Systemic treatments for metastatic cutaneous melanoma

Comparison 1. Polychemotherapy versus single agent chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Overall survival Show forest plot	6	594	Hazard Ratio (IV, Random, 95% CI)	0.99 [0.85, 1.16]
Open in figure viewer Analysis 1.1 Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 1: Overall survival
1.2 Progression‐free survival Show forest plot	5	398	Hazard Ratio (IV, Random, 95% CI)	1.07 [0.91, 1.25]
Open in figure viewer Analysis 1.2 Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 2: Progression‐free survival
1.3 Tumour response Show forest plot	14	1885	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.02, 1.58]
Open in figure viewer Analysis 1.3 Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 3: Tumour response
1.4 Toxicity (≥ G3) Show forest plot	3	514	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [1.44, 2.71]
Open in figure viewer Analysis 1.4 Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 4: Toxicity (≥ G3)

Comparison 2. Chemotherapy ± tamoxifen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Overall survival Show forest plot	4	643	Hazard Ratio (IV, Random, 95% CI)	1.03 [0.80, 1.33]
Open in figure viewer Analysis 2.1 Comparison 2: Chemotherapy ± tamoxifen, Outcome 1: Overall survival
2.2 Progression‐free survival Show forest plot	2	475	Hazard Ratio (IV, Random, 95% CI)	1.06 [0.93, 1.22]
Open in figure viewer Analysis 2.2 Comparison 2: Chemotherapy ± tamoxifen, Outcome 2: Progression‐free survival
2.3 Tumour response Show forest plot	4	643	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.94, 1.89]
Open in figure viewer Analysis 2.3 Comparison 2: Chemotherapy ± tamoxifen, Outcome 3: Tumour response
2.4 Toxicity (≥ G3) Show forest plot	1	271	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.38, 1.28]
Open in figure viewer Analysis 2.4 Comparison 2: Chemotherapy ± tamoxifen, Outcome 4: Toxicity (≥ G3)

Comparison 3. Temozolomide versus dacarbazine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Overall survival Show forest plot	3	1313	Hazard Ratio (IV, Random, 95% CI)	0.98 [0.85, 1.12]
Open in figure viewer Analysis 3.1 Comparison 3: Temozolomide versus dacarbazine, Outcome 1: Overall survival
3.2 Progression‐free survival Show forest plot	3	1313	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.74, 1.03]
Open in figure viewer Analysis 3.2 Comparison 3: Temozolomide versus dacarbazine, Outcome 2: Progression‐free survival
3.3 Tumour response Show forest plot	3	1313	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.85, 1.73]
Open in figure viewer Analysis 3.3 Comparison 3: Temozolomide versus dacarbazine, Outcome 3: Tumour response
3.4 Toxicity (≥ G3) Show forest plot	2	1164	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.98, 1.35]
Open in figure viewer Analysis 3.4 Comparison 3: Temozolomide versus dacarbazine, Outcome 4: Toxicity (≥ G3)

Comparison 4. Chemotherapy ± interferon‐alpha

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Overall survival Show forest plot	11	1785	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.73, 1.04]
Open in figure viewer Analysis 4.1 Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 1: Overall survival
4.2 Progression‐free survival Show forest plot	6	1272	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.74, 1.01]
Open in figure viewer Analysis 4.2 Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 2: Progression‐free survival
4.3 Tumour response Show forest plot	15	2419	Risk Ratio (M‐H, Random, 95% CI)	1.36 [1.12, 1.66]
Open in figure viewer Analysis 4.3 Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 3: Tumour response
4.4 Toxicity (≥ G3) Show forest plot	3	791	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.37, 7.95]
Open in figure viewer Analysis 4.4 Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 4: Toxicity (≥ G3)

Comparison 5. Chemotherapy ± interleukin‐2

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Overall survival Show forest plot	2	644	Hazard Ratio (IV, Random, 95% CI)	0.95 [0.82, 1.11]
Open in figure viewer Analysis 5.1 Comparison 5: Chemotherapy ± interleukin‐2, Outcome 1: Overall survival
5.2 Progression‐free survival Show forest plot	1	363	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.70, 1.08]
Open in figure viewer Analysis 5.2 Comparison 5: Chemotherapy ± interleukin‐2, Outcome 2: Progression‐free survival
5.3 Tumour response Show forest plot	3	735	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.64, 1.13]
Open in figure viewer Analysis 5.3 Comparison 5: Chemotherapy ± interleukin‐2, Outcome 3: Tumour response

Comparison 6. Chemotherapy ± interferon‐alpha and interleukin‐2

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Overall survival Show forest plot	7	1307	Hazard Ratio (IV, Random, 95% CI)	0.94 [0.84, 1.06]
Open in figure viewer Analysis 6.1 Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 1: Overall survival
6.2 Progression‐free survival Show forest plot	6	964	Hazard Ratio (IV, Random, 95% CI)	0.90 [0.83, 0.99]
Open in figure viewer Analysis 6.2 Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 2: Progression‐free survival
6.3 Tumour response Show forest plot	7	1307	Risk Ratio (M‐H, Random, 95% CI)	1.36 [1.11, 1.67]
Open in figure viewer Analysis 6.3 Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 3: Tumour response
6.4 Toxicity (≥ G3) Show forest plot	2	657	Risk Ratio (M‐H, Random, 95% CI)	1.35 [1.14, 1.61]
Open in figure viewer Analysis 6.4 Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 4: Toxicity (≥ G3)

