MD 0.01 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) 2 Downgraded by 1 level for study limitations; high risk of performance, detection and other bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 4 Downgraded by 1 level for study limitations; high risk of other bias 5 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (0.06 points, included benefit and no benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Pazopanib | Risk difference with Sorafenib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 377 | ⊕⊕⊕⊝ | HR 1.92 | Study population | |
| 380 per 1000 | 224 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 377 | ⊕⊕⊝⊝ | HR 1.22 | Study population | |
| 520 per 1000 | 70 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 366 | ⊕⊝⊝⊝ | RR 0.92 | Study population | |
| 639 per 1000 | 51 fewer per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 267 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was ‐9.9 | MD 3.1 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; unclear risk of selection, detection, and reporting bias and high risk of performance bias 2 Downgraded by 1 level for study limitations; unclear risk of selection, and reporting bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 4 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 5 Downgraded by 1 level for study limitations; unclear risk of selection, detection, and reporting bias and high risk of performance and attrition bias 6 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (3 points, included benefit and no benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Everolimus | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 471 | ⊕⊕⊕⊝ | HR 0.71 | Study population | |
| 300 per 1000 | 125 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 471 | ⊕⊕⊝⊝ | HR 0.90 | Study population | |
| 470 per 1000 | 37 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 469 | ⊕⊕⊕⊝ | RR 1.34 | Study population | |
| 471 per 1000 | 160 more per 1000 | ||||
| Health‐related quality of life | 288 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 65.5 | MD 5 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance, detection and other bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 3 Downgraded by 1 level for study limitations; high risk of other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (10 points, included harm and no harm) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Avelumab + Axitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: median 10.8 months | 886 | ⊕⊕⊕⊝ | HR 1.45 | Study population | |
| 550 per 1000 | 130 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 886 | ⊕⊕⊝⊝ | HR 1.28 | Study population | |
| 890 per 1000 | 29 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 873 | ⊕⊕⊝⊝ | RR 1.01 | Study population | |
| 705 per 1000 | 7 more per 1000 | ||||
| Health‐related quality of life4 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations: high risk of performance bias and unclear risk of reporting bias 2 Downgraded by 1 level for imprecision: confidence interval crossed the assumed threshold of a clinically important difference (included no benefit and harm) 3 Downgraded by 1 level for study limitations: unclear risk of reporting bias 4 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Pembrolizumab + Axitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: median 12.8 months | 861 | ⊕⊕⊕⊝ | HR 1.45 | Study population | |
| 590 per 1000 | 125 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 861 | ⊕⊕⊕⊝ | HR 1.90 | Study population | |
| 880 per 1000 | 96 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 854 | ⊕⊕⊝⊝ | RR 0.90 | Study population | |
| 604 per 1000 | 60 fewer per 1000 | ||||
| Health‐related quality of life4 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and little harm) 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Atezolizumab + Bevacizumab | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: range 15 months to 20.7 months | 1117 | ⊕⊕⊝⊝ | HR 1.18 | Study population | |
| 480 per 1000 | 59 fewer per 1000 | ||||
| Overall survival follow‐up: range 20.7 months to 24 months | 1117 | ⊕⊝⊝⊝ | HR 0.99 | Study population | |
| 630 per 1000 | 3 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1098 | ⊕⊝⊝⊝ | RR 1.22 | Study population | |
| 446 per 1000 | 98 more per 1000 | ||||
| Health‐related quality of life | 691 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life ranged from 0.56 to 1.57 | MD 1 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; MDASI: MD Anderson Symptom Inventory; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and little harm) 2 Downgraded by 1 level for study limitations; high and unclear risk of 1 or more domains. 3 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 4 Downgraded by 1 level for inconsistency; moderate to substantial heterogeneity: unexplained differences between study results 5 Downgraded by 1 level for imprecision; confidence interval reached the line of no difference and crossed the assumed threshold of a clinically important difference (included harm and no harm) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IMA901 + Sunitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) | 339 | ⊕⊝⊝⊝ | HR 0.95 | Study population | |
| 590 per 1000 | 16 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 339 | ⊕⊕⊝⊝ | HR 0.75 | Study population | |
| 800 per 1000 | 46 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 334 | ⊕⊕⊝⊝ | RR 0.74 | Study population | |
| 550 per 1000 | 143 fewer per 1000 | ||||
| Health‐related quality of life6 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 2 Downgraded by 1 level for study limitations; high risk of performance and other bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Downgraded by 1 level for study limitations: high risk of other bias 5 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) 6 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Interferon‐α (IFN‐α) | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 6 months) | 750 | ⊕⊕⊕⊝ | HR 0.54 | Study population | |
| 400 per 1000 | 210 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 750 | ⊕⊕⊝⊝ | HR 0.82 | Study population | |
| 480 per 1000 | 68 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 735 | ⊕⊕⊕⊝ | RR 1.75 | Study population | |
| 258 per 1000 | 194 more per 1000 | ||||
| Health‐related quality of life follow‐up: after 2 cycle | 544 | ⊕⊕⊕⊝ | ‐ | The mean health‐related quality of life was 0.74 | MD 0.01 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; unclear risk of selection bias and high risk of performance and other bias 2 Downgraded by 1 level for study limitations; unclear risk of selection bias and high risk of other bias 3 Downgraded by 1 level for imprecision; confidence interval reached the line of no difference and crossed the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Downgraded by 1 level for study limitations; unclear risk of selection and attrition bias and high risk of performance and other bias | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN‐α | Risk difference with Temsirolimus | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 416 | ⊕⊕⊝⊝ | HR 0.74 | Study population | |
| 100 per 1000 | 82 more per 1000 | ||||
| Overall survival survival (absolute effect size estimates based on survival rate at 12 months ) follow‐up: up to 80 months | 416 | ⊕⊕⊕⊝ | HR 0.78 | Study population | |
| 300 per 1000 | 91 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 408 | ⊕⊕⊝⊝ | RR 0.86 | Study population | |
| 780 per 1000 | 109 fewer per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 401 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 0.66 | MD 0.03 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and no benefit) 2 Downgraded by 1 level for study limitations; high risk of performance and detection bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Atezolizumab | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) | 204 | ⊕⊝⊝⊝ | HR 0.84 | Study population | |
| 420 per 1000 | 63 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 204 | ⊕⊝⊝⊝ | HR 0.94 | Moderate | |
| 630 per 1000 6 | 18 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 203 | ⊕⊕⊕⊝ | RR 1.73 | Study population | |
| 398 per 1000 | 291 more per 1000 | ||||
| Health‐related quality of life | 157 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 1.04 | MD 1.46 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; MDASI: MD Anderson Symptom Inventory; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 2 Downgraded by 1 level for study limitations; high risk of selection, performance and detection bias and unclear risk of other bias 3 Downgraded by 1 level for study limitations; high risk of selection and unclear risk of other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (1 point, included harm and little harm) 5 Downgraded by 1 level for study limitations; high risk of selection, performance and detection bias and unclear risk of other bias 6 Baseline risk for overall survival in the atezolizumab group was assumed to be 63% (moderate risk) at 24 months as reported in Rini 2019b | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN (+ placebo) | Risk difference with Bevacizumab + IFN | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: intervention: 13.3 months comparator: 12.8 months | 1381 | ⊕⊕⊕⊝ | HR 0.68 | Study population | |
| 200 per 1000 | 135 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: intervention: 23 months comparator: 21 months | 1381 | ⊕⊕⊝⊝ | HR 0.88 | Study population | |
| 500 per 1000 | 43 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1356 | ⊕⊕⊕⊝ | RR 1.31 | Study population | |
| 536 per 1000 | 166 more per 1000 | ||||
| Health‐related quality of life3 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high and unclear risk of 1 or more domains 2 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) 3 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN‐α | Risk difference with Temsirolimus + IFN‐α | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 417 | ⊕⊕⊝⊝ | HR 0.76 | Study population | |
| 100 per 1000 | 74 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 417 | ⊕⊕⊝⊝ | HR 0.93 | Study population | |
| 300 per 1000 | 26 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 408 | ⊕⊕⊝⊝ | RR 1.12 | Study population | |
| 780 per 1000 | 94 more per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 394 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 0.66 | MD 0.03 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and no benefit) 2 Downgraded by 1 level for study limitations; high risk of performance and detection bias 3 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 4 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and no harm) 5 Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias 6 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Bevacizumab + IFN‐α | Risk difference with Temsirolimus + Bevacizumab | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 791 | ⊕⊕⊝⊝ | HR 1.10 | Study population | |
| 420 per 1000 | 35 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 791 | ⊕⊕⊕⊝ | HR 1.08 | Study population | |
| 550 per 1000 | 26 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 784 | ⊕⊕⊝⊝ | RR 1.05 | Study population | |
| 760 per 1000 | 38 more per 1000 | ||||
| Health‐related quality of life3 assessed with: FKSI–15 Scale from: 0 to 60 | no available data | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 2 Downgraded by 1 level for study limitations; high risk of performance bias (we are not concerned with unclear risk of other bias) 3 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN α‐2a + Bevacizumab | Risk difference with Everolimus + Bevacizumab | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 18 months) follow‐up: not reported | 365 | ⊕⊝⊝⊝ | HR 0.91 | Study population | |
| 250 per 1000 | 33 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 365 | ⊕⊝⊝⊝ | HR 1.01 | Study population | |
| 533 per 1000 | 3 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 361 | ⊕⊕⊝⊝ | RR 1.06 | Study population | |
| 762 per 1000 | 46 more per 1000 | ||||
| Health‐related quality of life5 | no available data | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; unclear risk of selection, performance and other bias and high risk of detection bias 2 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 3 Downgraded by 1 level for study limitations; unclear risk of selection and other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 5 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type); IMDC intermediate, poor risk patients only. | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Nivolumab + Ipilimumab | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 30 months) | 847 | ⊕⊕⊝⊝ | HR 1.30 | Study population | |
| 280 per 1000 | 89 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 30 months) | 847 | ⊕⊕⊕⊕ | HR 1.52 | Study population | |
| 600 per 1000 | 140 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1082 | ⊕⊕⊕⊝ | RR 1.37 | Study population | |
| 457 per 1000 | 169 more per 1000 | ||||
| Health‐related quality of life Scale from: 0 to 76 | 460 | ⊕⊕⊕⊝ | ‐ | The mean health‐related quality of life was 2.6 | MD 4.1 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and no harm) 2 Downgraded by 1 level for study limitations; high risk of performance and detection bias 3 Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of attrition bias | |||||
| Patient or population: Previous treated and treatment‐naïve (54%) metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Placebo | Risk difference with Pazopanib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 435 | ⊕⊕⊕⊕ | HR 0.46 | Study population | |
| 180 per 1000 | 274 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 435 | ⊕⊕⊝⊝ | HR 0.91 | Study population | |
| 480 per 1000 | 33 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 435 | ⊕⊕⊕⊕ | RR 2.00 | Study population | |
| 200 per 1000 | 200 more per 1000 | ||||
| Health‐related quality of life | 300 | ⊕⊕⊕⊕ | ‐ | The mean health‐related quality of life was ‐0.5 | MD 3.1 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included both benefit and harm) | |||||
Background
Description of the condition
Renal cell carcinoma (RCC) incidence represents about 2.2% of all invasive cancers and has a projected 2018 population age‐standardised mortality rate of 1.8 per 100,000 worldwide (GLOBOCAN 2018; Howlader 2017). Two‐thirds of cases occur in men. These figures include both renal cell carcinoma and the less common urothelial carcinoma of the renal pelvis: the latter is biologically related to bladder cancer and we do not consider it here. Renal cell carcinoma is divided into different pathologic subtypes, of which the clear cell subtype represents about 75% (Srigley 2013). The more uncommon subtypes are collectively referred to by clinicians as non‐clear renal cell carcinomas: they respond differently to treatment as compared to clear cell renal cell carcinoma (Fernández‐Pello 2017). Death from renal cell carcinoma is usually from metastases, either detected during staging of newly‐diagnosed patients (Stage IV) or detected during follow‐up after nephrectomy. A minority of patients are diagnosed with locally advanced disease which is too advanced for surgical resection but without metastatic findings. The term 'advanced renal cell carcinoma' has been used by authors to include both metastatic and locally advanced disease that have aspects that require separate consideration.
There has been great interest in finding more effective treatments for metastatic renal cell carcinoma. The search for specific targets for therapy goes back at least to Paul Ehrlich's 'magic bullet' over a century ago (Strebhardt 2008). This concept has gained renewed interest owing to the identification of multiple molecular targets and the potential for associated therapies that are target‐specific and therefore might have greater efficacy with less toxicity (Sawyers 2004). Clinical proof of concept came with the remarkable success of single‐agent imatinib for chronic myeloid leukaemia (Deininger 2005). Here we review the subsequent development of targeted therapy for metastatic renal cell carcinoma.
Description of the intervention
Prior to the development of targeted agents, renal cell carcinoma was one of the most drug‐resistant malignancies. Hormonal and cytotoxic chemotherapy agents have not been demonstrated to improve overall survival (OS) for this condition, and remissions with those agents occur at a frequency similar to that seen with no therapy or with placebo (Gleave 1998; Oliver 1989). Until the past decades, immunotherapy was the main focus of the search for an effective drug therapy for renal cell carcinoma and was the main initial comparator for targeted therapy; it was the subject of a companion Cochrane Review (Coppin 2004). In summary, classic immunotherapy, for example interferon‐alpha or interleukin‐2, has been associated with very modest survival benefit at best. When targeted agents were first being evaluated, the immunotherapy agent interferon‐alpha was considered the standard comparator for first‐line therapy of metastatic renal cell carcinoma (Mickisch 2003; Motzer 2002); placebo‐controlled trials have been appropriate in the second‐line setting. One should be aware that the distribution of prognostic risk strata in clinical trials is changing to a more favourable profile, such that direct comparisons of interventions through head‐to‐head clinical trials remain essential (Patil 2010).
Molecular pathways with multiple targets that are of particular interest in renal cell carcinoma currently fall into two major groups: angiogenesis (Rini 2005), and intracellular signal transduction pathways (Adjei 2005). The presence of a target may or may not translate into benefit from a targeted agent (Bergsland 2006). Some agents have activity against multiple targets. Classic immunotherapies such as interferon‐alpha may have anti‐angiogenic activity but are considered a separate class of agent (Coppin 2004). Suitably large randomised controlled trials have a high financial and resource cost, so that selection of agents for phase III testing requires strategic decision‐making (Roberts 2003).
A new class of drugs has been introduced into the treatment paradigm of clear cell RCC (Motzer 2015a). Immune checkpoint inhibitors are a new type of targeted immunotherapy and have been very successfully tested in other immunogenic tumours such as melanoma.
Since neither multi‐kinase inhibitors nor immune checkpoint inhibitors are necessarily cytotoxic, it is possible that tumour shrinkage may not be a reliable indicator of drug activity (Stadler 2006); for example, objective stabilisation of previously progressive disease might result in extension of OS. This is especially the case for immune checkpoint inhibition which in second‐line RCC treatment leads to prolonged OS without benefit in progression‐free survival (PFS).
Drug therapy for metastatic renal cell carcinoma has yet to demonstrate curative potential. Improvement in OS is the preferred and definitive outcome of interest to patients, and is a realistic outcome if there is only one effective intervention for an incurable cancer, as was the situation for metastatic renal cell carcinoma at the beginning of the targeted era (i.e. from 2000 onwards). However, when participants with progressive cancer in one arm of a randomised trial are permitted cross‐over to the other arm, as is commonly done for ethical reasons or to enhance recruitment, then any survival benefit (or detriment) of the investigational agent might be obscured; the same problem might happen if sequential active therapies are applied. For these reasons and as in other cancer sites, the duration of freedom from cancer progression may be accepted by regulatory bodies as adequate evidence of benefit for drug approval purposes (Johnson 2011). Surrogate endpoints such as PFS should preferably be accompanied by patient‐reported outcomes.
How the intervention might work
Molecular analysis of renal cell carcinoma has shown that this cancer is not a homogeneous condition (Hacker 2010; Linehan 2005). A high proportion of sporadic clear cell renal cell carcinomas have biallelic abnormalities of the Von Hippel‒Lindau (VHL) tumour‐suppressor gene (Young 2009), whereas other subtypes do not. Absence of the active VHL gene produces results in unregulated activation of the hypoxia‐inducible system and accumulation of growth factors such as vascular endothelial growth factor (VEGF). In subtypes such as papillary and chromophobe RCC, other pathways such as MET proto‐oncogene (MET) and tuberous sclerosis (TSC) alterations have been identified through investigation of hereditary and sporadic forms. Therefore the mainstays of first‐line therapy until now are multi‐kinase inhibitors targeting predominantly the VEGF‐receptor kinases but other targets are included to various degrees, such as MET, AXL receptor tyrosine kinase (AXL), platelet‐derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR). Immune checkpoint inhibitors targeting the programmed death‐ligand (PD‐L1) or its receptor (PD‐1) have been tested successfully in second‐ and third‐line treatments after failure of one or two lines of VEGFR‐targeting therapies (Motzer 2015a). These drugs counteract the tumour‐driven inhibition of T‐cell receptor‐mediated activation of IL‐2 production and T‐cell proliferation which leads to a successful anti‐tumour T‐cell‐mediated immune activity. Currently, these drugs are tested in first‐line trials in combination with either multi‐kinase inhibitors or other monoclonal antibodies targeting circulating VEGF or anti‐CTLA4 against the current first‐line monotherapy with VEGFR‐targeted therapies. With more treatment options being approved and investigated, it will be necessary to distinguish the impact of therapy on different molecularly‐defined tumour types as well as on tumours which have been treated with previous lines of therapy to better select patients for a given drug based on their predicted outcome. Although available, the necessary technology is not yet used in clinical routine. The molecular complexities of both the disease (renal cell carcinoma) and the treatment (targeted therapy) are resulting in a rapidly‐evolving and exciting phase in the history of the treatment of metastatic disease. According to Uzzo 2003, "an understanding of the basic biology of renal cell carcinoma is more advanced than that of any other solid malignancy." Further molecular subclassification within clear cell renal cell carcinoma may well become feasible (Kaelin 2008).