Comparison 7. Chemotherapy ± interferon‐alpha and interleukin‐2 (first line)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Overall survival Show forest plot	5	1118	Hazard Ratio (IV, Random, 95% CI)	0.96 [0.83, 1.10]
Open in figure viewer Analysis 7.1 Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 1: Overall survival
7.2 Progression‐free survival Show forest plot	4	775	Hazard Ratio (IV, Random, 95% CI)	0.86 [0.76, 0.99]
Open in figure viewer Analysis 7.2 Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 2: Progression‐free survival
7.3 Tumour response Show forest plot	5	1118	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.15, 1.83]
Open in figure viewer Analysis 7.3 Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 3: Tumour response
7.4 Toxicity (≥ G3) Show forest plot	1	241	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.12, 1.87]
Open in figure viewer Analysis 7.4 Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 4: Toxicity (≥ G3)

Comparison 8. Chemotherapy ± Bacille Calmette‐Guérin (BCG)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Overall survival Show forest plot	2	154	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.61, 1.25]
Open in figure viewer Analysis 8.1 Comparison 8: Chemotherapy ± Bacille Calmette‐Guérin (BCG), Outcome 1: Overall survival
8.2 Tumour response Show forest plot	6	770	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.12]
Open in figure viewer Analysis 8.2 Comparison 8: Chemotherapy ± Bacille Calmette‐Guérin (BCG), Outcome 2: Tumour response

Comparison 9. Chemotherapy ± Corynebacterium parvum

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Overall survival Show forest plot	4	242	Hazard Ratio (IV, Random, 95% CI)	0.95 [0.74, 1.22]
Open in figure viewer Analysis 9.1 Comparison 9: Chemotherapy ± Corynebacterium parvum, Outcome 1: Overall survival
9.2 Tumour response Show forest plot	7	537	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.77, 1.38]
Open in figure viewer Analysis 9.2 Comparison 9: Chemotherapy ± Corynebacterium parvum, Outcome 2: Tumour response

Comparison 10. Anti‐CTLA4 monoclonal antibodies (first line)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Overall survival Show forest plot	2	1157	Hazard Ratio (IV, Random, 95% CI)	0.81 [0.65, 1.01]
Open in figure viewer Analysis 10.1 Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 1: Overall survival
10.2 Progression‐free survival Show forest plot	1	502	Hazard Ratio (IV, Random, 95% CI)	0.76 [0.63, 0.92]
Open in figure viewer Analysis 10.2 Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 2: Progression‐free survival
10.3 Tumour response Show forest plot	2	1157	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.92, 1.77]
Open in figure viewer Analysis 10.3 Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 3: Tumour response
10.4 Toxicity (≥ G3) Show forest plot	2	1142	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.19, 2.42]
Open in figure viewer Analysis 10.4 Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 4: Toxicity (≥ G3)

Comparison 11. Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Overall survival Show forest plot	2	784	Hazard Ratio (IV, Random, 95% CI)	0.83 [0.52, 1.33]
Open in figure viewer Analysis 11.1 Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 1: Overall survival
11.2 Progression‐free survival Show forest plot	2	785	Hazard Ratio (IV, Random, 95% CI)	1.06 [0.75, 1.51]
Open in figure viewer Analysis 11.2 Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 2: Progression‐free survival
11.3 Tumour response Show forest plot	2	785	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.38, 1.47]
Open in figure viewer Analysis 11.3 Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 3: Tumour response
11.4 Toxicity (≥ G3) Show forest plot	2	785	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.69, 1.11]
Open in figure viewer Analysis 11.4 Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 4: Toxicity (≥ G3)

Comparison 12. Anti‐PD1 monoclonal antibodies versus chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Overall survival Show forest plot	1	418	Hazard Ratio (IV, Random, 95% CI)	0.42 [0.37, 0.48]
Open in figure viewer Analysis 12.1 Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 1: Overall survival
12.2 Progression‐free survival Show forest plot	2	957	Hazard Ratio (IV, Random, 95% CI)	0.49 [0.39, 0.61]
Open in figure viewer Analysis 12.2 Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 2: Progression‐free survival
12.3 Tumour response Show forest plot	3	1367	Risk Ratio (M‐H, Random, 95% CI)	3.42 [2.38, 4.92]
Open in figure viewer Analysis 12.3 Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 3: Tumour response
12.4 Toxicity (≥ G3) Show forest plot	3	1360	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.31, 0.97]
Open in figure viewer Analysis 12.4 Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 4: Toxicity (≥ G3)

Comparison 13. Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Overall survival Show forest plot	1	834	Hazard Ratio (IV, Random, 95% CI)	0.63 [0.60, 0.66]
Open in figure viewer Analysis 13.1 Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 1: Overall survival
13.2 Progression‐free survival Show forest plot	2	1465	Hazard Ratio (IV, Random, 95% CI)	0.54 [0.50, 0.60]
Open in figure viewer Analysis 13.2 Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 2: Progression‐free survival
13.3 Tumour response Show forest plot	2	1465	Risk Ratio (M‐H, Random, 95% CI)	2.47 [2.01, 3.04]
Open in figure viewer Analysis 13.3 Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 3: Tumour response
13.4 Toxicity (≥ G3) Show forest plot	2	1435	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.54, 0.91]
Open in figure viewer Analysis 13.4 Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 4: Toxicity (≥ G3)

Comparison 14. Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Progression‐free survival Show forest plot	2	738	Hazard Ratio (IV, Random, 95% CI)	0.40 [0.35, 0.46]
Open in figure viewer Analysis 14.1 Comparison 14: Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone, Outcome 1: Progression‐free survival
14.2 Tumour response Show forest plot	2	738	Risk Ratio (M‐H, Random, 95% CI)	3.50 [2.07, 5.92]
Open in figure viewer Analysis 14.2 Comparison 14: Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone, Outcome 2: Tumour response
14.3 Toxicity (≥ G3) Show forest plot	2	764	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.85, 2.92]
Open in figure viewer Analysis 14.3 Comparison 14: Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone, Outcome 3: Toxicity (≥ G3)

Comparison 15. Chemotherapy ± sorafenib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Overall survival Show forest plot	3	1194	Hazard Ratio (IV, Random, 95% CI)	1.00 [0.88, 1.14]
Open in figure viewer Analysis 15.1 Comparison 15: Chemotherapy ± sorafenib, Outcome 1: Overall survival
15.2 Progression‐free survival Show forest plot	3	1194	Hazard Ratio (IV, Random, 95% CI)	0.89 [0.73, 1.09]
Open in figure viewer Analysis 15.2 Comparison 15: Chemotherapy ± sorafenib, Outcome 2: Progression‐free survival
15.3 Tumour response Show forest plot	3	1194	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.91, 1.50]
Open in figure viewer Analysis 15.3 Comparison 15: Chemotherapy ± sorafenib, Outcome 3: Tumour response
15.4 Toxicity (≥ G3) Show forest plot	3	1194	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.93, 1.26]
Open in figure viewer Analysis 15.4 Comparison 15: Chemotherapy ± sorafenib, Outcome 4: Toxicity (≥ G3)

Comparison 16. Chemotherapy ± elesclomol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Overall survival Show forest plot	1	651	Hazard Ratio (IV, Random, 95% CI)	1.10 [0.92, 1.32]
Open in figure viewer Analysis 16.1 Comparison 16: Chemotherapy ± elesclomol, Outcome 1: Overall survival
16.2 Progression‐free survival Show forest plot	2	732	Hazard Ratio (IV, Random, 95% CI)	0.75 [0.50, 1.13]
Open in figure viewer Analysis 16.2 Comparison 16: Chemotherapy ± elesclomol, Outcome 2: Progression‐free survival
16.3 Tumour response Show forest plot	2	732	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.98, 3.50]
Open in figure viewer Analysis 16.3 Comparison 16: Chemotherapy ± elesclomol, Outcome 3: Tumour response
16.4 Toxicity (≥ G3) Show forest plot	1	651	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.00, 1.50]
Open in figure viewer Analysis 16.4 Comparison 16: Chemotherapy ± elesclomol, Outcome 4: Toxicity (≥ G3)

Comparison 17. Chemotherapy ± anti‐angiogenic drugs

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 Overall survival Show forest plot	2	324	Hazard Ratio (IV, Random, 95% CI)	0.60 [0.45, 0.81]
Open in figure viewer Analysis 17.1 Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 1: Overall survival
17.2 Progression‐free survival Show forest plot	2	324	Hazard Ratio (IV, Random, 95% CI)	0.69 [0.52, 0.92]
Open in figure viewer Analysis 17.2 Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 2: Progression‐free survival
17.3 Tumour response Show forest plot	2	324	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.96, 3.03]
Open in figure viewer Analysis 17.3 Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 3: Tumour response
17.4 Toxicity (≥ G3) Show forest plot	2	324	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.09, 5.32]
Open in figure viewer Analysis 17.4 Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 4: Toxicity (≥ G3)

Comparison 18. Single agent BRAF inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 Overall survival Show forest plot	2	925	Hazard Ratio (IV, Random, 95% CI)	0.40 [0.28, 0.57]
Open in figure viewer Analysis 18.1 Comparison 18: Single agent BRAF inhibitor, Outcome 1: Overall survival
18.2 Progression‐free survival Show forest plot	2	925	Hazard Ratio (IV, Random, 95% CI)	0.27 [0.21, 0.34]
Open in figure viewer Analysis 18.2 Comparison 18: Single agent BRAF inhibitor, Outcome 2: Progression‐free survival
18.3 Tumour response Show forest plot	2	925	Risk Ratio (M‐H, Random, 95% CI)	6.78 [4.84, 9.49]
Open in figure viewer Analysis 18.3 Comparison 18: Single agent BRAF inhibitor, Outcome 3: Tumour response
18.4 Toxicity (≥ G3) Show forest plot	2	925	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.48, 3.33]
Open in figure viewer Analysis 18.4 Comparison 18: Single agent BRAF inhibitor, Outcome 4: Toxicity (≥ G3)