Why it is important to do this review
The topic of this review is systemic therapy of treatment‐naïve metastatic renal cell carcinoma, an important type of malignancy for which the therapy has changed greatly over the past decade and continues to be a strong focus of development of new agents and comparative studies. This review is needed to provide an objective and up‐to‐date resource for researchers, clinicians and consumers.
This is an update of a Cochrane Review first published in 2008 and previously updated in 2011 (Coppin 2008; Coppin 2011). Since the last date of full literature search, a number of additional studies have been published and there is an evolving shift to using previously validated targeted agents as the comparator rather than placebo, quasi‐placebo such as hormone therapy, or immunotherapy such as interferon‐alpha. There is also increasing emphasis on second‐line therapy now that targeted agents are established for first‐line therapy of metastatic renal cell carcinoma. In addition, new agents such as immune checkpoint inhibitors are increasingly being compared against first‐line standard therapies (Kuusk 2017).
This updated review reflects a restriction of scope in order to focus on metastatic renal cell carcinoma within the broader category of 'advanced disease' that additionally included locally‐advanced cancers without metastases. The main reason for this change of scope is because the management of locally‐advanced disease may include both systemic and surgical interventions, and therefore the complex interaction between the two modalities as well as additional outcomes such as resectability and local control rates. Other reasons include lack of criteria for inoperability that include both cancer and patient factors, and the possibility that drug response to the primary tumour might be different from the response of its metastases.
This review originates from a collaboration between the previous Cochrane Review authorship and the Renal Cell Carcinoma Guideline Panel of the European Association of Urology (EAU panel). Preliminary discussions with the EAU panel demonstrated a high level of overlap between the protocols of the two groups. This review is designed to minimise residual differences.
Objectives
To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, including randomised discontinuation trials in which treatment was stopped early because of obvious benefits or harms (Stadler 2006). Quasi‐randomised trials such as alternate allocation were eligible for consideration. We excluded randomised phase I trials as well as cluster‐randomised trials or trials of factorial design. Additionally, we imposed a stricter inclusion criterion of more than 100 patients per arm for study inclusion. This was a decision driven by pragmatic and methodological considerations, to avoid including small, methodologically‐flawed and underpowered studies with low internal and external validity and high clinical and methodological heterogeneity, whose findings are highly unlikely to inform, guide or influence clinical practice.
Types of participants
Participants were eligible if: older than 18 years of age; they had mRCC histologically or pathologically verified at presentation or relapse; they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 or equivalent. No prior systemic treatment was allowed.
Exclusion criteria were: the presence of symptomatic brain metastases; a life expectancy of less than 12 weeks; a serious acute or chronic illness or recent history of cardiac event.
Studies which allow solid tumours other than renal cell carcinoma were eligible only if participants with renal cell carcinoma were stratified and reported separately from other tumour types.
Diagnosis must be reported using the standard criteria (e.g. TNM Classification of Malignant Tumors) valid at the time that the trial began.
A predominant clear cell renal cell carcinoma histology was required.
We excluded studies for analysis of oncological outcomes that are designed for or include more than 20% of participants without metastases (i.e. locally‐advanced disease or unfit for nephrectomy). We included evaluation of adverse events if reported, however.
Types of interventions
Agents with known or presumed molecular targets were part of the therapeutic regimen of at least one study arm. Non‐specific agents considered previously were no longer eligible, as they are of historic interest only; these include ABT‐510, AE‐941, and carboxyaminoimidazole. We excluded classic immunotherapy agents, including recombinant cytokines and their predecessors, from the definition of targeted therapy, but they were allowed as part of combined regimens in any study arm (i.e. either as index interventions or as comparators).
Our approach to targeting immunotherapies (including PD1 or PD‐L1 checkpoint inhibitors) deserves special mention. As the main focus of the review was on VEGF‐targeted therapies on the basis of the earlier version of our review, and the fact that VEGF‐targeted therapies have been established as the mainstay of treatment for mRCC at the inception of this review, we considered targeting immunotherapies as a comparator intervention. In addition, targeted immunotherapies for mRCC are being considered as an index intervention in a separate Cochrane Review (Unverzagt 2017).
See Table 1 for a list of targeted agents to be sought, although additional targeted agents were identified during the search process. Studies in which maintenance therapy by a targeted agent was the randomised variable were eligible. Studies of dose or schedule of a targeted agent were eligible. There were no restrictions on drug route, dose, or schedule.
| Axitinib |
| Bevacizumab |
| Dovitinib |
| Erlotinib |
| Everolimus |
| Lapatinib |
| Pazopanib |
| Sorafenib |
| Sunitinib |
| Temsirolimus |
| Tivozanib |
| Other agents identified during search |
We investigated the following comparisons of target agents listed in Table 1 versus control/comparator.
Intervention
-
Targeted agent
Comparator
-
Targeted agent other than the ones used in intervention
-
Targeted agent in combination with immunotherapy
-
Immunotherapy
-
Combinations of immunotherapy
-
Placebo
We considered whether the control arm has been validated by a prior randomised study.
Minimum duration of intervention
Minimum duration of intervention was four weeks.
Minimum duration of follow‐up
Minimum duration of follow‐up was 12 weeks. We evaluated extended follow‐up periods after the trial termination only for adverse events.
Specific exclusion criteria
Studies observing neoadjuvant or adjuvant treatment or both with targeted agents were not eligible for analysis.
Types of outcome measures
Studies had to assess at least one efficacy outcome by allocation arm. We examined 'quality of life' outcomes where available, with reference to minimally important clinical differences where known for the assessment tools used. We evaluated adverse events in all studies. Our selection of outcomes for GRADE assessment was based on discussions amongst an expert panel (EAU panel) and authors of the previous review, and reflects outcomes of importance to stakeholders including patients, clinicians and healthcare providers.
Primary outcomes
-
Progression‐free survival (PFS)
-
Overall survival (OS)
-
Serious adverse events (SAEs; Grade 3 or 4)
Secondary outcomes
-
Health‐related quality of life (QoL)
-
Response rate
-
Minor adverse events (minor AEs; Grade 1 or 2)
Method and timing of outcome measurement
-
PFS: time from date of randomisation to date of clinical or radiological progression
-
OS: length of time from date of randomisation that participants are still alive
-
SAEs: all adverse events measured at any time that needed surgical, endoscopic, radiological or anesthesiological intervention, as well as any life‐threatening complications after participants received at least one treatment in intervention or comparator groups, classified by Common Terminology Criteria for Adverse Events (CTCAE)
-
QoL: evaluated by a validated instrument such as Supplementary Quality of Life Questionnaire (SQLQ), Functional Assessment of Cancer Therapy (FACT), Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI) or European Quality of Life‐5 Dimensions (EQ‐5D). If available, we focused on data of pre‐ to post‐treatment evaluation
-
Response rate: measured by Response Evaluation Criteria in Solid Tumors (RECIST) or modified RECIST criteria (Eisenhauer 2009)
-
Minor AEs: all adverse events measured at any time that could be managed by observation or pharmacological treatment after participants received at least one treatment in intervention or comparator groups, classified by Common Terminology Criteria for Adverse Events (CTCAE)
We considered a 5% absolute risk difference as clinically important for primary outcomes (PFS, OS and SAEs); we considered a 10% absolute risk difference as clinically important for the secondary outcomes of response rate and minor AEs. We used published threshold for QoL instruments.
If time‐to‐event data were not available, we tried to assess the number of events per total for dichotomised outcomes at certain time points (e.g. at one, two, three, four, five years, or at the longest reported follow‐up).
Main outcomes for 'Summary of findings' table
-
Progression‐free survival
-
Overall survival
-
Serious adverse events
-
Quality of life
Search methods for identification of studies
Overall time frame: we conducted a search from 1 January 2000 (we found no earlier studies in the previous version of this review) to an agreed cut‐off date that was at least one month before the date of search, to allow for indexing. We initially compared duplicate searches from separate time segments for consistency. For example the current authors have completed a search to 18 June 2020 using the algorithm in Appendix 1, and the Canadian authors have searched to 30 June 2010 as described previously (Coppin 2008, electronically updated to 30 June 2011 for Coppin 2011).
There were no restrictions by language or publication status.
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS databases, as well as trial registers ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch).
Searching other resources
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We handsearched abstracts in the proceedings of the annual meetings of the American Urological Association, the European Cancer Conference (ECCO), the European Society of Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO), all from 2000 to current year; and the annual ASCO genitourinary meeting (2008 to current year)
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We handsearched the bibliographies of included primary studies and of recent systematic reviews of targeted therapies for metastatic or advanced renal cell carcinoma
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We consulted clinical experts (EAU panel) to identify additional potentially important or seminal studies which may have been missed by the electronic searches
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We tried to identify other potentially eligible trials or ancillary publications by searching the reference lists of included trials, systematic reviews, meta‐analyses and health technology assessment reports. We also contacted authors of included trials to identify any additional information on the retrieved trials, and to determine if further trials exist that we may have missed. We also searched databases from regulatory agencies (European Medicines Agency (EMA) and US Food and Drugs Administration (FDA)) (Hart 2012; Schroll 2015).
Data collection and analysis
Selection of studies
Inclusion and exclusion of studies
Two review authors (FH; and LM or TL or AB or BL) independently conducted searches, assessed full‐text records, and independently mapped records to potentially eligible studies for inclusion/exclusion. We resolved disagreements by discussion.
We referred to trials by their eight‐digit NCT number where known. We classified studies as included studies, excluded studies, studies awaiting classification, or ongoing studies, in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017a). We documented the search process in a study flow diagram.
We document reasons for exclusion of identified studies not suitable for this review in the Excluded studies table. We included studies that did not report on our primary or secondary outcomes, and considered them for qualitative analysis.
Data extraction and management
Two review authors (FH; and LM or TL or AB) independently extracted data using an agreed template which we had piloted, and resolved any disagreements by consensus, with recourse to a third review author (TL or AB) if needed. We constructed a master database of consensus‐agreed data, which was available to all review authors.
Data extraction fields for each study included:
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basic study design features (e.g. parallel‐group randomised trial);
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dates when the study was conducted;
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study setting;
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participant eligibility criteria and actual accrual by arm for age, race, gender, performance status, prior nephrectomy, prior systemic therapy, histologic subtype, and prognostic risk method and distribution;
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stratification parameters, if any;
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detailed interventions, including criteria for discontinuing therapy and cross‐over to the investigational arm;
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the sample size for each included study and for each intervention/comparator group;
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details (such as dose, route, frequency, duration, as applicable) of each intervention/comparator relevant to this review;
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treatment delivery evaluation such as time point of administration and masking of treatment in interventional/comparator groups;
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frequency and protocol status (e.g. planned versus later protocol modification) of cross‐over to the investigational arm;
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details of the outcome definition for outcomes relevant to this review that were assessed in each study, method of outcome measurement for each outcome, timing of outcome measurement for each outcome, subgroups relevant to this review that were assessed for each outcome;
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reported statistics for each time‐dependent outcome, i.e. hazard ratio and two‐sided log rank P value;
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all adverse events reported by allocation;
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study funding sources;
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details of declarations of interest among the trialists.
We attempted to contact study investigators to obtain missing data for primary outcomes for eligible studies.
We report identified studies in the Characteristics of included studies table. If an eligible trial was ongoing and did not report any results, we collected information in the Characteristics of ongoing studies table.
Dealing with duplicate and companion publications
In the event of duplicate publications, companion documents or multiple reports of a primary trial, we maximised the information yield by collating all available data and used the most complete data set aggregated across all known publications. We listed duplicate publications, companion documents, multiple reports of a primary trial and trial documents of included trials (such as trial registry information) as secondary references under the study ID of the included trial. We also listed duplicate publications, companion documents, multiple reports of a trial and trial documents of excluded trials (such as trial registry information) as secondary references under the study ID of the excluded trial.
Data from clinical trial registers
In cases where data of included trials were available as study results in clinical trial registers such as ClinicalTrials.gov or similar resources, we made full use of this information and extracted data. If there was also a full publication of the trial, we collated and critically appraised all available data. If an included trial was marked as a completed study in a clinical trial register but no additional information (study results, publication or both) was available, we added this trial to the table Characteristics of studies awaiting classification.
Assessment of risk of bias in included studies
Two review authors (FH; and TL or ECH) independently used the latest version of the Cochrane tool for assessing risk of bias to construct a 'Risk of bias' table for each study, resolving disagreements by discussion (Higgins 2017b). If needed, a third review author (either AB or BL) was involved to enable us to reach consensus. We rated the following domains at low, high, or unclear risk of bias.
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Random sequence generation
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Allocation concealment
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Blinding of participants and personnel
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Blinding of outcome assessment
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Incomplete outcome data
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Selective reporting
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Other potential sources of bias
We assessed the 'Risk of bias' domains 'Blinding of participants and personnel', 'Blinding of outcome assessment', and 'Incomplete outcome data' on an outcome‐specific basis, grouping subjective outcomes and objective outcomes for the blinding domains, and grouping outcomes according to similar completeness of data for the outcome‐specific assessment of 'Incomplete outcome data'. We regarded all outcomes except for 'Overall survival of the total population' as susceptible to performance bias and detection bias. We summarised the risk of bias across domains for each outcome in each included study. We assessed the risk of attrition bias in three combined outcome groups that we defined by oncological, adverse event and quality‐of‐life outcomes. We present our judgements in a 'Risk of bias' summary and 'Risk of bias' graph.
Measures of treatment effect
When at least two included trials were available for a comparison and a given outcome, we tried to express dichotomous data as a risk ratio (RR) or odds ratio (OR) with 95% confidence intervals (CIs). For continuous outcomes measured on the same scale we estimated the intervention effect using the mean difference (MD) with 95% CIs. For continuous outcomes measuring the same underlying concept but using different measurement scales, we calculated the standardised mean difference (SMD). We expressed time‐to‐event data as a hazard ratio (HR) with 95% CIs.
Unit of analysis issues
If more than one comparison from the same trial was eligible for inclusion in the same meta‐analysis, we either combined groups to create a single pairwise comparison or appropriately reduced the sample size so that the same participants do not contribute to multiple comparisons (splitting the 'shared' group into two or more groups). While the latter approach offered some solution to adjusting the precision of the comparison, it did not account for correlation arising from the same set of participants being in multiple comparisons (Higgins 2017a).
Dealing with missing data
We planned to perform intention‐to‐treat analyses where data were available; however, we did not impute missing data. We included studies that combine outcomes from metastatic and locally‐advanced disease in tabulations if the locally‐advanced subgroup is documented as less than 20% of the total participants randomised; we considered other studies separately.
Whenever possible, we obtained missing data from the authors of the included trials. We carefully evaluated important numerical data such as screened, randomly‐assigned participants as well as intention‐to‐treat, and 'as treated' and 'per protocol' populations. We investigated attrition rates (e.g. dropouts, losses to follow‐up, withdrawals), and we critically appraised issues concerning missing data and use of imputation methods (e.g. last observation carried forward).
Assessment of heterogeneity
In the event of substantial clinical or methodological heterogeneity, we did not report trial results as the pooled effect estimate in a meta‐analysis. We identified heterogeneity (inconsistency) by visually inspecting the forest plots and by using a standard Chi² test with a significance level of α = 0.1. In view of the low power of this test, we also considered the I² statistic, which quantifies inconsistency across trials, to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003). We interpret the I² statistic as follows.
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0% to 40%: may not be important
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30% to 60%: represents moderate heterogeneity
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50% to 90%: represents substantial heterogeneity
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75% to 100%: represents considerable heterogeneity
We attempted to determine possible reasons for heterogeneity by examining individual study and subgroup characteristics.
Assessment of reporting biases
We did not find 10 or more trials that investigate a particular outcome, and did not use funnel plots to assess small‐trial effects. Several explanations may account for funnel plot asymmetry, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials) and publication bias, so we were cautious in our interpretation of results (Sterne 2011).
Data synthesis
We conducted (or displayed) a meta‐analysis only if we judged participants, interventions, comparisons and outcomes to be sufficiently similar to ensure an answer that is clinically meaningful. Unless good evidence showed homogeneous effects across trials, we primarily summarised low risk of bias data using a random‐effects model (Wood 2008). We interpreted random‐effects meta‐analyses with due consideration for the whole distribution of effects, ideally by presenting a prediction interval (Higgins 2009). This specifies a predicted range for the true treatment effect in an individual trial (Riley 2011). For rare events such as event rates below 1% we planned to use the Peto odds ratio, provided that there was no substantial imbalance between intervention and comparator group sizes, and that intervention effects were not exceptionally large. We also performed statistical analyses using Review Manager 5 software provided by Cochrane (Review Manager 2020), according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017a).