Comparison 19. Single agent MEK inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
19.1 Overall survival Show forest plot	3	496	Hazard Ratio (IV, Random, 95% CI)	0.85 [0.58, 1.25]
Open in figure viewer Analysis 19.1 Comparison 19: Single agent MEK inhibitor, Outcome 1: Overall survival
19.2 Progression‐free survival Show forest plot	3	496	Hazard Ratio (IV, Random, 95% CI)	0.58 [0.42, 0.80]
Open in figure viewer Analysis 19.2 Comparison 19: Single agent MEK inhibitor, Outcome 2: Progression‐free survival
19.3 Tumour response Show forest plot	3	496	Risk Ratio (M‐H, Random, 95% CI)	2.01 [1.35, 2.99]
Open in figure viewer Analysis 19.3 Comparison 19: Single agent MEK inhibitor, Outcome 3: Tumour response
19.4 Toxicity (≥ G3) Show forest plot	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.08, 2.41]
Open in figure viewer Analysis 19.4 Comparison 19: Single agent MEK inhibitor, Outcome 4: Toxicity (≥ G3)

Comparison 20. Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
20.1 Overall survival Show forest plot	4	1784	Hazard Ratio (IV, Random, 95% CI)	0.70 [0.59, 0.82]
Open in figure viewer Analysis 20.1 Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 1: Overall survival
20.2 Progression‐free survival Show forest plot	4	1784	Hazard Ratio (IV, Random, 95% CI)	0.56 [0.44, 0.71]
Open in figure viewer Analysis 20.2 Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 2: Progression‐free survival
20.3 Tumour response Show forest plot	4	1784	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.20, 1.46]
Open in figure viewer Analysis 20.3 Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 3: Tumour response
20.4 Toxicity (≥ G3) Show forest plot	4	1774	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.85, 1.20]
Open in figure viewer Analysis 20.4 Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 4: Toxicity (≥ G3)

Comparison 21. Immunostimulating agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
21.1 Overall survival Show forest plot	4	1458	Hazard Ratio (IV, Random, 95% CI)	0.82 [0.67, 0.99]
Open in figure viewer Analysis 21.1 Comparison 21: Immunostimulating agents, Outcome 1: Overall survival
21.2 Progression‐free survival Show forest plot	4	1458	Hazard Ratio (IV, Random, 95% CI)	0.92 [0.74, 1.14]
Open in figure viewer Analysis 21.2 Comparison 21: Immunostimulating agents, Outcome 2: Progression‐free survival
21.3 Tumour response Show forest plot	4	1451	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.60, 2.50]
Open in figure viewer Analysis 21.3 Comparison 21: Immunostimulating agents, Outcome 3: Tumour response
21.4 Toxicity (≥ G3) Show forest plot	4	1458	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.77, 1.08]
Open in figure viewer Analysis 21.4 Comparison 21: Immunostimulating agents, Outcome 4: Toxicity (≥ G3)

RAS‐RAF‐MEK‐ERK pathway. Copyright © 2018 Claire Gorry: reproduced with permission.

Figure 1

Figure 2

Study flow diagram.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 5

Network plot

Figure 6

Interval plot: network meta‐analysis results for progression‐free survival. The network included eight treatment modalities. The effect measure is reported as hazard ratio (HR). CI: confidence interval; PrI: predictive interval.

Figure 7

Interval plot: network meta‐analysis results for high grade toxicity. The network included eight treatment modalities. The effect measure is reported as relative risk (RR). CI: confidence interval; PrI: predictive interval.

Figure 8

Ranking plot. Ranking plot representing simultaneously the efficacy (progression‐free survival) on the X axis and the acceptability (the inverse of toxicity) on the Y axis. The network included eight treatments for patients with metastatic melanoma. Optimal treatment should be characterised by both high efficacy and acceptability and should be in the right upper corner of this graph.

Figure 9

Comparison adjusted funnel plot for network meta‐analysis of progression‐free survival

Analysis 1.1

Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 1: Overall survival

Analysis 1.2

Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 2: Progression‐free survival

Analysis 1.3

Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 3: Tumour response

Analysis 1.4

Comparison 1: Polychemotherapy versus single agent chemotherapy, Outcome 4: Toxicity (≥ G3)

Analysis 2.1

Comparison 2: Chemotherapy ± tamoxifen, Outcome 1: Overall survival

Analysis 2.2

Comparison 2: Chemotherapy ± tamoxifen, Outcome 2: Progression‐free survival

Analysis 2.3

Comparison 2: Chemotherapy ± tamoxifen, Outcome 3: Tumour response

Analysis 2.4

Comparison 2: Chemotherapy ± tamoxifen, Outcome 4: Toxicity (≥ G3)

Analysis 3.1

Comparison 3: Temozolomide versus dacarbazine, Outcome 1: Overall survival

Analysis 3.2

Comparison 3: Temozolomide versus dacarbazine, Outcome 2: Progression‐free survival

Analysis 3.3

Comparison 3: Temozolomide versus dacarbazine, Outcome 3: Tumour response

Analysis 3.4

Comparison 3: Temozolomide versus dacarbazine, Outcome 4: Toxicity (≥ G3)

Analysis 4.1

Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 1: Overall survival

Analysis 4.2

Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 2: Progression‐free survival

Analysis 4.3

Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 3: Tumour response

Analysis 4.4

Comparison 4: Chemotherapy ± interferon‐alpha, Outcome 4: Toxicity (≥ G3)

Analysis 5.1

Comparison 5: Chemotherapy ± interleukin‐2, Outcome 1: Overall survival

Analysis 5.2

Comparison 5: Chemotherapy ± interleukin‐2, Outcome 2: Progression‐free survival

Analysis 5.3

Comparison 5: Chemotherapy ± interleukin‐2, Outcome 3: Tumour response

Analysis 6.1

Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 1: Overall survival

Analysis 6.2

Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 2: Progression‐free survival

Analysis 6.3

Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 3: Tumour response

Analysis 6.4

Comparison 6: Chemotherapy ± interferon‐alpha and interleukin‐2, Outcome 4: Toxicity (≥ G3)

Analysis 7.1

Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 1: Overall survival

Analysis 7.2

Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 2: Progression‐free survival

Analysis 7.3

Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 3: Tumour response

Analysis 7.4

Comparison 7: Chemotherapy ± interferon‐alpha and interleukin‐2 (first line), Outcome 4: Toxicity (≥ G3)

Analysis 8.1

Comparison 8: Chemotherapy ± Bacille Calmette‐Guérin (BCG), Outcome 1: Overall survival

Analysis 8.2

Comparison 8: Chemotherapy ± Bacille Calmette‐Guérin (BCG), Outcome 2: Tumour response

Analysis 9.1

Comparison 9: Chemotherapy ± Corynebacterium parvum, Outcome 1: Overall survival

Analysis 9.2

Comparison 9: Chemotherapy ± Corynebacterium parvum, Outcome 2: Tumour response

Analysis 10.1

Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 1: Overall survival

Analysis 10.2

Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 2: Progression‐free survival

Analysis 10.3

Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 3: Tumour response

Analysis 10.4

Comparison 10: Anti‐CTLA4 monoclonal antibodies (first line), Outcome 4: Toxicity (≥ G3)

Analysis 11.1

Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 1: Overall survival

Analysis 11.2

Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 2: Progression‐free survival

Analysis 11.3

Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 3: Tumour response

Analysis 11.4

Comparison 11: Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line), Outcome 4: Toxicity (≥ G3)

Analysis 12.1

Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 1: Overall survival

Analysis 12.2

Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 2: Progression‐free survival

Analysis 12.3

Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 3: Tumour response

Analysis 12.4

Comparison 12: Anti‐PD1 monoclonal antibodies versus chemotherapy, Outcome 4: Toxicity (≥ G3)

Analysis 13.1

Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 1: Overall survival

Analysis 13.2

Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 2: Progression‐free survival

Analysis 13.3

Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 3: Tumour response

Analysis 13.4

Comparison 13: Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies, Outcome 4: Toxicity (≥ G3)

Analysis 14.1

Comparison 14: Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone, Outcome 1: Progression‐free survival

Analysis 14.2

Comparison 14: Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone, Outcome 2: Tumour response

Analysis 14.3

Comparison 14: Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone, Outcome 3: Toxicity (≥ G3)

Analysis 15.1

Comparison 15: Chemotherapy ± sorafenib, Outcome 1: Overall survival

Analysis 15.2

Comparison 15: Chemotherapy ± sorafenib, Outcome 2: Progression‐free survival

Analysis 15.3

Comparison 15: Chemotherapy ± sorafenib, Outcome 3: Tumour response

Analysis 15.4

Comparison 15: Chemotherapy ± sorafenib, Outcome 4: Toxicity (≥ G3)

Analysis 16.1

Comparison 16: Chemotherapy ± elesclomol, Outcome 1: Overall survival

Analysis 16.2

Comparison 16: Chemotherapy ± elesclomol, Outcome 2: Progression‐free survival

Analysis 16.3

Comparison 16: Chemotherapy ± elesclomol, Outcome 3: Tumour response

Analysis 16.4

Comparison 16: Chemotherapy ± elesclomol, Outcome 4: Toxicity (≥ G3)

Analysis 17.1

Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 1: Overall survival

Analysis 17.2

Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 2: Progression‐free survival

Analysis 17.3

Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 3: Tumour response

Analysis 17.4

Comparison 17: Chemotherapy ± anti‐angiogenic drugs, Outcome 4: Toxicity (≥ G3)

Analysis 18.1

Comparison 18: Single agent BRAF inhibitor, Outcome 1: Overall survival

Analysis 18.2

Comparison 18: Single agent BRAF inhibitor, Outcome 2: Progression‐free survival

Analysis 18.3

Comparison 18: Single agent BRAF inhibitor, Outcome 3: Tumour response

Analysis 18.4

Comparison 18: Single agent BRAF inhibitor, Outcome 4: Toxicity (≥ G3)

Analysis 19.1

Comparison 19: Single agent MEK inhibitor, Outcome 1: Overall survival

Analysis 19.2

Comparison 19: Single agent MEK inhibitor, Outcome 2: Progression‐free survival

Analysis 19.3

Comparison 19: Single agent MEK inhibitor, Outcome 3: Tumour response

Analysis 19.4

Comparison 19: Single agent MEK inhibitor, Outcome 4: Toxicity (≥ G3)

Analysis 20.1

Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 1: Overall survival

Analysis 20.2

Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 2: Progression‐free survival

Analysis 20.3

Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 3: Tumour response

Analysis 20.4

Comparison 20: Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor, Outcome 4: Toxicity (≥ G3)

Analysis 21.1

Comparison 21: Immunostimulating agents, Outcome 1: Overall survival

Analysis 21.2

Comparison 21: Immunostimulating agents, Outcome 2: Progression‐free survival

Analysis 21.3

Comparison 21: Immunostimulating agents, Outcome 3: Tumour response

Analysis 21.4

Comparison 21: Immunostimulating agents, Outcome 4: Toxicity (≥ G3)