Statistical analysis
We anticipated analysis of four types of outcomes: categorical outcomes, such as tumour remission; single time‐dependent outcomes, such as OS; quality‐of‐life surveys; and toxicity tables. Of these, methods for analysis of dichotomous outcomes were fully covered by standard Cochrane procedures (Deeks 2017). We considered multidimensional quality‐of‐life and toxicity outcomes individually. Time‐dependent outcomes were potentially problematic. Where only a single study was available for a comparison, we accepted any standard statistical analysis, such as the log‐rank test used by the author, but we preferred the hazard ratio and log‐rank testing. For meta‐analysis of multiple studies of the same type, we used extraction of a dichotomous endpoint such as survival at one year from randomisation (see also Measures of treatment effect above).
Subgroup analysis and investigation of heterogeneity
We planned to perform a subgroup analysis for the following.
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Nephrectomy done or not done prior to treatment
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ECOG performance status (0, 1 or 2)
Sensitivity analysis
We planned a sensitivity analysis for studies that were at a high risk of bias for sequence generation, allocation concealment and blinding versus studies at low risk of bias. We planned to conduct a separate meta‐analysis for validation of results of studies at low risk of bias only.
Summary of findings and assessment of the certainty of the evidence
We present results for the outcomes as described in the Types of outcome measures section. We present the overall certainty of the evidence for each outcome according to the GRADE approach, which takes into account five criteria not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias), but also to external validity, such as directness of results (Guyatt 2008). For each comparison, two review authors (ECH, FH) independently rated the quality of evidence for each outcome as 'high', 'moderate', 'low', or 'very low', using GRADEpro Guideline Development Tool (GDT) software (GRADEpro GDT 2015). We resolved any disagreements by discussion or, if needed, by recourse to a third review author (TL, AB). For each comparison, we present a summary of the evidence for the main outcomes in a 'Summary of findings' table, which provides key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011; Schünemann 2017). We justified all decisions to downgrade the quality of trials using footnotes, and we made comments to aid the reader's understanding of the Cochrane Review where necessary.
Results
Description of studies
Our literature search identified 7738 records eligible for screening. We excluded 7668 records that did not meet our predefined inclusion criteria from further evaluation. Of these, we marked four as ongoing and included them in the Characteristics of ongoing studies section.
Results of the search
We found 70 titles and abstracts to be eligible for full‐text evaluation. Of these, we selected 18 trials for qualitative synthesis and included four of them in a quantitative analysis. We excluded 52 articles; our reasons are presented in Figure 1 and under Characteristics of excluded studies.
Study flow diagram.
Included studies
Additional information on included studies is available in the following tables: Characteristics of included studies; Participants disposition (Table 2); and Baseline characteristics (Table 3).
| Studies | Intervention(s)/ Comparator(s) | Randomised (N) | Received treatment (N) | Discontinued treatment (N) | Efficacy analysis (N) | Safety analysis (N) |
|---|---|---|---|---|---|---|
| Eichelberg 2015 | Soreafenib/ Sunitinib | 182 | 177 | 161 | 182 | 177 |
| Sunitinib/ Sorafenib | 183 | 176 | 156 | 183 | 176 | |
| Escudier 2010 | Bevacizumab + IFN‐a2a | 327 | 325 | 206 | 327 | 337 |
| IFN‐a2a + Placebo | 322 | 316 | 274 | 322 | 304 | |
| Escudier 2017 1 | Sunitinib | 546 | 535 | 438 | 546 | 535 |
| Nivolumab + Ipilimumab | 550 | 547 | 419 | 550 | 547 | |
| Hudes 2007 | Temsirolimus | 209 | 208 | 199 | 209 | 208 |
| Temsirolimus + Interferon | 210 | 208 | 193 | 210 | 208 | |
| Interferon | 207 | 200 | 194 | 207 | 200 | |
| McDermott 2017 | Sunitinib | 101 | 100 | 83 | 101 | 100 |
| Atezolizumab + Bevacizumab | 101 | 101 | 69 | 101 | 101 | |
| Atezolizumab | 103 | 103 | 80 | 103 | 103 | |
| Motzer 2010 | Sunitinib | 375 | 375 | 127 | 375 | 375 |
| IFN‐a2a | 375 | 360 | 234 | 375 | 360 | |
| Motzer 2013a | Pazopanib | 557 | 554 | 486 | 557 | 554 |
| Sunitinib | 553 | 548 | 483 | 553 | 548 | |
| Motzer 2013b | Tivozanib | 260 | 259 | 154 | 260 | 259 |
| Sorafenib | 257 | 257 | 192 | 257 | 257 | |
| Motzer 2014 | Sunitinib/ Everolimus | 233 | 231 | 192 | 233 | 231 |
| Everolimus/ Sunitinib | 238 | 238 | 201 | 238 | 238 | |
| Motzer 2019 | Sunitinib | 444 | 439 | 227 | 444 | 439 |
| Avelumab + Axitinib | 442 | 434 | 187 | 442 | 434 | |
| Ravaud 2015 | Everolimus + Bevacizumab | 182 | 180 | 175 | 182 | 180 |
| Interferon + Bevacizumab | 183 | 181 | 175 | 183 | 181 | |
| Retz 2019 | Sorafenib/ Pazopanib | 189 | 183 | 115 | 189 | 183 |
| Pazopanib/ Sorafenib | 188 | 183 | 110 | 188 | 183 | |
| Rini 2008 | Bevacizumab + IFN‐a2b | 369 | 366 | 355 | 369 | 366 |
| IFN‐a2b | 363 | 350 | 355 | 363 | 349 | |
| Rini 2014 | Temsirolimus + Bevacizumab | 400 | 393 | 372 | 400 | 393 |
| Temsirolimus + Interferon | 391 | 391 | 354 | 391 | 391 | |
| Rini 2016 | Sunitinib | 135 | 130 | 23 | 135 | 132 |
| IMA901 + Sunitinib | 204 | 185 | 28 | 204 | 202 | |
| Rini 2019a | Sunitinib | 429 | 425 | 242 | 429 | 425 |
| Pembrolizumab + Axitinib | 432 | 429 | 176 | 432 | 429 | |
| Rini 2019b | Sunitinib | 461 | 446 | 308 | 461 | 446 |
| Atezolizumab + Bevacizumab | 454 | 451 | 265 | 454 | 451 | |
| Sternberg 2010 | Pazopanib | 290 | 290 | 227 | 290 | 290 |
| Placebo | 145 | 145 | 131 | 145 | 145 | |
| Total | 11590 | 11419 | 8366 | 11590 | 11437 | |
1 Included overall population; but in the data and analyses section and summary of findings table, we used IMDC intermediate and poor risk patients for efficacy analysis.
| Studies | Phase of study | Accrual | Blinding | RCC subtype | Prior therapy | Intervention |
|---|---|---|---|---|---|---|
| Comparator | ||||||
| Eichelberg 2015 | 3 | Feb 2009 to Dec 2011 | open label study | any, 87% clear cell | naïve | Soreafenib/Sunitinib |
| Sunitinib/Sorafenib | ||||||
| Escudier 2010 | 3 | Jun 2004 to Oct 2005 | double‐blind study | clear cell | naïve | Bevacizumab + IFN‐a2a |
| IFN‐a2a + Placebo | ||||||
| Escudier 2017 | 3 | Oct 2014 to Feb 2016 | open label study | clear cell | naïve | Sunitinib |
| Nivolumab + Ipilimumab | ||||||
| Hudes 2007 | 3 | Jul 2003 to Apr 2005 | open label study | any, 80% clear cell | naïve | Temsirolimus |
| Temsirolimus + Interferon | ||||||
| Inferferon | ||||||
| McDermott 2017 | 2 | Jan 2014 to Mar 2015 | open label study | clear cell | naïve | Sunitinib |
| Atezolizumab + Bevacizumab | ||||||
| Atezolizumab | ||||||
| Motzer 2010 | 3 | Aug 2004 to Oct 2005 | radiologic assessment | clear cell | naïve | Sunitinib |
| IFN‐a2a | ||||||
| Motzer 2013a | 3 | Aug 2008 to Sep 2011 | open label study | clear cell | naïve | Pazopanib |
| Sunitinib | ||||||
| Motzer 2013b | 2 | Feb 2010 to Aug 2010 | open label study | clear cell | naïve | Tivozanib |
| Sorafenib | ||||||
| Motzer 2014 | 2 | Sep 2009 to Jun 2012 | open label study | any, 85% clear cell | naïve | Sunitinib/ Everolimus |
| Everolimus/ Sunitinib | ||||||
| Motzer 2019 | 3 | Mar 2016 to Dec 2017 | open label study | clear cell | naïve | Sunitinib |
| Avelumab + Axitinib | ||||||
| Ravaud 2015 | 2 | ‐ | open label study | any 96% clear cell | naïve | Everolimus + Bevacizumab |
| Interferon + Bevacizumab | ||||||
| Retz 2019 | 3 | Jun 2012 to Nov 2016 | open label study | any, 87% clear cell | naïve | Sorafenib/ Pazopanib |
| Pazopanib/ Sorafenib | ||||||
| Rini 2008 | 3 | Oct 2003 to Jul 2005 | open label study | clear cell | naïve | Bevacizumab + IFN‐a2b |
| IFN‐a2b | ||||||
| Rini 2014 | 3 | Apr 2008 to Oct 2010 | open label study | any, 80% clear cell | naïve | Temsirolimus + Bevacizumab |
| Bevacizumab + Inferferon | ||||||
| Rini 2016 | 3 | Dec 2010 to Dec 2012 | open label study | clear cell | naïve | Sunitinib |
| IMA901 + Sunitinib | ||||||
| Rini 2019a | 3 | Oct 2016 to Jan 2018 | open label study | clear cell | naïve | Sunitinib |
| Pembrolizumab + Axitinib | ||||||
| Rini 2019b | 3 | May 2015 to Oct 2016 | open label study | clear cell | naïve | Sunitinib |
| Atezolizumab + Bevacizumab | ||||||
| Sternberg 2010 | 3 | Apr 2006 to Apr 2007 | double‐blind study | clear cell | 54% naive | Pazopanib |
| Placebo | ||||||
| ‐ denotes not reported | ||||||
IFN: interferon; RCC: renal cell carcinoma
Source of data
In total we included 18 trials in this review, all of which we identified by electronic database search. All trials were available as peer‐reviewed publications and published in English. We contacted corresponding authors of nine trials to obtain additional information on results (Escudier 2017; Hudes 2007; Motzer 2010; Motzer 2014; Ravaud 2015; Retz 2019; Rini 2008; Rini 2014; Sternberg 2010). We received three replies (Retz 2019; Rini 2014; Sternberg 2010); and could include additional data for one trial (Retz 2019).
Study design and settings
Two of the 18 included randomised controlled trials were conducted with a double blind design in which participants and personnel were unaware of allocated intervention (Escudier 2010; Sternberg 2010). All other studies were open label without masking treatments. Three trials used a phase 2 trial design (McDermott 2018; Motzer 2014; Ravaud 2015); all others were performed in a phase 3 setting. Eight trials allowed a cross‐over between treatment arms or to active treatment if disease progression occurred (Eichelberg 2015; Escudier 2010; McDermott 2018; Motzer 2010; Motzer 2013b; Motzer 2014; Retz 2019; Sternberg 2010). All trials were multicentre studies with an accrual period between 2003 and 2019.
Participants
Combining the numbers of all studies, there were 11,590 participants included of which 11,419 received the allocated treatment. All randomised participants were included in the efficacy analysis, 98% were assessed for safety. Most trials allowed only participants with a clear cell histology or a clear cell component. Six trials allowed any histology but 85% of the participants were diagnosed with clear cell renal cell carcinoma (Eichelberg 2015; Hudes 2007; Motzer 2014; Ravaud 2015; Retz 2019; Rini 2014). Median age amongst the total population was 61 years; 72% were males; and 9048 were treated with a nephrectomy prior to systemic therapy.
Interventions
Most trials had two arms comparing either two active treatments or an active treatment against placebo. Two trials had a design with multiple comparisons (Hudes 2007; McDermott 2018).
Five trials compared two different targeted therapies against each other; sorafenib versus sunitinib (Eichelberg 2015), pazopanib versus sunitinib (Motzer 2013a), tivozanib versus sorafenib (Motzer 2013b), sorafenib versus pazopanib (Retz 2019), sunitinib versus everolimus (Motzer 2014).
One trial compared pazopanib against a placebo (Sternberg 2010).
Four trials assessed the effectiveness of sunitinib against targeted immunotherapy in combination with targeted therapy. Avelumab and axitinib (Motzer 2019), pembrolizumab and axitinib (Rini 2019a), and atezolizumab and bevacizumab (Rini 2019b; McDermott 2018) were used as comparators. McDermott 2018 had a three‐arm design which even included a direct comparison of sunitinib against atezolizumab. Another trial compared sunitinib against the combination of nivolumab and ipilimumab (Escudier 2017).
One trial compared sunitinib against a combination of tumour vaccine, chemotherapy and sunitinib (Rini 2016).
Interferon alpha was compared to targeted therapy or combinations of targeted therapy in four studies: sunitinib (Motzer 2010); temsirolimus (Hudes 2007); temsirolimus and interferon alpha (Hudes 2007); and bevacizumab and interferon alpha (Escudier 2010; Rini 2008).
Combinations of targeted therapies were used in two trials. Rini 2014 compared temsirolimus and bevacizumab against bevacizumab and interferon alpha; Ravaud 2015 compared everolimus and bevacizumab against interferon alpha and bevacizumab.
Outcomes
All included studies reported our primary outcomes PFS, OS and SAEs as well as response rates and minor AEs which were predefined secondary outcomes. An assessment of QoL was performed in 11 trials (Escudier 2017; Hudes 2007; McDermott 2018; Motzer 2010; Motzer 2013a; Motzer 2013b; Motzer 2014; Retz 2019; Rini 2014; Rini 2019b; Sternberg 2010).
Excluded studies
We excluded 52 trials at the stage of full‐text screening. The main reasons for exclusion were: less than 100 participants in one treatment arm in 25 trials (Broom 2015; Bukowski 2007; Choueiri 2017; Cirkel 2016; Eisen 2015; Escudier 2009; Flaherty 2015; Hainsworth 2015; Jonasch 2010; Mulders 2012; Négrier 2011; Nosov 2012; Pal 2015; Pili 2015; Powles 2014; Powles 2016a; Powles 2016b; Procopio 2011; Ratain 2006; Rini 2013; Tannir 2016; Tannir 2018; Tomita 2014; Twardowski 2015; Yang 2003); participants were not treatment naïve in 12 studies (Choueiri 2015; Dorff 2015; Escudier 2010a; Hutson 2013; Hutson 2014; Jonasch 2017; Motzer 2008; Motzer 2014b; Motzer 2015a; Motzer 2015b; Motzer 2015c; Rini 2011); the intervention or comparison did not include a targeted therapy in nine trials (Escudier 2007; Gordon 2004; Hawkins 2016; Lee 2006; Madhusudan 2004; Ravaud 2008, Rini 2012; Srinivas 2005; Stadler 2005); both intervention and comparison arms used the same drug with different dosages in five trials (Atkins 2004; Bracarda 2010; Ebbinghaus 2007; Lee 2015; Motzer 2012); and one trial included only non‐clear cell renal cell carcinoma participants (Armstrong 2016).
Risk of bias in included studies
For details, please refer to 'Characteristics of included studies' section, the 'Risk of bias' table, and each 'Summary of findings table', as well as Figure 2 and Figure 3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Categories: green point (+) = low risk of bias; yellow point (?) = unclear risk of bias; red point (‐) = high risk of bias.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Random sequence generation
We judged 15 trials to have a low risk of bias (Eichelberg 2015; Escudier 2010; Escudier 2017; Hudes 2007; McDermott 2018; Motzer 2013a; Motzer 2013b; Motzer 2014; Motzer 2019; Rini 2008; Rini 2014; Rini 2016; Rini 2019a; Rini 2019b; Sternberg 2010). The remaining three trials had an unclear risk of bias.
Allocation concealment
We judged 14 trials to have a low risk of bias (Eichelberg 2015; Escudier 2010; Escudier 2017; Hudes 2007; Motzer 2013a; Motzer 2013b; Motzer 2014; Motzer 2019; Rini 2008; Rini 2014; Rini 2016; Rini 2019a; Rini 2019b; Sternberg 2010). Three trials had an unclear risk of bias (Motzer 2010; Ravaud 2015; Retz 2019); and we judged one trial to have a high risk of bias (McDermott 2018).
Blinding
Blinding of participants and personnel
For objective outcomes we judged all studies to have a low risk of bias. For subjective outcomes we rated only two trials as low risk of bias (Escudier 2010; Sternberg 2010); and one we rated unclear risk of bias (Ravaud 2015). The remaining trials had a high risk of bias.
Blinding of outcome assessment
We rated all trials at low risk of bias for assessment of objective outcomes. Ten trials had a high risk of bias (Eichelberg 2015; Escudier 2017; Hudes 2007; McDermott 2018; Motzer 2013a; Motzer 2013b; Motzer 2014; Ravaud 2015; Rini 2008; Rini 2019b); one we rated unclear risk of bias (Retz 2019); and seven had a low risk of bias for subjective outcomes.