Summary of findings 1. Anti‐PD1 monoclonal antibodies versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Anti‐PD1 monoclonal antibodies compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: anti‐PD1 monoclonal antibodies Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	Anti‐PD1
Overall survival†	600 per 1000†	320 per 1000† (290 to 360)	HR 0.42 (0.37 to 0.48)	N = 418 (n = 1)	⊕⊕⊕⊕ high^a	‐
Progression‐free survival†	850 per 1000†	610 per 1000† (520 to 690)	HR 0.49 (0.39 to 0.61)	N = 957 (n = 2)	⊕⊕⊕⊝ moderate^b	‐
Tumour response	81 per 1000	277 per 1000 (193 to 398)	RR 3.42 (2.38 to 4.92)	N = 1367 (n = 3)	⊕⊕⊕⊕ high^a	‐
Toxicity (≥ G3)	300 per 1000	165 per 1000 (93 to 291)	RR0.55 (0.31 to 0.97)	N = 1360 (n = 3)	⊕⊕⊝⊝ low^c	‐
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; HR: hazard ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence. ^b Downgraded by one level: inconsistency (between‐study heterogeneity). ^c Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (CI includes both a meaningful benefit (relative risk reduction > 25%) and a small/null benefit (relative risk reduction < 10%)).

Summary of findings 1. Anti‐PD1 monoclonal antibodies versus chemotherapy

Summary of findings 2. Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Anti‐PD1 monoclonal antibodies compared with anti‐CTLA4 monoclonal antibodies for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: anti‐PD1 monoclonal antibodies Comparison: anti‐CTLA4 monoclonal antibodies
	Assumed risk	Corresponding risk
	Anti‐CTLA4	Anti‐PD1
Overall survival†	600 per 1000†	438 per 1000† (423 to 454)	HR 0.63 (0.60 to 0.66)	N = 764 (n = 1)	⊕⊕⊕⊕ high^a	‐
Progression‐free survival†	850 per 1000†	641 per 1000† (612 to 679)	HR 0.54 (0.50 to 0.60)	n = 1465 (n = 2)	⊕⊕⊕⊕ high^a	‐
Tumour response	157 per 1000	388 per 1000 (315 to 477)	RR 2.47 (2.01 to 3.04)	N = 1465 (n = 2)	⊕⊕⊕⊕ high^a	‐
Toxicity (≥ G3)	398 per 1000	278 per 1000 (215 to 362)	RR 0.70 (0.54 to 0.91)	N = 1465 (n = 2)	⊕⊕⊝⊝ low^b	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; RR: risk ratio; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence. ^b Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (CI includes both a meaningful benefit (relative risk reduction > 25%) and a small/null benefit (relative risk reduction < 10%).

Summary of findings 2. Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies

Summary of findings 3. Anti‐CTLA4 monoclonal antibodies plus chemotherapy versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative Effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Anti‐CTLA4 monoclonal antibodies plus chemotherapy compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: anti‐CTLA4 monoclonal antibodies plus chemotherapy (combo) Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	Combo
Overall survival†	600 per 1000†	524 per 1000† (449 to 604)	HR 0.81 (0.65 to 1.01)	N = 1157 (n = 2)	⊕⊕⊝⊝ low^a	‐
Progression‐free survival†	850 per 1000†	763 per 1000† (697 to 825)	HR 0.76 (0.63 to 0.92)	N = 502 (n = 1)	⊕⊕⊕⊝ moderate^b	‐
Tumour response	100 per 1000	128 per 1000 (92 to 177)	RR 1.28 (0.92 to 1.77)	N = 1157 (n = 2)	⊕⊕⊕⊝ moderate^c	‐
Toxicity (≥ G3)	352 per 1000	595 per 1000 (419 to 852)	RR 1.69 (1.19 to 2.42)	N = 1142 (n = 2)	⊕⊕⊕⊝ moderate^d	‐
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (CI includes both a meaningful benefit (relative risk reduction > 25%) and a harmful effect). ^b Downgraded by one level: imprecision (CI includes both a meaningful benefit (relative risk reduction > 25%) and a small/null benefit (relative risk reduction < 10%)). ^c Downgraded by one level: imprecision (CI includes both a meaningful benefit (relative risk increase > 25%) and a harmful effect). ^d Downgraded by one level: inconsistency (between‐study heterogeneity).

Summary of findings 3. Anti‐CTLA4 monoclonal antibodies plus chemotherapy versus chemotherapy

Summary of findings 4. Anti‐CTLA4 monoclonal antibodies with versus without anti‐PD1 monoclonal antibodies

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Anti‐CTLA4 plus anti‐PD1 monoclonal antibodies compared with anti‐CTLA4 monoclonal antibodies for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: Anti‐CTLA4 plus Anti‐PD1 monoclonal antibodies (combo) Comparison: Anti‐CTLA4 monoclonal antibodies
	Assumed risk	Corresponding risk
	Anti‐CTLA4	Combo
Overall survival	See comment	See comment	See comment	See comment	See comment	Outcome not measured
Progression‐free survival†	750 per 1000†	425 per 1000† (375 to 478)	HR 0.40 (0.35 to 0.46)	N = 738 (n = 2)	⊕⊕⊕⊕ high^a	‐
Tumour response	182 per 1000	636 per 1000 (376 to 1073)	RR 3.50 (2.07 to 5.92)	N = 738 (n = 2)	⊕⊕⊕⊕ high^a	‐
Toxicity (≥ G3)	521 per 1000	818 per 1000 (442 to 1521)	RR 1.57 (0.85 to 2.92)	N = 764 (n = 2)	⊕⊕⊝⊝ low^b	‐
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. progression rates). CI: confidence interval
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year progression‐free survival rate = 25%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence. ^b Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (CI includes both a meaningful harm (relative risk increase > 25%) and a beneficial effect)