Incomplete outcome data
All studies had a low risk of bias for OS and PFS. One trial we judged to have a high risk of bias for tumour response data (Hudes 2007); the remaining trials we judged as low risk of bias. For QoL, we rated four trials as unclear risk of bias (Escudier 2017; Motzer 2010; Ravaud 2015; Rini 2019b); three trials at high risk of bias (Hudes 2007; Motzer 2013a; Retz 2019); five trials we judged at low risk of bias (.McDermott 2018; Motzer 2013b; Motzer 2014; Rini 2014; Sternberg 2010); and the remaining trials did not assess the QoL.
Selective reporting
Two studies had an unclear risk of bias (Motzer 2019; Retz 2019); the remaining 16 we judged at low risk because both the outcomes reported and the analytic approach in the published report matched those of the predefined protocol.
Other potential sources of bias
We found eight trials to have a low risk of bias (Escudier 2017; Hudes 2007; Motzer 2019; Retz 2019; Rini 2008; Rini 2019a; Rini 2019b; Sternberg 2010); six trials we rated unclear risk of bias (Eichelberg 2015; Escudier 2010; McDermott 2018; Motzer 2013a; Ravaud 2015; Rini 2014); and four studies had a high risk of bias (Motzer 2010; Motzer 2013b; Motzer 2014; Rini 2016)
Effects of interventions
See: Summary of findings 1 Sorafenib compared to sunitinib (targeted agent versus targeted agent); Summary of findings 2 Pazopanib compared to sunitinib (targeted agent versus targeted agent); Summary of findings 3 Tivozanib compared to sorafenib (targeted agent versus targeted agent); Summary of findings 4 Sorafenib compared to pazopanib (targeted agent versus targeted agent); Summary of findings 5 Sunitinib compared to everolimus (targeted agent versus targeted agent); Summary of findings 6 Sunitinib compared to avelumab + axitinib (targeted agent versus immunotherapy + targeted agent); Summary of findings 7 Sunitinib compared to pembrolizumab + axitinib (targeted agent versus immunotherapy + targeted agent); Summary of findings 8 Sunitinib compared to atezolizumab + bevacizumab (targeted agent versus immunotherapy + targeted agent); Summary of findings 9 Sunitinib compared to IMA901 + sunitinib (targeted agent versus tumour vaccine + targeted agent); Summary of findings 10 Sunitinib compared to interferon‐α (IFN‐α) (targeted agent versus classic immunotherapy); Summary of findings 11 Temsirolimus compared to IFN‐α (targeted agent versus classic immunotherapy); Summary of findings 12 Sunitinib compared to atezolizumab (targeted therapy versus immunotherapy); Summary of findings 13 Bevacizumab + IFN compared to IFN (+ placebo) (targeted agent + classic immunotherapy versus classic immunotherapy); Summary of findings 14 Temsirolimus + IFN‐α compared to IFN‐α (targeted agent + classic immunotherapy versus classic immunotherapy); Summary of findings 15 Temsirolimus + bevacizumab compared to bevacizumab + IFN‐α (targeted agent + targeted agent versus targeted agent + classic immunotherapy); Summary of findings 16 Everolimus + bevacizumab compared to IFN α‐2a + bevacizumab (targeted agent + targeted agent versus targeted agent + classic immunotherapy); Summary of findings 17 Sunitinib compared to nivolumab + ipilimumab (targeted agent versus combinations of immunotherapy); Summary of findings 18 Pazopanib compared to placebo (targeted agent versus placebo)
We performed two meta‐analyses using studies which had the same population and the same comparison (Escudier 2010; McDermott 2018; Rini 2008; Rini 2019b). The remaining trials had considerable clinical heterogeneity and we judged them inappropriate for pooling of data and meta‐analysis.
1. Sorafenib versus sunitinib
Please refer to summary of findings Table 1.
Primary outcomes
Progression‐free survival (PFS)
Sorafenib may reduce PFS when compared to sunitinib (HR 1.19, 95% CI 0.92 to 1.53; 1 study, 365 participants; low‐certainty evidence; Analysis 1.1) although the CI also includes the possibility of no effect. Based on a control event risk of 340 per 1000 in this trial at 10 months, this corresponds to 63 fewer participants experiencing PFS (95% CI 148 fewer to 31 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with little to no increase in PFS.
Overall survival (OS)
We are very uncertain how sorafenib compares to sunitinib for OS (HR 0.99, 95% CI 0.74 to 1.33; 1 study, 365 participants; very low‐certainty evidence; Analysis 1.2). We rated the certainty of evidence as very low due to study limitations (other bias, downgraded one level) and imprecision (downgraded two levels), given that the CI was compatible with both an appreciable reduction in OS as well as an appreciable increase in OS.
Serious adverse events (SAEs, assessed with: CTCAE v3.0)
We are very uncertain how sorafenib compares to sunitinib with regard to SAEs (RR 0.99, 95% CI 0.85 to 1.14; 1 study, 353 participants; very low certainty evidence; Analysis 1.3). We rated the certainty of evidence as very low due to study limitations (performance, detection and other bias, downgraded one level) and imprecision (downgraded two levels), given that the CI was compatible with both an appreciable reduction in SAEs as well as an appreciable increase in SAEs.
Secondary outcomes
Quality of life (QoL)
We found no studies that reported this outcome.
Response rate (assessed with: RECIST version not reported)
Sorafenib may result in little to no difference in response rate as compared to sunitinib (RR 1.07, 95% CI 0.78 to 1.47; 1 study, 353 participants; low‐certainty evidence; Analysis 1.4). Based on the control event risk of 290 per 1000 in this trial, this corresponds to 20 more response (95% CI 64 fewer to 136 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in the response rate.
Minor adverse events (AEs, assessed with: CTCAE v3.0)
Sorafenib may result in little to no difference in minor AEs as compared to sunitinib (RR 1.13, 95% CI 0.77 to 1.65; 1 study, 353 participants; low‐certainty evidence; Analysis 1.5). Based on the control event risk of 216 per 1000 in this trial, this corresponds to 28 more minor AEs (95% CI 50 fewer to 140 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in minor AEs.
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
2. Pazopanib versus sunitinib
Please refer to summary of findings Table 2.
Primary outcomes
PFS
Pazopanib may result in little to no difference in PFS as compared to sunitinib (HR 1.05, 95% CI 0.90 to 1.23; 1 study, 1110 participants; low‐certainty evidence; Analysis 2.1). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable reduction in PFS.
OS
Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low‐certainty evidence; Analysis 2.2). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more participants experiencing OS (95% CI 19 fewer to 70 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (other bias) and imprecision, given that the CI was also compatible with an appreciable increase in OS.
SAEs (assessed with: CTCAE v3.0)
Pazopanib may result in little to no difference in SAEs as compared to sunitinib (RR 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low‐certainty evidence; Analysis 2.3). Based on the control event risk of 734 per 1000 in this trial, this corresponds to seven more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in SAEs.
Secondary outcomes
QoL
Pazopanib may increase QoL as compared to sunitinib (MD 3.60, 95% CI 1.76 to 5.44; 1 study, 467 participants; low‐certainty evidence; Analysis 2.4) assessed with FACIT‐F (scale 0 to 52; higher scores indicating less fatigue; MCID: 3 points). We rated the certainty of evidence as low due to study limitations (performance, detection, attrition and other bias), and imprecision, given that the CI was also compatible with no increase in QoL.
Response rate (assessed by RECIST v1.0)
Pazopanib may result in little to no difference in response rate as compared to sunitinib (RR 1.24, 95% CI 1.02 to 1.50; 1 study, 1110 participants; low‐certainty evidence; Analysis 2.5). Based on the control event risk of 248 per 1000 in this trial, this corresponds to 59 more response (95% CI 5 more to 124 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in the response rate.
Minor AEs (assessed with: CTCAE v3.0)
Pazopanib probably results in little to no difference in minor AEs as compared to sunitinib (RR 1.00, 95% CI 0.81 to 1.23; 1 study, 1102 participants; moderate‐certainty evidence; Analysis 2.6). Based on the control event risk of 237 per 1000 in this trial, this corresponds to no fewer minor AEs (95% CI 45 fewer to 55 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance, detection and other bias).
Subgroup analyses
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analyses
We were unable to perform a sensitivity analysis because there was only one study.
3. Tivozanib versus sorafenib
Please refer to summary of findings Table 3.
Primary outcomes
PFS
Tivozanib may extend PFS as compared to sorafenib (HR 0.79, 95% CI 0.64 to 0.99; 1 study, 517 participants; low‐certainty evidence; Analysis 3.1). Based on the control event risk of 360 per 1000 in this trial at 12 months, this corresponds to 86 more participants experiencing PFS (95% CI 4 more to 160 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with a little to no increase in PFS.
OS
Tivozanib may reduce OS as compared to sorafenib (HR 1.25, 95% CI 0.95 to 1.64; 1 study, 517 participants; low‐certainty evidence; Analysis 3.2) although the CI also includes the possibility of no effect. Based on the control event risk of 620 per 1000 in this trial at 24 months, this would result in 70 fewer OSs (95% CI 163 fewer to 15 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (other bias) and imprecision, given that the CI was also compatible with little to no increase in OS.
SAEs (assessed with: CTCAE v3.0)
Tivozanib may reduce SAEs as compared to sorafenib (RR 0.85, 95% CI 0.74 to 0.97; 1 study, 516 participants; low‐certainty evidence; Analysis 3.3). Based on the control event risk of 689 per 1000 in this trial, this corresponds to 103 fewer SAEs (95% CI 179 fewer to 21 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with little to no reduction in SAEs.
Secondary outcomes
QoL
Tivozanib may result in little to no difference in QoL (assessed with EQ‐5D; scale: −0.59 to 1; higher values reflect better QoL; MCID 0.06) as compared to sorafenib (MD 0.01, 95% CI −0.05 to 0.07; 1 study, 506 participants; low‐certainty evidence; Analysis 3.4). We rated the certainty of evidence as low due to study limitations (performance, detection and other bias), and imprecision, given that the CI was also compatible with an increase in QoL.
Response rate (assessed by RECIST v1.0)
Tivozanib may increase the response rate as compared to sorafenib (RR 1.42, 95% CI 1.07 to 1.88; 1 study, 517 participants; low‐certainty evidence; Analysis 3.5). Based on the control event risk of 233 per 1000 in this trial, this corresponds to 98 more responses (16 more to 205 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with little to no increase in the response rate.
Minor AEs (assessed with: CTCAE v3.0)
Tivozanib may result in little to no difference in minor AEs as compared to sorafenib (RR 1.16, 95% CI 0.89 to 1.51; 1 study, 516 participants; low‐certainty evidence; Analysis 3.6). Based on the control event risk of 280 per 1000 in this trial, this corresponds to 45 more minor AEs (95% CI 31 fewer to 143 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in minor AEs.
Subgroup analyses
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analyses
We were unable to perform a sensitivity analyses because there was only one study.
4. Sorafenib versus pazopanib
Please refer to summary of findings Table 4.
Primary outcomes
PFS
Sorafenib probably reduces PFS as compared to pazopanib (HR 1.92, 95% CI 1.74 to 2.11; 1 study, 377 participants; moderate‐certainty evidence; Analysis 4.1). Based on the control event risk of 380 per 1000 in this trial at 12 months, this corresponds to 224 fewer participants experiencing PFS (95% CI 250 fewer to 194 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance, detection, and reporting bias).
OS
Sorafenib may reduce OS as compared to pazopanib (HR 1.22, 95% CI 0.91 to 1.64; 1 study, 377 participants; low‐certainty evidence; Analysis 4.2) although the CI also includes the possibility of no effect. Based on the control event risk of 520 per 1000 in this trial at 24 months, this would result in 70 fewer OSs (95% CI 178 fewer to 32 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (selection and reporting bias) and imprecision, given that the CI was also compatible with little to no reduction in OS.
SAEs (assessed with: CTCAE v4.03)
We are very uncertain how sorafenib compares to pazopanib (RR 0.92, 95% CI 0.78 to 1.09; 1 study, 366 participants; very low certainty evidence; Analysis 4.3) with regard to SAEs. We rated the certainty of evidence as very low due to study limitations (selection, performance, detection, and reporting bias, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with both an appreciable reduction in SAEs as well as an appreciable increase in SAEs.
Secondary outcomes
QoL
Sorafenib may increase QoL slightly (assessed with FACIT‐F; scale 0 to 52; higher scores indicating less fatigue; MCID: 3 points) as compared to pazopanib (MD 3.10, 95% CI −1.82 to 8.02; 1 study, 267 participants; low‐certainty evidence; Analysis 4.4). We rated the certainty of evidence as low due to study limitations (selection, performance, detection, attrition and reporting bias) and imprecision, given that the CI was also compatible with no increase in QoL.
Response rate (assessed with RECIST v1.1)
Sorafenib may reduce the response rate as compared to pazopanib (RR 0.62, 95% CI 0.47 to 0.81; 1 study, 377 participants; low‐certainty evidence; Analysis 4.5). Based on the control event risk of 463 per 1000 in this trial, this corresponds to 176 fewer response (95% CI 245 fewer to 88 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (selection, performance, detection, and reporting bias) and imprecision, given that the CI was also compatible with no reduction in the response rate.
Minor AEs (assessed with: CTCAE v4.03)
Sorafenib may result in little to no difference in minor AEs (assessed with: CTCAE v4.03) as compared to pazopanib (RR 1.15, 95% CI 0.87 to 1.52; 1 study, 366 participants; low‐certainty evidence; Analysis 4.6). Based on the control event risk of 328 per 1000 in this trial, this corresponds to 49 more minor AEs (95% CI 43 fewer to 170 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (selection, performance, detection, and reporting bias) and imprecision, given that the CI was also compatible with an appreciable increase in minor AEs.
Subgroup analyses
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analyses
We were unable to perform a sensitivity analysis because there was only one study.
5. Sunitinib versus everolimus
Please refer to summary of findings Table 5.
Primary outcomes
PFS
Sunitinib probably increases PFS as compared to everolimus (HR 0.71, 95% CI 0.59 to 0.87; 1 study, 471 participants; moderate‐certainty evidence; Analysis 5.1). Based on the control event risk of 300 per 1000 in this trial at 12 months, this corresponds to 125 participants experiencing PFS (95% CI 51 more to 191 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance, detection and other bias).
OS
Sunitinib may result in little to no difference in OS as compared to everolimus (HR 0.90, 95% CI 0.72 to 1.11; 1 study, 471 participants; low‐certainty evidence; Analysis 5.2). Based on the control event risk of 470 per 1000 in this trial at 24 months, this would result in 37 more OSs (95% CI 37 fewer to 111 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (other bias) and imprecision, given that the CI was also compatible with an appreciable increase in OS.
SAEs (assessed with: CTCAE v3.0)
Sunitinib probably increases SAEs as compared to everolimus (RR 1.34, 95% CI 1.14 to 1.59; 1 study, 469 participants; moderate‐certainty evidence; Analysis 5.3). Based on the control event risk of 471 per 1000 in this trial, this corresponds to 160 more SAEs (95% CI 66 more to 278 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance, detection and other bias).
Secondary outcomes
QoL
Sunitinib may result in little to no difference in QoL (assessed with EORTC QLQ‐C30; scale: 0 to 100; high score represent better functioning, MCID: 10 points) as compared to everolimus (MD −5.00, 95% CI −10.40 to 0.40; 1 study, 288 participants; low‐certainty evidence; Analysis 5.4). We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with a decrease in QoL.
Response rate (assessed with RECIST v1.0)
Sunitinib may increase response rate as compared to everolimus (RR 3.33, 95% CI 2.06 to 5.39; 1 study, 471 participants; low‐certainty evidence; Analysis 5.5). Based on the control event risk of 80 per 1000 in this trial, this corresponds to 186 more responses (95% CI 85 more to 350 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and other bias) and imprecision, given that the CI was also compatible with little to no increase in response rate.
Minor AEs (assessed with: CTCAE v3.0)
Sunitinib probably results in little to no difference in minor AEs as compared to everolimus (RR 1.02, 95% CI 0.99 to 1.04; 1 study, 469 participants; moderate‐certainty evidence; Analysis 5.6). Based on the control event risk of 971 per 1000 in this trial, this corresponds to 19 more minor AEs (95% CI 10 fewer to 39 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance, detection and other bias).
Subgroup analyses
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analyses
We were unable to perform a sensitivity analysis because there was only one study.
6. Sunitinib versus avelumab + axitinib
Please refer to summary of findings Table 6.
Primary outcomes
PFS
Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate‐certainty evidence; Analysis 6.1). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias and reporting bias).
OS
Sunitinib may result in little to no difference in OS as compared to avelumab plus axitinib (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low‐certainty evidence; Analysis 6.2). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (reporting bias) and imprecision given that the CI was also compatible with an appreciable reduction in OS.
SAEs (assessed with: CTCAE v4.03)
Sunitinib may result in little to no difference in SAEs as compared to avelumab plus axitinib (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low‐certainty evidence; Analysis 6.3). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance bias and reporting bias) and imprecision given that the CI was also compatible with an increase in SAEs.
Secondary outcomes
QoL
We found no studies that reported this outcome.
Response rate (assessed with: RECIST v1.1)
Sunitinib probably reduces the response rate as compared to avelumab plus axitinib (RR 0.50, 95% CI 0.42 to 0.60; 1 study, 886 participants; moderate‐certainty evidence; Analysis 6.4). Based on the control event risk of 514 per 1000 in this trial, this corresponds to 257 fewer responses (95% CI 298 fewer to 205 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias and reporting bias).