Summary of findings 4. Anti‐CTLA4 monoclonal antibodies with versus without anti‐PD1 monoclonal antibodies

Summary of findings 5. BRAF inhibitors versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
BRAF inhibitors compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: BRAF inhibitors Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	BRAF inhibitors
Overall survival†	600 per 1000†	307 per 1000† (226 to 407)	HR 0.40 (0.28 to 0.57)	N = 925 (n = 2)	⊕⊕⊕⊕ high^a	‐
Progression‐free survival†	850 per 1000†	401 per 1000† (328 to 475)	HR 0.27 (0.21 to 0.34)	N = 925 (n = 2)	⊕⊕⊕⊕ high^a	‐
Tumour response	82 per 1000	556 per 1000 (397 to 778)	RR 6.78 (4.84 to 9.49)	N = 925 (n = 2)	⊕⊕⊕⊕ high^a	‐
Toxicity (≥ G3)	341 per 1000	433 per 1000 (163 to 1135)	RR 1.27 (0.48 to 3.33)	N = 408 (n = 2)	⊕⊕⊝⊝ low^b	‐
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence. ^b Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (CI includes both a meaningful harm (relative risk increase > 25%) and a meaningful benefit (relative risk reduction > 25%)).

Summary of findings 5. BRAF inhibitors versus chemotherapy

Summary of findings 6. MEK inhibitors versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
MEK inhibitors compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: MEK inhibitors Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	MEK inhibitors
Overall survival†	600 per 1000†	541 per 1000† (412 to 682)	HR 0.85 (0.58 to 1.25)	N = 496 (n = 3)	⊕⊕⊝⊝ low^a	‐
Progression‐free survival†	850 per 1000†	667 per 1000† (549 to 781)	HR 0.58 (0.42 to 0.80)	N = 496 (n = 3)	⊕⊕⊕⊝ moderate^b	‐
Tumour response	138 per 1000	277 per 1000 (186 to 413)	RR 2.01 (1.35 to 2.99)	N = 496 (n = 3)	⊕⊕⊕⊕ high^c	‐
Toxicity (≥ G3)	413 per 1000	665 per 1000 (446 to 995)	RR 1.61 (1.08 to 2.41)	N = 91 (n = 1)	⊕⊕⊕⊝ moderate^d	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; RR: risk ratio; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (CI includes both a meaningful benefit (relative risk reduction > 25%) and a harmful effect). ^b Downgraded by one level: inconsistency (between‐study heterogeneity). ^c Not downgraded: high‐quality evidence. ^d Downgraded by one level: imprecision (sample size lower than optimal information size, calculated to be equal to 400 participants).

Summary of findings 6. MEK inhibitors versus chemotherapy

Summary of findings 7. BRAF plus MEK inhibitors versus BRAF inhibitors

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
BRAF plus MEK inhibitors compared with BRAF inhibitors for the treatment of metastatic melanoma
Patient or population: people cutaneous melanoma Settings: hospital (metastatic disease) Intervention: BRAF inhibitor plus MEK inhibitor (combo) Comparison: BRAF inhibitor
	Assumed risk	Corresponding risk
	BRAF inhibitor	Combo
Overall survival†	350 per 1000†	260 per 1000† (204 to 321)	HR 0.70 (0.59 to 0.82)	N = 1784 (n = 4)	⊕⊕⊕⊕ high^a	‐
Progression‐free survival†	700 per 1000†	490 per 1000† (411 to 574)	HR 0.56 (0.44 to 0.71)	N = 1784 (n = 4)	⊕⊕⊕⊝ moderate^b	‐
Tumour response	494 per 1000	652 per 1000 (593 to 721)	RR 1.32 (1.20 to 1.46)	N = 1784 (n = 4)	⊕⊕⊕⊕ high^a	‐
Toxicity (≥ G3)	495 per 1000	500 per 1000 (421 to 594)	RR 1.01 (0.85 to 1.20)	N = 1774 (n = 4)	⊕⊕⊕⊝ moderate^b	‐
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI confidence interval; HR: hazard ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 65%. Assumed risk in the control population: 1‐year progression‐free survival rate = 30%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence. ^b Downgraded by one level: inconsistency (between‐study heterogeneity).

Summary of findings 7. BRAF plus MEK inhibitors versus BRAF inhibitors

Summary of findings 8. Anti‐angiogenic drugs plus chemotherapy versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Anti‐angiogenic drugs plus chemotherapy compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: Anti‐angiogenic drug plus chemotherapy (combo) Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	Combo
Overall survival†	600 per 1000†	423 per 1000† (338 to 524)	HR 0.60 (0.45 to 0.81)	N = 324 (n = 2)	⊕⊕⊕⊝ moderate^a	‐
Progression‐free survival†	850 per 1000†	730 per 1000† (627 to 825)	HR 0.69 (0.52 to 0.92)	N = 324 (n = 2)	⊕⊕⊕⊝ moderate^a	‐
Tumour response	104 per 1000	178 per 1000 (100 to 315)	RR 1.71 (0.96 to 3.03)	N = 324 (n = 2)	⊕⊕⊕⊝ moderate^a	‐
Toxicity (≥ G3)	272 per 1000	185 per 1000 (25 to 1447)	RR 0.68 (0.09 to 5.32)	N = 324 (n = 2)	⊕⊕⊝⊝ low^b	‐
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Downgraded by one level: imprecision (sample size lower than optimal information size, calculated to be equal to 400 participants). ^b Downgraded by two levels: inconsistency (between‐study heterogeneity) and imprecision (sample size lower than optimal information size, calculated to be equal to 400 participants).