Minor AEs (assessed with CTCAE v4.03)
Sunitinib probably results in little to no difference in minor AEs as compared to avelumab plus axitinib (RR 0.97, 95% CI 0.78 to 1.19; 1 study, 873 participants; moderate‐certainty evidence; Analysis 6.5). Based on the control event risk of 290 per 1000 in this trial, this corresponds to nine fewer minor AEs (95% CI 64 fewer to 55 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias and reporting bias)
Subgroup analyses
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analyses
We were unable to perform a sensitivity analysis because there was only one study.
7. Sunitinib versus pembrolizumab + axitinib
Please refer to summary of findings Table 7.
Primary outcomes
PFS
Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate‐certainty evidence; Analysis 7.1). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias).
OS
Sunitinib probably reduces OS as compared to pembrolizumab plus axitinib (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate‐certainty evidence; Analysis 7.2). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to imprecision, given that the CI was also compatible with little to no reduction in OS.
SAEs (assessed with CTCAE v4.0)
Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low‐certainty evidence; Analysis 7.3) although the CI also includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance bias) and imprecision, given that the CI was also compatible with little to no increase in SAEs.
Secondary outcomes
QoL
We found no studies that reported this outcome.
Response rate (assessed with: RECIST v1.1)
Sunitinib probably reduces the response rate as compared to pembrolizumab plus axitinib (RR 0.60, 95% CI 0.52 to 0.70; 1 study, 861 participants; moderate‐certainty evidence; Analysis 7.4). Based on the control event risk of 593 per 1000 in this trial, this corresponds to 237 fewer response (95% CI 284 fewer to 178 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias)
Minor AEs (assessed with CTCAE v4.0)
Sunitinib may result in little to no difference in minor AEs as compared to pembrolizumab plus axitinib (RR 1.19, 95% CI 0.99 to 1.42; 1 study, 854 participants; low‐certainty evidence; Analysis 7.5). Based on the control event risk of 333 per 1000 in this trial, this corresponds to 63 more minor AEs (95% CI 3 fewer to 140 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance bias) and imprecision, given that the CI was also compatible with an increase in minor AEs.
Subgroup analyses
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analyses
We were unable to perform a sensitivity analysis because there was only one study.
8. Sunitinib versus atezolizumab + bevacizumab
Please refer to summary of findings Table 8.
Primary outcomes
PFS
Sunitinib may reduce PFS as compared to atezolizumab plus bevacizumab (HR 1.18, 95% CI 1.02 to 1.36; 2 studies, 1117 participants; I² = 0%; low‐certainty evidence; Analysis 8.1). Based on the control event risk of 480 per 1000 in this trial at 12 months, this corresponds to 59 fewer PFSs (95% CI 111 fewer to 7 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (high and unclear risk of one or more domains) and imprecision, given that the CI was also compatible with no reduction in PFS.
OS
We are very uncertain how sunitinib compares to atezolizumab plus bevacizumab for OS (HR 0.99, 95% CI 0.73 to 1.33; 2 studies, 1117 participants; I² = 37%; very low certainty evidence; Analysis 8.2). We rated the certainty of evidence as very low due to study limitations (high and unclear risk of one or more domains, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with an appreciable reduction in the OS as well as an appreciable increase in OS.
SAEs (assessed with: CTCAE v4.0)
We are very uncertain how sunitinib compares to atezolizumab plus bevacizumab for SAEs as compared to atezolizumab + bevacizumab (RR 1.22, 95% CI 1.00 to 1.49; 2 studies, 1098 participants; I² = 64%; very low certainty evidence; Analysis 8.3). We rated the certainty of evidence as very low due to study limitations (high and unclear risk of one or more domains), inconsistency (unexplained differences between study results) and imprecision, given that the CI was compatible with no increase in SAEs as well as an appreciable increase in SAEs.
Secondary outcomes
QoL
Sunitinib may decrease QoL (assessed with MD Anderson Symptom Inventory Interference Score (MDASI); scale 0 to 10; higher scores indicate worse QoL; MCID 1.0) as compared to atezolizumab plus bevacizumab (MD 1.00, 95% CI 0.68 to 1.32; 2 studies, 691 participants; I² = 0%; low‐certainty evidence; Analysis 8.4). We rated the certainty of evidence as low due to study limitations (high and unclear risk of one or more domains) and imprecision, given that the CI was compatible with possibly no decrease in QoL.
Response rate (assessed with: RECIST v1.1)
Sunitinib probably results in little to no difference in response rate as compared to atezolizumab plus bevacizumab (RR 0.91, 95% CI 0.77 to 1.07; 2 studies, 1117 participants; I² = 0%; moderate‐certainty evidence; Analysis 8.5). Based on the control event risk of 357 per 1000 in this trial, this corresponds to 32 fewer responses (95% CI 82 fewer to 25 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (high and unclear risk of one or more domains).
Minor AEs (assessed with CTCAE v4.0)
Sunitinib may result in little to no difference in minor AEs as compared to atezolizumab plus bevacizumab (RR 0.85, 95% CI 0.74 to 0.97; 2 studies, 1098 participants; I² = 0%; low‐certainty evidence; Analysis 8.6). Based on the control event risk of 467 per 1000 in this trial, this corresponds to 70 fewer minor AEs (95% CI 112 fewer to 14 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (high and unclear risk of one or more domains) and imprecision, given that the CI was also compatible with an appreciable reduction in minor AEs.
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We rated all of the included studies as high or unclear risk of bias and were unable to perform a sensitivity analysis.
9. Sunitinib versus IMA901 + sunitinib
Please refer to summary of findings Table 9.
Primary outcomes
PFS
We are very uncertain about the effect of sunitinib on PFS as compared to IMA901 plus sunitinib (HR 0.95, 95% CI 0.70 to 1.30; 1 study, 339 participants; very low certainty evidence; Analysis 9.1). We rated the certainty of evidence as very low due to study limitations (performance and other bias, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with an appreciable reduction in PFS as well as an appreciable increase in PFS.
OS
Sunitinib may result in little to no difference in OS as compared to IMA901 plus sunitinib (HR 0.75, 95% CI 0.54 to 1.04; 1 study, 339 participants; low‐certainty evidence; Analysis 9.2). Based on the control event risk of 800 per 1000 in this trial at 12 months, this would result in 46 more OSs (95% CI 7 fewer to 86 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (other bias) and imprecision, given that the CI was also compatible with an increase in OS.
SAEs (assessed with CTCAE v4.0)
Sunitinib may reduce SAEs as compared to IMA901 plus sunitinib (RR 0.74, 95% CI 0.59 to 0.95; 1 study, 334 participants; low‐certainty evidence; Analysis 9.3). Based on the control event risk of 550 per 1000 in this trial, this corresponds to 143 fewer SAEs (95% CI 225 fewer to 27 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and other bias) and imprecision, given that the CI was also compatible with a small to no reduction in SAEs.
Secondary outcomes
QoL
We found no studies that reported this outcome.
Response rate (assessed with: RECIST v1.1)
Sunitinib may result in little to no difference in response rate as compared to IMA901 plus sunitinib (RR 0.87, 95% CI 0.64 to 1.19; 1 study, 339 participants; low‐certainty evidence; Analysis 9.4). Based on the control event risk of 358 per 1000 in this trial, this corresponds to 47 fewer response (95% CI 129 fewer to 68 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and other bias) and imprecision, given that the CI was also compatible with an appreciable reduction in response rate.
Minor AEs (assessed with CTCAE v4.0)
Sunitinib may result in little to no difference in minor AEs as compared to IMA901 plus sunitinib (RR 1.29, 95% CI 0.96 to 1.72; 1 study, 334 participants; low‐certainty evidence; Analysis 9.5). Based on the control event risk of 312 per 1000 in this trial, this corresponds to 90 more minor AEs (95% CI 12 fewer to 225 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in minor AEs.
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
10. Sunitinib versus interferon‐α (IFN‐α) (targeted agent versus classic immunotherapy)
Please refer to summary of findings Table 10.
Primary outcomes
PFS
Sunitinib probably increases PFS as compared to IFN‐α (HR 0.54, 95% CI 0.45 to 0.64; 1 study, 750 participants; moderate‐certainty evidence; Analysis 10.1). Based on the control event risk of 400 per 1000 in this trial at six months, this corresponds to 210 more PFSs (95% CI 156 more to 262 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance and other bias).
OS
Sunitinib may increase OS as compared to IFN‐α (HR 0.82, 95% CI 0.67 to 1.00; 1 study, 750 participants; low‐certainty evidence; Analysis 10.2) although the CI also includes the possibility of no effect. Based on the control event risk of 480 per 1000 in this trial at 24 months, this would result in 68 more OSs (95% CI 0 fewer to 132 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (selection and other bias) and imprecision, given that the CI was also compatible with no increase in OS.
SAEs (assessed with CTCAE v3.0)
Sunitinib probably increases SAEs as compared to IFN‐α (RR 1.75, 95% CI 1.43 to 2.16; 1 study, 735 participants; moderate‐certainty evidence; Analysis 10.3). Based on the control event risk of 258 per 1000 in this trial, this corresponds to 194 more SAEs (95% CI 111 more to 300 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance and other bias).
Secondary outcomes
QoL
Sunitinib probably results in little to no difference in QoL (assessed with EQ‐5D; scale: −0.59 to 1.00 with higher scores indicating better QoL; MCID 0.06) as compared to IFN‐α (MD −0.01, 95% CI −0.05 to 0.03; 1 study, 544 participants; moderate‐certainty evidence; Analysis 10.4). We rated the certainty of evidence as moderate due to study limitations (selection, performance and other bias).
Response rate (assessed with RECIST v1.0)
Sunitinib probably increases response rate as compared to IFN‐α (RR 3.83, 95% CI 2.86 to 5.12; 1 study, 750 participants; moderate‐certainty evidence; Analysis 10.5). Based on the control event risk of 123 per 1000 in this trial, this corresponds to 347 more response (95% CI 228 more to 505 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance and other bias).
Minor AEs (assessed with CTCAE v3.0)
Sunitinib probably results in little to no difference in minor AEs as compared to IFN‐α (RR 1.03, 95% CI 1.00 to 1.05; 1 study, 735 participants; moderate‐certainty evidence; Analysis 10.6). Based on the control event risk of 956 per 1000 in this trial, this corresponds to 29 more minor AEs (95% CI 0 fewer to 48 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance and other bias).
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
11. Temsirolimus versus IFN‐α (targeted agent versus classic immunotherapy)
Please refer to summary of findings Table 11.
Primary outcomes
PFS
Temsirolimus may increase PFS as compared to IFN‐α (HR 0.74, 95% CI 0.60 to 0.91; 1 study, 416 participants; low‐certainty evidence; Analysis 11.1). Based on the control event risk of 100 per 1000 in this trial at 12 months, this corresponds to 82 more PFSs (95% CI 23 more to 151 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was also compatible with a small or no increase in PFS.
OS
Temsirolimus probably increases OS as compared to IFN‐α (HR 0.78, 95% CI 0.63 to 0.97; 1 study, 416 participants; moderate‐certainty evidence; Analysis 11.2). Based on the control event risk of 300 per 1000 in this trial at 12 months, this would result in 91 more OSs (95% CI 11 more to 168 more) per 1000 participants. We rated the certainty of evidence as moderate due to imprecision, given that the CI was also compatible with a small or no increase in OS.
SAEs (assessed with CTCAE version not reported)
Temsirolimus may reduce SAEs as compared to IFN‐α (RR 0.86, 95% CI 0.76 to 0.97; 1 study, 408 participants; low‐certainty evidence; Analysis 11.3). Based on the control event risk of 780 per 1000 in this trial, this corresponds to 109 fewer SAEs (95% CI 187 fewer to 23 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was also compatible with a small or no reduction in SAEs.
Secondary outcomes
QoL
Temsirolimus may result in little to no difference in QoL (assessed with EQ‐5D; scale −0.59 to 1.0 with higher values indicating better QoL; MCID: 0.06) as compared to IFN‐α (MD 0.03, 95% CI −0.01 to 0.07; 1 study, 401 participants; low‐certainty evidence; Analysis 11.4). We rated the certainty of evidence as low due to study limitations (performance, detection and attrition bias), and imprecision, given that the CI was also compatible with an increase in QoL.
Response rate (assessed with RECIST version not reported)
Temsirolimus may result in little to no difference in response rate as compared to IFN‐α (RR 1.78, 95% CI 0.84 to 3.77; 1 study, 416 participants; low‐certainty evidence; Analysis 11.5). Based on the control event risk of 48 per 1000 in this trial, this corresponds to 38 more response (95% CI 8 fewer to 134 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and attrition bias), and imprecision, given that the CI is also compatible with an appreciable increase in response rate.
Minor AEs (assessed with CTCAE version not reported)
Temsirolimus probably results in little to no difference in minor AEs as compared to IFN‐α (RR 1.02, 95% CI 1.00 to 1.04; 1 study, 408 participants; moderate‐certainty evidence; Analysis 11.6). Based on the control event risk of 985 per 1000 in this trial, this corresponds to 20 more minor AEs (95% CI 0 fewer to 39 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance and detection bias).
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
12. Sunitinib versus atezolizumab (targeted therapy versus immunotherapy)
Please refer to summary of findings Table 12.
Primary outcomes
PFS
We are very uncertain how sunitinib affects PFS as compared to atezolizumab (HR 0.84, 95% CI 0.58 to 1.22; 1 study, 204 participants; very low certainty evidence; Analysis 12.1). We rated the certainty of evidence as very low due to study limitations (selection, performance, detection and other bias, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with both an appreciable reduction and increase in PFS.
OS
We are very uncertain how sunitinib affects OS as compared to atezolizumab (HR 0.94, 95% CI 0.58 to 1.54; 1 study, 204 participants; very low certainty evidence; Analysis 12.2). We rated the certainty of evidence as very low due to study limitations (selection and other bias, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with both an appreciable reduction and increase in OS.
SAEs (assessed with: CTCAE v4.0)
Sunitinib probably increases SAEs as compared to atezolizumab (RR 1.73, 95% CI 1.32 to 2.27; 1 study, 203 participants; moderate‐certainty evidence; Analysis 12.3). Based on the control event risk of 398 per 1000 in this trial, this corresponds to 291 more SAEs (95% CI 127 more to 506 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance, detection and other bias).
Secondary outcomes
QoL
Sunitinib may decrease QoL slightly (assessed with MD Anderson Symptom Inventory Interference Score (MDASI); scale 0 to 10; higher scores indicate worse QoL; MCID 1.0) as compared to atezolizumab (MD 1.46, 95% CI 0.80 to 2.12; 1 study, 157 participants; low‐certainty evidence; Analysis 12.4). We rated the certainty of evidence as low due to study limitations (selection, performance, detection, attrition and other bias) and imprecision, given that the CI was also compatible with no decrease in QoL.
Response rate (assessed with: RECIST v1.1)
Sunitinib may result in little to no difference in response rate as compared to atezolizumab (RR 1.14, 95% CI 0.72 to 1.79; 1 study, 204 participants; low‐certainty evidence; Analysis 12.5). Based on the control event risk of 252 per 1000 in this trial, this corresponds to 35 more response (95% CI 71 fewer to 199 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (selection, performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in response rate.
Minor AEs (assessed with: CTCAE v4.0)
Sunitinib probably reduces minor AEs as compared to atezolizumab (RR 0.50, 95% CI 0.35 to 0.71; 1 study, 203 participants; moderate‐certainty evidence; Analysis 12.6). Based on the control event risk of 563 per 1000 in this trial, this corresponds to 282 fewer minor AEs (95% CI 366 fewer to 163 fewer) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance, detection and other bias).
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
13. Bevacizumab + IFN versus IFN (+ placebo)
Please refer to summary of findings Table 13.
Primary outcomes
PFS
Bevacizumab plus IFN probably increases PFS as compared to IFN (+ placebo) (HR 0.68, 95% CI 0.60 to 0.77; 2 studies, 1381 participants; I² = 14%; moderate‐certainty evidence; Analysis 13.1). Based on the control event risk of 200 per 1000 in this trial at 12 months, this corresponds to 135 more PFSs (95% CI 90 more to 181 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (high and unclear risk of one or more domains).
OS
Bevacizumab + IFN may result in little to no difference in OS as compared to IFN (+ placebo) (HR 0.88, 95% CI 0.79 to 0.99; 2 studies, 1381 participants; I² = 0%; low‐certainty evidence; Analysis 13.2). Based on the control event risk of 500 per 1000 in this trial at 24 months, this would result in 43 more OSs (95% CI 3 more to 78 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (high and unclear risk of one or more domains) and imprecision, given that the CI was also compatible with an increase in OS.
SAEs (assessed with: CTCAE v3.0)
Bevacizumab plus IFN probably increases SAEs as compared to IFN (+ placebo) (RR 1.31, 95% CI 1.20 to 1.42; 2 studies, 1356 participants; I² = 0%; moderate‐certainty evidence; Analysis 13.3). Based on the control event risk of 536 per 1000 in this trial, this corresponds to 166 more SAEs (95% CI 107 more to 225 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (high and unclear risk of one or more domains).
Secondary outcomes
QoL
We found no studies that reported this outcome.
Response rate (assessed with: RECIST v1.0)
Bevacizumab plus IFN may increase response rate as compared to IFN (+ placebo) (RR 2.45, 95% CI 1.74 to 3.45; 1 study, 595 participants; low‐certainty evidence; Analysis 13.4). Based on the control event risk of 128 per 1000 in this trial, this corresponds to 186 more response (95% CI 95 more to 314 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (unclear risk of other bias) and imprecision, given that the CI was also compatible with a small or no increase response rate.
Minor AEs (assessed with: CTCAE v3.0)
Bevacizumab plus IFN may reduce minor AEs (grade 1 or 2) as compared to IFN (+ placebo) (RR 0.75, 95% CI 0.63 to 0.90; 1 study, 641 participants; low‐certainty evidence; Analysis 13.5). Based on the control event risk of 493 per 1000 in this trial, this corresponds to 123 fewer minor AEs (95% CI 183 fewer to 49 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (unclear risk of other bias) and imprecision, given that the CI was also compatible with a small or no reduction in minor AEs.
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We rated all of the included studies as high or unclear risk of bias and were unable to perform a sensitivity analysis.
14. Temsirolimus + IFN‐α versus IFN‐α
Please refer to summary of findings Table 14.
Primary outcomes
PFS
Temsirolimus plus IFN‐α may increase PFS as compared to IFN‐α (HR 0.76, 95% CI 0.62 to 0.93; 1 study, 417 participants; low‐certainty evidence; Analysis 14.1). Based on the control event risk of 100 per 1000 in this trial at 12 months, this corresponds to 74 more PFSs (95% CI 17 more to 140 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was also compatible with little to no increase in PFS.
OS
Temsirolimus plus IFN‐α may result in little to no difference in OS as compared to IFN‐α (HR 0.93, 95% CI 0.75 to 1.15; 1 study, 417 participants; low‐certainty evidence; Analysis 14.2). Based on the control event risk of 300 per 1000 in this trial at 12 months, this would result in 26 more OSs (95% CI 50 fewer to 105 more) per 1000 participants. We rated the certainty of evidence as low due to imprecision (downgrade two levels), given that the CI was also compatible with both an appreciable reduction or increase in OS.
SAEs (assessed with: CTCAE version not reported)
Temsirolimus plus IFN‐α may increase SAEs as compared to IFN‐α (RR 1.12, 95% CI 1.02 to 1.22; 1 study, 408 participants; low‐certainty evidence; Analysis 14.3). Based on the control event risk of 780 per 1000 in this trial, this corresponds to 94 more SAEs (95% CI 16 more to 172 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was also compatible with little to no increase in SAEs.
Secondary outcomes
QoL
Temsirolimus plus IFN‐α may result in little to no difference in QoL (assessed with EQ‐5D; scale −0.59 to 1.0 with higher scores indicating better QoL; MCID 0.06) as compared to IFN‐α (MD 0.03, 95% CI −0.01 to 0.07; 1 study, 394 participants; low‐certainty evidence; Analysis 14.4). We rated the certainty of evidence as low due to study limitations (performance, detection and attrition bias), and imprecision, given that the CI was also compatible with an increase in QoL.
Response rate (assessed with: RECIST version not reported)
Temsirolimus plus IFN‐α may result in little to no difference in response rate as compared to IFN‐α (RR 1.68, 95% CI 0.79 to 3.57; 1 study, 417 participants; low‐certainty evidence; Analysis 14.5). Based on the control event risk of 48 per 1000 in this trial, this corresponds to 33 more response (95% CI 10 fewer to 124 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance, detection and attrition bias), and imprecision, given that the CI was also compatible with an appreciable increase in response rate.
Minor AEs (assessed with: CTCAE version not reported)
Temsirolimus plus IFN‐α probably results in little to no difference in minor AEs (grade 1 or 2) as compared to IFN‐α (RR 1.00, 95% CI 0.98 to 1.02; 1 study, 408 participants; moderate‐certainty evidence; Analysis 14.6). Based on the control event risk of 985 per 1000 in this trial, this corresponds to zero fewer minor AEs (95% CI 20 fewer to 20 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance and detection bias).
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
15. Temsirolimus + bevacizumab versus bevacizumab + IFN‐α
Please refer to summary of findings Table 15.
Primary outcomes
PFS
Temsirolimus plus bevacizumab may result in little to no difference in PFS as compared to bevacizumab plus IFN‐α (HR 1.10, 95% CI 0.90 to 1.34; 1 study, 791 participants; low‐certainty evidence; Analysis 15.1). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 35 fewer PFSs (95% CI 107 fewer to 38 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance bias) and imprecision, given that the CI was also compatible with an appreciable reduction in PFS.
OS
Temsirolimus plus bevacizumab probably results in little to no difference in OS as compared to bevacizumab plus IFN‐α (HR 1.08, 95% CI 0.90 to 1.30; 1 study, 791 participants; moderate‐certainty evidence; Analysis 15.2). Based on the control event risk of 550 per 1000 in this trial at 24 months, this would result in 26 fewer OSs (95% CI 90 fewer to 34 more) per 1000 participants. We rated the certainty of evidence as moderate due to imprecision, given that the CI was also compatible with a reduction in OS.
SAEs (assessed with: CTCAE v3.0)
Temsirolimus plus bevacizumab may result in little to no difference in SAEs (grade 3 or 4) as compared to bevacizumab plus IFN‐α (RR 1.05, 95% CI 0.98 to 1.13; 1 study, 784 participants; low‐certainty evidence; Analysis 15.3). Based on the control event risk of 760 per 1000 in this trial, this corresponds to 38 more SAEs (95% CI 15 fewer to 99 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance bias) and imprecision, given that the CI was also compatible with an appreciable increase in SAEs.
Secondary outcomes
QoL
Rini 2014 reported QoL measured by Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI)–15, which contains 15 questions representing concerns specific to patients with advanced kidney cancer and FKSI‐Disease Related Symptoms (FKSI‐DRS) subscale. We could not obtain a mean and standard deviation in each arm, however, and therefore we were unable to estimate this outcome.
Response rate (assessed with: RECIST version not reported)
Temsirolimus plus bevacizumab probably results in little to no difference in response rate as compared to bevacizumab plus IFN‐α (RR 0.99, 95% CI 0.79 to 1.24; 1 study, 791 participants; moderate‐certainty evidence; Analysis 15.4). Based on the control event risk of 274 per 1000 in this trial, this corresponds to 3 fewer response (95% CI 57 fewer to 66 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias).
Minor AEs (assessed with: CTCAE v3.0)
Temsirolimus plus bevacizumab probably results in little to no difference in minor AEs as compared to bevacizumab plus IFN‐α (RR 1.01, 95% CI 0.98 to 1.03; 1 study, 784 participants; moderate‐certainty evidence; Analysis 15.5). Based on the control event risk of 967 per 1000 in this trial, this corresponds to 10 more minor AEs (95% CI 19 fewer to 29 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance bias).
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
16. Everolimus + bevacizumab versus IFN α‐2a + bevacizumab
Please refer to summary of findings Table 16.
Primary outcomes
PFS
We are very uncertain how everolimus plus bevacizumab affects PFS as compared to IFN α‐2a plus bevacizumab (HR 0.91, 95% CI 0.69 to 1.20; 1 study, 365 participants; very low certainty evidence; Analysis 16.1). We rated the certainty of evidence as very low due to study limitations (selection, performance, detection and other bias, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with both an appreciable reduction and increase in PFS.
OS
We are very uncertain how everolimus plus bevacizumab affects OS as compared to IFN α‐2a plus bevacizumab (HR 1.01, 95% CI 0.75 to 1.36; 1 study, 365 participants; very low certainty evidence; Analysis 16.2). We rated the certainty of evidence as very low due to study limitations (selection and other bias, downgrade one level) and imprecision (downgrade two levels), given that the CI was compatible with both an appreciable reduction and increase in OS.
SAEs (assessed with: CTCAE v3.0)
Everolimus plus bevacizumab may result in little to no difference in SAEs as compared to IFN α‐2a plus bevacizumab (RR 1.06, 95% CI 0.95 to 1.18; 1 study, 361 participants; low‐certainty evidence; Analysis 16.3). Based on the control event risk of 762 per 1000 in this trial, this corresponds to 46 more SAEs (95% CI 38 fewer to 137 more) per 1000 participants. We rated the certainty of evidence as low due to study limitations (selection, performance, detection and other bias) and imprecision, given that the CI was also compatible with an appreciable increase in SAEs.
Secondary outcomes
QoL
Ravaud 2015 reported time to deterioration of global health status measured by the European Organisation for the Research and Treatment of Cancer (EORTC)‐Core Quality of Life Questionnaire (QLQ‐C30) (NCT00719264). We could not obtain a mean and standard deviation in each arm, however, and therefore we were unable to estimate this outcome.
Response rate (assessed with: RECIST v1.0)
Everolimus plus bevacizumab probably results in little to no difference in response rate as compared to IFN α‐2a plus bevacizumab (RR 0.97, 95% CI 0.69 to 1.35; 1 study, 365 participants; moderate‐certainty evidence; Analysis 16.4). Based on the control event risk of 279 per 1000 in this trial, this corresponds to 8 fewer response (95% CI 86 fewer to 98 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance, detection and other bias).
Minor AEs (assessed with CTCAE v3.0)
Everolimus plus bevacizumab probably results in little to no difference in minor AEs as compared to IFN α‐2a plus bevacizumab (RR 0.63, 95% CI 0.34 to 1.16; 1 study, 361 participants; moderate‐certainty evidence; Analysis 16.5). Based on the control event risk of 133 per 1000 in this trial, this corresponds to 49 fewer minor AEs (95% CI 88 fewer to 21 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (selection, performance, detection and other bias).
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
17. Sunitinib versus nivolumab + ipilimumab (Targeted agent versus combinations of immunotherapy)
Please refer to summary of findings Table 17.
Primary outcomes
PFS
Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low‐certainty evidence; Analysis 17.1). Based on the control event risk of 280 per 1000 in this trial at 30 months, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was also compatible with no reduction in PFS.
OS
Sunitinib reduces OS as compared to nivolumab plus ipilimumab (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high‐certainty evidence; Analysis 17.2). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. We rated the certainty of evidence as high.
SAEs (assessed with: CTCAE v4.0)
Sunitinib probably increases SAEs (grade 3 or 4) as compared to nivolumab plus ipilimumab (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate‐certainty evidence; Analysis 17.3). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. We rated the certainty of evidence as moderate due to study limitations (performance and detection bias).
Secondary outcomes
QoL
Sunitinib probably reduces QoL (assessed with FKSI‐19; scale 0 to 76 with higher scores indicating better QoL; MCID: 2) as compared to nivolumab plus ipilimumab (MD −4.10, 95% CI −5.75 to −2.45; 1 study, 460 participants; moderate‐certainty evidence; Analysis 17.4). We rated the certainty of evidence as moderate due to study limitations (performance, detection and attrition bias).
Response rate (assessed with: RECIST v1.1)
Sunitinib may reduce response rate as compared to nivolumab plus ipilimumab (RR 0.70, 95% CI 0.58 to 0.84; 1 study, 847 participants; low‐certainty evidence; Analysis 17.5). Based on the control event risk of 419 per 1000 in this trial, this corresponds to 126 fewer response (95% CI 176 fewer to 67 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was also compatible with little to no reduction in response rate.
Minor AEs (assessed with CTCAE v4.0)
Sunitinib may reduce minor AEs as compared to nivolumab plus ipilimumab (RR 0.74, 95% CI 0.64 to 0.86; 1 study, 1082 participants; low‐certainty evidence; Analysis 17.6). Based on the control event risk of 459 per 1000 in this trial, this corresponds to 119 fewer minor AEs (95% CI 165 fewer to 64 fewer) per 1000 participants. We rated the certainty of evidence as low due to study limitations (performance and detection bias) and imprecision, given that the CI was compatible with little to no reduction in minor AEs.
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
18. Pazopanib versus placebo (targeted agent versus placebo)
Please refer to summary of findings Table 18.
Primary outcomes
PFS
Pazopanib increases PFS as compared to placebo (HR 0.46, 95% CI 0.34 to 0.62; 1 study, 435 participants; high‐certainty evidence; Analysis 18.1). Based on the control event risk of 180 per 1000 in this trial at 12 months, this corresponds to 274 more PFSs (95% CI 165 more to 378 more) per 1000 participants.
OS
Pazopanib may result in little to no difference in OS as compared to placebo (HR 0.91, 95% CI 0.72 to 1.16; 1 study, 435 participants; low‐certainty evidence; Analysis 18.2). Based on the control event risk of 480 per 1000 in this trial at 24 months, this would result in 33 more OSs (95% CI 53 fewer to 110 more) per 1000 participants. We rated the certainty of evidence as low due to imprecision (downgrade two levels), given that the CI was both compatible with an appreciable reduction and increase in OS.
SAEs (assessed with CTCAE v3.0)
Pazopanib increases SAEs as compared to placebo (RR 2.00, 95% CI 1.40 to 2.85; 1 study, 435 participants; high‐certainty evidence; Analysis 18.3). Based on the control event risk in this trial of 200 per 1000, this corresponds to 200 more SAEs (95% CI 80 more to 370 more) per 1000 participants.
Secondary outcomes
QoL
Pazopanib results in little to no difference in QoL (assessed with EORTC QLQ‐C30; scale 0 to 100 with higher values reflecting better QoL; MCID 10) as compared to placebo (MD −3.10, 95% CI −7.76 to 1.56; 1 study, 300 participants; high‐certainty evidence; Analysis 18.4).
Response rate (assessed with: RECIST v1.0)
Pazopanib probably increases response rate as compared to placebo (RR 8.80, 95% CI 3.65 to 21.19; 1 study, 435 participants; moderate‐certainty evidence; Analysis 18.5). Based on the control event risk of 34 per 1000 in this trial, this corresponds to 269 more response (95% CI 91 more to 696 more) per 1000 participants. We rated the certainty of evidence as moderate due to imprecision, given that the CI was also compatible with little to no increase in response rate.
Minor AEs (assessed with CTCAE v3.0)
Pazopanib probably increases minor AEs as compared to placebo (RR 1.31, 95% CI 1.13 to 1.52; 1 study, 435 participants; moderate‐certainty evidence; Analysis 18.6). Based on the control event risk of 600 per 1000 in this trial, this corresponds to 186 more minor AEs (95% CI 78 more to 312 more) per 1000 participants. We rated the certainty of evidence as moderate due to imprecision, given that the CI was also compatible with little to no increase in minor AEs.
Subgroup analysis
We were unable to perform any of the predefined subgroup analyses.
Sensitivity analysis
We were unable to perform a sensitivity analysis because there was only one study.
Discussion
For this review, we considered targeted therapies as the index intervention. This group of drugs included VEGFR‐TKIs (e.g. sunitinib, sorafenib, pazopanib, tivozanib and axitinib), VEGF‐inhibitors (e.g. bevacizumab) and mTOR inhibitors (e.g. everolimus or temsirolimus). Comparators included placebo, alternative targeted therapy (i.e. targeted therapy vs targeted therapy), cytokines (i.e. classic non‐targeted immunotherapy, e.g. interferon‐alpha), immune checkpoint inhibitors, or combinations of different classes of drugs. Immune checkpoint inhibitors included programmed death 1 inhibitors (PD‐1), programmed death ligand 1 inhibitors (PD‐L1) and cytotoxic T‐lymphocyte associated antigen 4 (CTLA‐4) inhibitors (e.g. avelumab, pembrolizumab, atezolizumab, nivolumab and ipilimumab).
Summary of main results
One trial compared targeted agent (pazopanib) against placebo (summary of findings Table 18). There was high quality evidence showing pazopanib was significantly superior to placebo in terms of PFS, but inferior in terms of incidence of SAEs. There was low certainty evidence showing no difference between the groups in terms of OS.
For the intra‐group comparison of single‐agent targeted therapy against each other, we found some differences between them (summary of findings Table 1; summary of findings Table 2; summary of findings Table 3; summary of findings Table 4; summary of findings Table 5). Pazopanib and tivozanib were both superior to sorafenib in terms of PFS but there were some differences in terms of OS; the certainty of evidence was moderate for pazopanib for PFS and low for OS but low for tivozanib for both PFS and OS. Sunitinib was superior to everolimus for PFS although there was no difference for OS, with moderate to low certainty of evidence for both outcomes. Sorafenib was inferior to sunitinib for PFS but there was no difference for OS (low and very low certainty evidence, respectively), nor between pazopanib versus sunitinib for PFS and OS (low certainty evidence for both). For AE, there was very low to low‐certainty evidence that there were no statistically significant differences between the drugs, except for sunitinib versus everolimus; sunitinib appeared to have a higher incidence of SAEs compared with everolimus (moderate‐certainty evidence).
Next, for the comparison of targeted therapy versus cytokines (i.e. classic non‐targeted immunotherapy, summary of findings Table 10; summary of findings Table 11; summary of findings Table 13; summary of findings Table 14; summary of findings Table 15; summary of findings Table 16), there was low‐ to moderate‐certainty evidence showing that single‐agent targeted therapy was superior to single‐agent interferon‐alpha for PFS and OS (for sunitinib and temsirolimus). Regarding the incidence of SAEs, temsirolimus was better than interferon‐alpha (low‐certainty evidence), but sunitinib was worse than interferon‐alpha (moderate‐certainty evidence). The results for the comparison between combination of targeted therapies with each other or with interferon‐alpha versus single‐agent interferon‐alpha suggest combinations of targeted therapy involving either bevacizumab or temsirolimus with interferon‐alpha are superior to single‐agent interferon‐alpha for PFS (low‐ to moderate‐certainty evidence) but there was no difference in OS (low‐certainty evidence); however the targeted therapy combinations had a significantly higher incidence of SAEs (low‐ to moderate‐certainty evidence). The comparison of combinations of targeted therapy (temsirolimus and bevacizumab, and everolimus and bevacizumab) versus combination of bevacizumab and interferon‐alpha did not show any differences in PFS, OS nor SAEs (very low to moderate‐certainty evidence).
For the comparison of targeted therapy versus combination of tumour vaccine (IMA901) with sunitinib, (summary of findings Table 9), there was low‐certainty evidence that single‐agent sunitinib had significantly better OS and better SAEs profile compared with combination of IMA901 plus sunitinib.
For the comparison of single‐agent targeted therapy (all based on sunitinib) versus immune checkpoint inhibitor, the results can be summarised into three sub‐sections: (1) sunitinib versus single‐agent immune checkpoint inhibitor (atezolizumab, summary of findings Table 12); (2) sunitinib versus combination of targeted drug with immune checkpoint inhibitor (axitinib + avelumab; axitinib + pembrolizumab; and bevacizumab + atezolizumab; summary of findings Table 6; summary of findings Table 7; summary of findings Table 8); and (3) sunitinib versus combination of immune checkpoint inhibitors (nivolumab + ipilimumab, summary of findings Table 17). For the comparison of sunitinib versus atezolizumab, there were no significant differences between them for PFS and OS (very low certainty evidence); however, sunitinib had worse incidence of SAEs (moderate certainty evidence). For the comparison of sunitinib versus combination of targeted therapy with immune checkpoint inhibitor, sunitinib appeared to have worse PFS than two of the combinations (moderate‐certainty evidence) and worse OS (moderate‐certainty evidence) than one combination of targeted drug and immune checkpoint inhibitor; Sunitinib may have no difference or less SAEs compared to combinations (low‐certainty evidence). Finally, for the comparison of sunitinib versus combination of immune checkpoint inhibitors (nivolumab + ipilimumab), sunitinib had worse PFS (low‐certainty evidence), worse OS (high‐certainty evidence) and worse incidence of SAEs (moderate‐certainty evidence) compared with the combination of nivolumab and ipilimumab. Sunitinib was also associated with worse QoL (moderate‐certainty evidence) and worse response rate (low‐certainty evidence).
In summary, when comparing targeted therapy (i.e. sunitinib) against immune checkpoint inhibitor either singly or in combination, there was high‐ to moderate‐quality evidence (from two trials) demonstrating sunitinib was inferior to a combination of targeted therapy with immune checkpoint inhibitor (i.e. axitinib + pembrolizumab), and a combination of immune checkpoint inhibitors (i.e. nivolumab + ipilimumab), in terms of OS. The result for PFS was also worse for sunitinib compared with the other combinations involving immune checkpoint inhibitors, with low‐ to moderate‐certainty evidence across all studies. There was also moderate‐quality evidence from two studies that sunitinib had worse incidence of SAEs compared with immune checkpoint inhibitors (involving atezolizumab as single agent, and nivolumab + ipilimumab combination). Although sunitinib was the comparator in all of those trials, a meta‐analysis was only possible for the two studies which used the combination of atezolizumab and bevacizumab. This was due to considerable clinical heterogeneity across the trials namely in the use of eligibility criteria, primary endpoints (e.g. results reported only for the intention‐to‐treat the population or those with PD‐L1 expression on tumour cells or tumour‐infiltrating lymphocytes), inconsistent use validated risk scores such as the Memorial Sloan Kettering Cancer Center (MSKCC) or International Metastatic RCC Database Consortium (IMDC) risks models, and experimental drugs used.
Overall completeness and applicability of evidence
We identified studies to include in this review by independent searches. Results were comparable and we resolved disagreements by discussion within the author group. We also identified trials through hand searching of conference proceedings and tried to acquire additional data whenever they were needed by contacting authors.
Participants were comparable amongst the identified studies, which all had a multicentre design. All except two trials (Motzer 2013b and Sternberg 2010) had a homogeneous population which had not received previous treatment. A phase 3 study was the favoured trial design which was used in 15 trials. Another three used a phase 2 design. All included studies investigated our primary and secondary outcomes except for QoL data, which was not available in seven trials.
We imposed strict criteria for study inclusion for methodological reasons which excluded studies with less than 100 participants per arm. This meant excluding the CABOSUN trial comparing cabozantinib versus sunitinib, an initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk (n = 157 in total) (Choueiri 2017). Guidelines panels of ESMO and EAU consider cabozantinib an alternative for IMDC intermediate‐ and poor‐risk patients only who cannot receive immune checkpoint inhibitor combination therapies but on the same par as sunitinib and pazopanib, which have been tested in randomised controlled phase 3 trials in this setting (EAU Guidelines 2020; ESMO Clinical Practice Guidelines 2019). This decision was taken because CABOSUN was a randomised phase 2 trial in which cabozantinib had a PFS but no OS benefit compared to sunitinib. This was considered not enough evidence to argue that cabozantinib is qualitatively superior to sunitinib.
Quality of the evidence
We used GRADE to rate the quality of evidence and created 18 'Summary of findings' tables for the different comparisons. We rated most of the comparisons at a low to moderate level of evidence. The main reasons for downgrading were study limitations, especially those due to lack of blinding with the risk of performance and detection bias. Imprecision was another important factor for lowering the certainty of evidence in efficacy outcomes.
Potential biases in the review process
Two reviewers screened all search results independently. There were no language restrictions but all identified studies were published in the English language. We did not receive additional data after contacting authors except for one study, which could be a source of bias.
After publication of our protocol we amended our inclusion criteria. We chose to limit the number of participants to a minimum of 100 per study arm to ensure our evidence synthesis was based on more robust data by reducing the risk of small‐study bias. We also chose to only include participants who were naïve to systemic therapy. This decision was mainly driven by the large number of studies assessing patients with metastatic renal cell carcinoma in the second‐line treatment setting or beyond. Including these trials would have distracted us from the main focus of our review which was on the first‐line treatment setting, and the burden of work would have become unfeasibly high.
For the interpretation of clinically important effect sizes, we used absolute effect estimates that were informed by the input of expert clinicians on our team; unless there were published thresholds (as was the case for quality of life instruments) we used 5% for the most patient‐important primary outcomes of PFS and OS and 10% for the secondary outcomes of response rates and minor AEs. We recognise that different thresholds might lead to different interpretations and have therefore made all our judgments as transparent as possible.
Agreements and disagreements with other studies or reviews
A systematic review with a broader approach on systemic treatment for metastatic renal cell carcinoma was published in 2018 (Lalani 2018). In total 26 trials were identified for first and later line treatments. All studies of that review that met our inclusion criteria were also identified and included in our review. The authors expected combinations therapies to become the new promising standard of care in treatment‐naïve renal cell carcinoma.
Another systematic review, also published in 2018, was focusing on first line systemic therapy for metastatic renal cell carcinoma (Wallis 2018). Of the 37 identified trials for a qualitative synthesis 13 were eligible for a quantitative synthesis. All trials that meet our inclusion criteria were part of our review. Cabozantinib was judged as being highly likely to provide the greatest PFS benefit, while the combination of nivolumab plus ipilimumab was most likely to provide the greatest OS benefit. The later combination was rated likely to have the most beneficial tolerance profile.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Categories: green point (+) = low risk of bias; yellow point (?) = unclear risk of bias; red point (‐) = high risk of bias.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1: Sorafenib versus Sunitinib, Outcome 1: Progression‐free survival
Comparison 1: Sorafenib versus Sunitinib, Outcome 2: Overall survival
Comparison 1: Sorafenib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 1: Sorafenib versus Sunitinib, Outcome 4: Response rate
Comparison 1: Sorafenib versus Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 2: Pazopanib versus Sunitinib, Outcome 1: Progression‐free survival
Comparison 2: Pazopanib versus Sunitinib, Outcome 2: Overall survival
Comparison 2: Pazopanib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 2: Pazopanib versus Sunitinib, Outcome 4: Health‐related quality of life
Comparison 2: Pazopanib versus Sunitinib, Outcome 5: Response rate
Comparison 2: Pazopanib versus Sunitinib, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 3: Tivozanib versus Sorafenib, Outcome 1: Progression‐free survival
Comparison 3: Tivozanib versus Sorafenib, Outcome 2: Overall survival
Comparison 3: Tivozanib versus Sorafenib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 3: Tivozanib versus Sorafenib, Outcome 4: Health‐related quality of life
Comparison 3: Tivozanib versus Sorafenib, Outcome 5: Response rate
Comparison 3: Tivozanib versus Sorafenib, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 4: Sorafenib versus Pazopanib, Outcome 1: Progression‐free survival
Comparison 4: Sorafenib versus Pazopanib, Outcome 2: Overall survival
Comparison 4: Sorafenib versus Pazopanib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 4: Sorafenib versus Pazopanib, Outcome 4: Health‐related quality of life
Comparison 4: Sorafenib versus Pazopanib, Outcome 5: Response rate
Comparison 4: Sorafenib versus Pazopanib, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 5: Sunitinib versus Everolimus, Outcome 1: Progression‐free survival
Comparison 5: Sunitinib versus Everolimus, Outcome 2: Overall survival
Comparison 5: Sunitinib versus Everolimus, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 5: Sunitinib versus Everolimus, Outcome 4: Health‐related quality of life
Comparison 5: Sunitinib versus Everolimus, Outcome 5: Response rate
Comparison 5: Sunitinib versus Everolimus, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 1: Progression‐free survival
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 2: Overall survival
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 4: Response rate
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 1: Progression‐free survival
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 2: Overall survival
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 4: Response rate
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 1: Progression‐free survival
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 2: Overall survival
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 4: Health‐related quality of life
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 5: Response rate
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 1: Progression‐free survival
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 2: Overall survival
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 4: Response rate
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 1: Progression‐free survival
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 2: Overall survival
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 4: Health‐related quality of life
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 5: Response rate
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 11: Temsirolimus versus IFN‐α, Outcome 1: Progression‐free survival
Comparison 11: Temsirolimus versus IFN‐α, Outcome 2: Overall survival
Comparison 11: Temsirolimus versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 11: Temsirolimus versus IFN‐α, Outcome 4: Health‐related quality of life
Comparison 11: Temsirolimus versus IFN‐α, Outcome 5: Response rate
Comparison 11: Temsirolimus versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 12: Sunitinib versus Atezolizumab, Outcome 1: Progression‐free survival
Comparison 12: Sunitinib versus Atezolizumab, Outcome 2: Overall survival
Comparison 12: Sunitinib versus Atezolizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 12: Sunitinib versus Atezolizumab, Outcome 4: Health‐related quality of life
Comparison 12: Sunitinib versus Atezolizumab, Outcome 5: Response rate
Comparison 12: Sunitinib versus Atezolizumab, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 1: Progression‐free survival
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 2: Overall survival
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 4: Response rate
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 1: Progression‐free survival
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 2: Overall survival
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 4: Health‐related quality of life
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 5: Response rate
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 1: Progression‐free survival
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 2: Overall survival
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 4: Response rate
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 1: Progression‐free survival
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 2: Overall survival
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 4: Response rate
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 1: Progression‐free survival
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 2: Overall survival
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 4: Health‐related quality of life
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 5: Response rate
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 18: Pazopanib versus Placebo, Outcome 1: Progression‐free survival
Comparison 18: Pazopanib versus Placebo, Outcome 2: Overall survival
Comparison 18: Pazopanib versus Placebo, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 18: Pazopanib versus Placebo, Outcome 4: Health‐related quality of life
Comparison 18: Pazopanib versus Placebo, Outcome 5: Response rate
Comparison 18: Pazopanib versus Placebo, Outcome 6: Minor adverse events (Grade 1 or 2)
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sunitinib | Risk difference with Sorafenib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 10 months) | 365 | ⊕⊕⊝⊝ | HR 1.19 | Study population | |
| 340 per 1000 | 63 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 365 | ⊕⊝⊝⊝ | HR 0.99 | Study population | |
| 550 per 1000 | 3 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 353 | ⊕⊝⊝⊝ | RR 0.99 | Study population | |
| 670 per 1000 | 7 fewer per 1000 | ||||
| Health‐related quality of life5 | not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of other bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 3 Downgraded by 1 level for study limitations; unclear risk of other bias 4 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 5 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sunitinib | Risk difference with Pazopanib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 1110 | ⊕⊕⊝⊝ | HR 1.05 | Study population | |
| 420 per 1000 | 18 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 1110 | ⊕⊕⊝⊝ | HR 0.92 | Study population | |
| 550 per 1000 | 27 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1102 | ⊕⊕⊝⊝ | RR 1.01 | Study population | |
| 734 per 1000 | 7 more per 1000 | ||||
| Health‐related quality of life (mean change value) follow‐up: after 4 cycle | 467 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life (mean change value) was ‐6.5 | MD 3.6 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;FACIT‐F: Functional Assessment of Chronic Illness Therapy–Fatigue scale; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of other bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 3 Downgraded by 1 level for study limitations; unclear risk of other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included no benefit and benefit) 5 Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias and unclear risk of other bias 6 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (3 points, included benefit and little benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sorafenib | Risk difference with Tivozanib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 517 | ⊕⊕⊝⊝ | HR 0.79 | Study population | |
| 360 per 1000 | 86 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 517 | ⊕⊕⊝⊝ | HR 1.25 | Study population | |
| 620 per 1000 | 70 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 516 | ⊕⊕⊝⊝ | RR 0.85 | Study population | |
| 689 per 1000 | 103 fewer per 1000 | ||||
| Health‐related quality of life | 506 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was ‐0.06 | MD 0.01 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) 2 Downgraded by 1 level for study limitations; high risk of performance, detection and other bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 4 Downgraded by 1 level for study limitations; high risk of other bias 5 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (0.06 points, included benefit and no benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Pazopanib | Risk difference with Sorafenib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 377 | ⊕⊕⊕⊝ | HR 1.92 | Study population | |
| 380 per 1000 | 224 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 377 | ⊕⊕⊝⊝ | HR 1.22 | Study population | |
| 520 per 1000 | 70 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 366 | ⊕⊝⊝⊝ | RR 0.92 | Study population | |
| 639 per 1000 | 51 fewer per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 267 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was ‐9.9 | MD 3.1 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; unclear risk of selection, detection, and reporting bias and high risk of performance bias 2 Downgraded by 1 level for study limitations; unclear risk of selection, and reporting bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 4 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 5 Downgraded by 1 level for study limitations; unclear risk of selection, detection, and reporting bias and high risk of performance and attrition bias 6 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (3 points, included benefit and no benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Everolimus | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 471 | ⊕⊕⊕⊝ | HR 0.71 | Study population | |
| 300 per 1000 | 125 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 471 | ⊕⊕⊝⊝ | HR 0.90 | Study population | |
| 470 per 1000 | 37 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 469 | ⊕⊕⊕⊝ | RR 1.34 | Study population | |
| 471 per 1000 | 160 more per 1000 | ||||
| Health‐related quality of life | 288 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 65.5 | MD 5 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance, detection and other bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 3 Downgraded by 1 level for study limitations; high risk of other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (10 points, included harm and no harm) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Avelumab + Axitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: median 10.8 months | 886 | ⊕⊕⊕⊝ | HR 1.45 | Study population | |
| 550 per 1000 | 130 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 886 | ⊕⊕⊝⊝ | HR 1.28 | Study population | |
| 890 per 1000 | 29 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 873 | ⊕⊕⊝⊝ | RR 1.01 | Study population | |
| 705 per 1000 | 7 more per 1000 | ||||
| Health‐related quality of life4 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations: high risk of performance bias and unclear risk of reporting bias 2 Downgraded by 1 level for imprecision: confidence interval crossed the assumed threshold of a clinically important difference (included no benefit and harm) 3 Downgraded by 1 level for study limitations: unclear risk of reporting bias 4 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Pembrolizumab + Axitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: median 12.8 months | 861 | ⊕⊕⊕⊝ | HR 1.45 | Study population | |
| 590 per 1000 | 125 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 861 | ⊕⊕⊕⊝ | HR 1.90 | Study population | |
| 880 per 1000 | 96 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 854 | ⊕⊕⊝⊝ | RR 0.90 | Study population | |
| 604 per 1000 | 60 fewer per 1000 | ||||
| Health‐related quality of life4 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high risk of performance bias 2 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and little harm) 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Atezolizumab + Bevacizumab | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: range 15 months to 20.7 months | 1117 | ⊕⊕⊝⊝ | HR 1.18 | Study population | |
| 480 per 1000 | 59 fewer per 1000 | ||||
| Overall survival follow‐up: range 20.7 months to 24 months | 1117 | ⊕⊝⊝⊝ | HR 0.99 | Study population | |
| 630 per 1000 | 3 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1098 | ⊕⊝⊝⊝ | RR 1.22 | Study population | |
| 446 per 1000 | 98 more per 1000 | ||||
| Health‐related quality of life | 691 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life ranged from 0.56 to 1.57 | MD 1 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; MDASI: MD Anderson Symptom Inventory; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and little harm) 2 Downgraded by 1 level for study limitations; high and unclear risk of 1 or more domains. 3 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 4 Downgraded by 1 level for inconsistency; moderate to substantial heterogeneity: unexplained differences between study results 5 Downgraded by 1 level for imprecision; confidence interval reached the line of no difference and crossed the assumed threshold of a clinically important difference (included harm and no harm) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IMA901 + Sunitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) | 339 | ⊕⊝⊝⊝ | HR 0.95 | Study population | |
| 590 per 1000 | 16 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 339 | ⊕⊕⊝⊝ | HR 0.75 | Study population | |
| 800 per 1000 | 46 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 334 | ⊕⊕⊝⊝ | RR 0.74 | Study population | |
| 550 per 1000 | 143 fewer per 1000 | ||||
| Health‐related quality of life6 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 2 Downgraded by 1 level for study limitations; high risk of performance and other bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Downgraded by 1 level for study limitations: high risk of other bias 5 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) 6 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Interferon‐α (IFN‐α) | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 6 months) | 750 | ⊕⊕⊕⊝ | HR 0.54 | Study population | |
| 400 per 1000 | 210 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 750 | ⊕⊕⊝⊝ | HR 0.82 | Study population | |
| 480 per 1000 | 68 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 735 | ⊕⊕⊕⊝ | RR 1.75 | Study population | |
| 258 per 1000 | 194 more per 1000 | ||||
| Health‐related quality of life follow‐up: after 2 cycle | 544 | ⊕⊕⊕⊝ | ‐ | The mean health‐related quality of life was 0.74 | MD 0.01 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; unclear risk of selection bias and high risk of performance and other bias 2 Downgraded by 1 level for study limitations; unclear risk of selection bias and high risk of other bias 3 Downgraded by 1 level for imprecision; confidence interval reached the line of no difference and crossed the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Downgraded by 1 level for study limitations; unclear risk of selection and attrition bias and high risk of performance and other bias | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN‐α | Risk difference with Temsirolimus | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 416 | ⊕⊕⊝⊝ | HR 0.74 | Study population | |
| 100 per 1000 | 82 more per 1000 | ||||
| Overall survival survival (absolute effect size estimates based on survival rate at 12 months ) follow‐up: up to 80 months | 416 | ⊕⊕⊕⊝ | HR 0.78 | Study population | |
| 300 per 1000 | 91 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 408 | ⊕⊕⊝⊝ | RR 0.86 | Study population | |
| 780 per 1000 | 109 fewer per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 401 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 0.66 | MD 0.03 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and no benefit) 2 Downgraded by 1 level for study limitations; high risk of performance and detection bias 3 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) 4 Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Atezolizumab | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) | 204 | ⊕⊝⊝⊝ | HR 0.84 | Study population | |
| 420 per 1000 | 63 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 204 | ⊕⊝⊝⊝ | HR 0.94 | Moderate | |
| 630 per 1000 6 | 18 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 203 | ⊕⊕⊕⊝ | RR 1.73 | Study population | |
| 398 per 1000 | 291 more per 1000 | ||||
| Health‐related quality of life | 157 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 1.04 | MD 1.46 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; MDASI: MD Anderson Symptom Inventory; RCT: Randomized controlled trial; RR: Risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 2 Downgraded by 1 level for study limitations; high risk of selection, performance and detection bias and unclear risk of other bias 3 Downgraded by 1 level for study limitations; high risk of selection and unclear risk of other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (1 point, included harm and little harm) 5 Downgraded by 1 level for study limitations; high risk of selection, performance and detection bias and unclear risk of other bias 6 Baseline risk for overall survival in the atezolizumab group was assumed to be 63% (moderate risk) at 24 months as reported in Rini 2019b | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN (+ placebo) | Risk difference with Bevacizumab + IFN | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: intervention: 13.3 months comparator: 12.8 months | 1381 | ⊕⊕⊕⊝ | HR 0.68 | Study population | |
| 200 per 1000 | 135 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: intervention: 23 months comparator: 21 months | 1381 | ⊕⊕⊝⊝ | HR 0.88 | Study population | |
| 500 per 1000 | 43 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1356 | ⊕⊕⊕⊝ | RR 1.31 | Study population | |
| 536 per 1000 | 166 more per 1000 | ||||
| Health‐related quality of life3 | Not reported | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; high and unclear risk of 1 or more domains 2 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) 3 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN‐α | Risk difference with Temsirolimus + IFN‐α | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 417 | ⊕⊕⊝⊝ | HR 0.76 | Study population | |
| 100 per 1000 | 74 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 417 | ⊕⊕⊝⊝ | HR 0.93 | Study population | |
| 300 per 1000 | 26 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 408 | ⊕⊕⊝⊝ | RR 1.12 | Study population | |
| 780 per 1000 | 94 more per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 394 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 0.66 | MD 0.03 higher |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and no benefit) 2 Downgraded by 1 level for study limitations; high risk of performance and detection bias 3 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 4 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and no harm) 5 Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias 6 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Bevacizumab + IFN‐α | Risk difference with Temsirolimus + Bevacizumab | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 791 | ⊕⊕⊝⊝ | HR 1.10 | Study population | |
| 420 per 1000 | 35 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 791 | ⊕⊕⊕⊝ | HR 1.08 | Study population | |
| 550 per 1000 | 26 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 784 | ⊕⊕⊝⊝ | RR 1.05 | Study population | |
| 760 per 1000 | 38 more per 1000 | ||||
| Health‐related quality of life3 assessed with: FKSI–15 Scale from: 0 to 60 | no available data | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 2 Downgraded by 1 level for study limitations; high risk of performance bias (we are not concerned with unclear risk of other bias) 3 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IFN α‐2a + Bevacizumab | Risk difference with Everolimus + Bevacizumab | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 18 months) follow‐up: not reported | 365 | ⊕⊝⊝⊝ | HR 0.91 | Study population | |
| 250 per 1000 | 33 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 365 | ⊕⊝⊝⊝ | HR 1.01 | Study population | |
| 533 per 1000 | 3 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 361 | ⊕⊕⊝⊝ | RR 1.06 | Study population | |
| 762 per 1000 | 46 more per 1000 | ||||
| Health‐related quality of life5 | no available data | ‐ | ‐ | ‐ | ‐ |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for study limitations; unclear risk of selection, performance and other bias and high risk of detection bias 2 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) 3 Downgraded by 1 level for study limitations; unclear risk of selection and other bias 4 Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) 5 Health‐related quality of life: no available data | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type); IMDC intermediate, poor risk patients only. | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Nivolumab + Ipilimumab | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 30 months) | 847 | ⊕⊕⊝⊝ | HR 1.30 | Study population | |
| 280 per 1000 | 89 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 30 months) | 847 | ⊕⊕⊕⊕ | HR 1.52 | Study population | |
| 600 per 1000 | 140 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1082 | ⊕⊕⊕⊝ | RR 1.37 | Study population | |
| 457 per 1000 | 169 more per 1000 | ||||
| Health‐related quality of life Scale from: 0 to 76 | 460 | ⊕⊕⊕⊝ | ‐ | The mean health‐related quality of life was 2.6 | MD 4.1 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and no harm) 2 Downgraded by 1 level for study limitations; high risk of performance and detection bias 3 Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of attrition bias | |||||
| Patient or population: Previous treated and treatment‐naïve (54%) metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Placebo | Risk difference with Pazopanib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported | 435 | ⊕⊕⊕⊕ | HR 0.46 | Study population | |
| 180 per 1000 | 274 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 435 | ⊕⊕⊝⊝ | HR 0.91 | Study population | |
| 480 per 1000 | 33 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 435 | ⊕⊕⊕⊕ | RR 2.00 | Study population | |
| 200 per 1000 | 200 more per 1000 | ||||
| Health‐related quality of life | 300 | ⊕⊕⊕⊕ | ‐ | The mean health‐related quality of life was ‐0.5 | MD 3.1 lower |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | |||||
| GRADE Working Group grades of evidence | |||||
| 1 Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included both benefit and harm) | |||||
| Axitinib |
| Bevacizumab |
| Dovitinib |
| Erlotinib |
| Everolimus |
| Lapatinib |
| Pazopanib |
| Sorafenib |
| Sunitinib |
| Temsirolimus |
| Tivozanib |
| Other agents identified during search |
| Studies | Intervention(s)/ Comparator(s) | Randomised (N) | Received treatment (N) | Discontinued treatment (N) | Efficacy analysis (N) | Safety analysis (N) |
|---|---|---|---|---|---|---|
| Eichelberg 2015 | Soreafenib/ Sunitinib | 182 | 177 | 161 | 182 | 177 |
| Sunitinib/ Sorafenib | 183 | 176 | 156 | 183 | 176 | |
| Escudier 2010 | Bevacizumab + IFN‐a2a | 327 | 325 | 206 | 327 | 337 |
| IFN‐a2a + Placebo | 322 | 316 | 274 | 322 | 304 | |
| Escudier 2017 1 | Sunitinib | 546 | 535 | 438 | 546 | 535 |
| Nivolumab + Ipilimumab | 550 | 547 | 419 | 550 | 547 | |
| Hudes 2007 | Temsirolimus | 209 | 208 | 199 | 209 | 208 |
| Temsirolimus + Interferon | 210 | 208 | 193 | 210 | 208 | |
| Interferon | 207 | 200 | 194 | 207 | 200 | |
| McDermott 2017 | Sunitinib | 101 | 100 | 83 | 101 | 100 |
| Atezolizumab + Bevacizumab | 101 | 101 | 69 | 101 | 101 | |
| Atezolizumab | 103 | 103 | 80 | 103 | 103 | |
| Motzer 2010 | Sunitinib | 375 | 375 | 127 | 375 | 375 |
| IFN‐a2a | 375 | 360 | 234 | 375 | 360 | |
| Motzer 2013a | Pazopanib | 557 | 554 | 486 | 557 | 554 |
| Sunitinib | 553 | 548 | 483 | 553 | 548 | |
| Motzer 2013b | Tivozanib | 260 | 259 | 154 | 260 | 259 |
| Sorafenib | 257 | 257 | 192 | 257 | 257 | |
| Motzer 2014 | Sunitinib/ Everolimus | 233 | 231 | 192 | 233 | 231 |
| Everolimus/ Sunitinib | 238 | 238 | 201 | 238 | 238 | |
| Motzer 2019 | Sunitinib | 444 | 439 | 227 | 444 | 439 |
| Avelumab + Axitinib | 442 | 434 | 187 | 442 | 434 | |
| Ravaud 2015 | Everolimus + Bevacizumab | 182 | 180 | 175 | 182 | 180 |
| Interferon + Bevacizumab | 183 | 181 | 175 | 183 | 181 | |
| Retz 2019 | Sorafenib/ Pazopanib | 189 | 183 | 115 | 189 | 183 |
| Pazopanib/ Sorafenib | 188 | 183 | 110 | 188 | 183 | |
| Rini 2008 | Bevacizumab + IFN‐a2b | 369 | 366 | 355 | 369 | 366 |
| IFN‐a2b | 363 | 350 | 355 | 363 | 349 | |
| Rini 2014 | Temsirolimus + Bevacizumab | 400 | 393 | 372 | 400 | 393 |
| Temsirolimus + Interferon | 391 | 391 | 354 | 391 | 391 | |
| Rini 2016 | Sunitinib | 135 | 130 | 23 | 135 | 132 |
| IMA901 + Sunitinib | 204 | 185 | 28 | 204 | 202 | |
| Rini 2019a | Sunitinib | 429 | 425 | 242 | 429 | 425 |
| Pembrolizumab + Axitinib | 432 | 429 | 176 | 432 | 429 | |
| Rini 2019b | Sunitinib | 461 | 446 | 308 | 461 | 446 |
| Atezolizumab + Bevacizumab | 454 | 451 | 265 | 454 | 451 | |
| Sternberg 2010 | Pazopanib | 290 | 290 | 227 | 290 | 290 |
| Placebo | 145 | 145 | 131 | 145 | 145 | |
| Total | 11590 | 11419 | 8366 | 11590 | 11437 | |
| 1 Included overall population; but in the data and analyses section and summary of findings table, we used IMDC intermediate and poor risk patients for efficacy analysis. | ||||||
| Studies | Phase of study | Accrual | Blinding | RCC subtype | Prior therapy | Intervention |
|---|---|---|---|---|---|---|
| Comparator | ||||||
| Eichelberg 2015 | 3 | Feb 2009 to Dec 2011 | open label study | any, 87% clear cell | naïve | Soreafenib/Sunitinib |
| Sunitinib/Sorafenib | ||||||
| Escudier 2010 | 3 | Jun 2004 to Oct 2005 | double‐blind study | clear cell | naïve | Bevacizumab + IFN‐a2a |
| IFN‐a2a + Placebo | ||||||
| Escudier 2017 | 3 | Oct 2014 to Feb 2016 | open label study | clear cell | naïve | Sunitinib |
| Nivolumab + Ipilimumab | ||||||
| Hudes 2007 | 3 | Jul 2003 to Apr 2005 | open label study | any, 80% clear cell | naïve | Temsirolimus |
| Temsirolimus + Interferon | ||||||
| Inferferon | ||||||
| McDermott 2017 | 2 | Jan 2014 to Mar 2015 | open label study | clear cell | naïve | Sunitinib |
| Atezolizumab + Bevacizumab | ||||||
| Atezolizumab | ||||||
| Motzer 2010 | 3 | Aug 2004 to Oct 2005 | radiologic assessment | clear cell | naïve | Sunitinib |
| IFN‐a2a | ||||||
| Motzer 2013a | 3 | Aug 2008 to Sep 2011 | open label study | clear cell | naïve | Pazopanib |
| Sunitinib | ||||||
| Motzer 2013b | 2 | Feb 2010 to Aug 2010 | open label study | clear cell | naïve | Tivozanib |
| Sorafenib | ||||||
| Motzer 2014 | 2 | Sep 2009 to Jun 2012 | open label study | any, 85% clear cell | naïve | Sunitinib/ Everolimus |
| Everolimus/ Sunitinib | ||||||
| Motzer 2019 | 3 | Mar 2016 to Dec 2017 | open label study | clear cell | naïve | Sunitinib |
| Avelumab + Axitinib | ||||||
| Ravaud 2015 | 2 | ‐ | open label study | any 96% clear cell | naïve | Everolimus + Bevacizumab |
| Interferon + Bevacizumab | ||||||
| Retz 2019 | 3 | Jun 2012 to Nov 2016 | open label study | any, 87% clear cell | naïve | Sorafenib/ Pazopanib |
| Pazopanib/ Sorafenib | ||||||
| Rini 2008 | 3 | Oct 2003 to Jul 2005 | open label study | clear cell | naïve | Bevacizumab + IFN‐a2b |
| IFN‐a2b | ||||||
| Rini 2014 | 3 | Apr 2008 to Oct 2010 | open label study | any, 80% clear cell | naïve | Temsirolimus + Bevacizumab |
| Bevacizumab + Inferferon | ||||||
| Rini 2016 | 3 | Dec 2010 to Dec 2012 | open label study | clear cell | naïve | Sunitinib |
| IMA901 + Sunitinib | ||||||
| Rini 2019a | 3 | Oct 2016 to Jan 2018 | open label study | clear cell | naïve | Sunitinib |
| Pembrolizumab + Axitinib | ||||||
| Rini 2019b | 3 | May 2015 to Oct 2016 | open label study | clear cell | naïve | Sunitinib |
| Atezolizumab + Bevacizumab | ||||||
| Sternberg 2010 | 3 | Apr 2006 to Apr 2007 | double‐blind study | clear cell | 54% naive | Pazopanib |
| Placebo | ||||||
| ‐ denotes not reported | ||||||
| IFN: interferon; RCC: renal cell carcinoma | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 1.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 1.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 1.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 2.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 2.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 3.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 3.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 3.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 4.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 4.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 4.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 4.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 5.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 5.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 5.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 5.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 6.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 6.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 6.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 7.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 7.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 7.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 7.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 8.1 Progression‐free survival Show forest plot | 2 | 1117 | Hazard Ratio (IV, Random, 95% CI) | 1.18 [1.02, 1.36] |
| 8.2 Overall survival Show forest plot | 2 | 1117 | Hazard Ratio (IV, Random, 95% CI) | 0.99 [0.73, 1.33] |
| 8.3 Serious adverse events (Grade 3 or 4) Show forest plot | 2 | 1098 | Risk Ratio (M‐H, Random, 95% CI) | 1.22 [1.00, 1.49] |
| 8.4 Health‐related quality of life Show forest plot | 2 | 691 | Mean Difference (IV, Random, 95% CI) | 1.00 [0.68, 1.32] |
| 8.5 Response rate Show forest plot | 2 | 1117 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.77, 1.07] |
| 8.6 Minor adverse events (Grade 1 or 2) Show forest plot | 2 | 1098 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.74, 0.97] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 9.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 9.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 9.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 9.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 10.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 10.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 10.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 10.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 10.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 11.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 11.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 11.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 11.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 11.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 12.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 12.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 12.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 12.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 12.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 13.1 Progression‐free survival Show forest plot | 2 | 1381 | Hazard Ratio (IV, Random, 95% CI) | 0.68 [0.60, 0.77] |
| 13.2 Overall survival Show forest plot | 2 | 1381 | Hazard Ratio (IV, Random, 95% CI) | 0.88 [0.79, 0.99] |
| 13.3 Serious adverse events (Grade 3 or 4) Show forest plot | 2 | 1356 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [1.20, 1.42] |
| 13.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 13.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 14.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 14.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 14.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 14.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 14.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 14.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 15.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 15.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 15.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 15.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 15.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 16.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 16.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 16.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 16.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 16.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 17.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 17.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 17.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 17.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 17.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 17.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 18.1 Progression‐free survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 18.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| 18.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 18.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 18.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 18.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