Summary of findings 8. Anti‐angiogenic drugs plus chemotherapy versus chemotherapy

Summary of findings 9. Biochemotherapy versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Biochemotherapy compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: biochemotherapy (chemotherapy combined with both interferon‐alpha and interleukin‐2) Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	Biochemotherapy
Overall survival†	600 per 1000†	577 per 1000† (537 to 621)	HR 0.94 (0.84 to 1.06)	N = 1317 (n = 7)	⊕⊕⊕⊕ high^a	‐
Progression‐free survival†	850 per 1000 °	818 per 1000† (793 to 847)	HR 0.90 (0.83 to 0.99)	N = 964 (n = 6)	⊕⊕⊕⊕ high^a	‐
Tumour response	192 per 1000	262 per 1000 (214 to 321)	RR 1.36 (1.12 to 1.66)	N = 770 (n = 7)	⊕⊕⊕⊕ high^a	‐
Toxicity (≥ G3)	631 per 1000	852 per 1000 (719 to 1000)	RR 1.35 (1.14 to 1.61)	N = 631 (n = 2)	⊕⊕⊕⊕ high^a	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; RR: risk ratio; HR: hazard ratio.
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence.

Summary of findings 9. Biochemotherapy versus chemotherapy

Summary of findings 10. Polychemotherapy versus chemotherapy

Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Polychemotherapy compared with chemotherapy for the treatment of metastatic melanoma
Patient or population: people with cutaneous melanoma Settings: hospital (metastatic disease) Intervention: polychemotherapy Comparison: chemotherapy
	Assumed risk	Corresponding risk
	Chemotherapy	Polychemotherapy
Overall survival†	600 per 1000†	596 per 1000† (541 to 655)	HR 0.99 (0.85 to 1.16)	N = 594 (n = 6)	⊕⊕⊕⊕ high^a	‐
Progression‐freesurvival†	850 per 1000†	869 per 1000† (822 to 907)	HR 1.07 (0.91 to 1.25)	N = 398 (n = 5)	⊕⊕⊕⊕ high^a	‐
Tumour response	143 per 1000	182 per 1000 (146 to 226)	RR 1.27 (1.02 to 1.58)	N = 1885 (n = 5)	⊕⊕⊕⊝ moderate^b	‐
Toxicity (≥ G3)	189 per 1000	372 per 1000 (272 to 512)	RR 1.97 (1.44 to 2.71)	N = 390 (n = 3)	⊕⊕⊕⊝ moderate^c	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). † Numbers presented refer to event rates (i.e. death rates and progression rates). CI: confidence interval; RR: risk ratio; HR: hazard ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
Assumed risk in the control population: 1‐year overall survival rate = 40%. Assumed risk in the control population: 1‐year progression‐free survival rate = 15%. Assumed risk in the control population: tumour response rate across control arms of included trials. Assumed risk in the control population: toxicity rate across control arms of included trials. ^a Not downgraded: high‐quality evidence. ^b Downgraded by one level: imprecision (CI includes both a meaningful benefit (relative risk increase > 25%) and a small/null benefit (relative risk increase < 10%)). ^c Downgraded by one level: imprecision (sample size lower than optimal information size, calculated to be equal to 400 participants).

Summary of findings 10. Polychemotherapy versus chemotherapy

Table 1. Glossary of terms used

Term	Explanation
Actinomycin‐D	A polypeptide used as an antibiotic and antineoplastic agent as a result of its ability to inhibit transcription
AJCC TNM staging	This is the most widely used tumour staging classification system, which has been developed and constantly updated by the American Joint Committee on Cancer (AJCC) for describing the extent of disease progression in people with cancer. It uses in part the TNM scoring system: tumour size, lymph nodes affected, metastases. Individuals affected by specific tumour type are assigned to categories describing risk of death
AJCC TNM stage III	People at this disease stage have melanoma metastasis in their regional lymph node (i.e. the first lymph nodes draining the skin area affected by the melanoma)
AJCC TNM stage IIIC	Stage IIIC is a higher risk subgroup among people with lymph node metastasis. The category includes people with all primary tumour stages (T stages) and those with clinically positive lymph nodes, or 4 or more positive lymph nodes
AJCC TNM stage IV	People with this disease stage have melanoma metastasis to distant sites (e.g. lung, liver, brain, bone)
Anti‐angiogenic agents	Drugs aimed to disrupt tumour vascularisation and reduce blood supply to malignant cells; examples include bevacizumab and endostar
Antigen	A substance that invokes the body's immune response
Aranoza	An alkylating agent that is used as a chemotherapy drug for various cancers including melanoma as part of combination chemotherapy regimens
Bacille Calmette‐Guérin (BCG)	BCG is a vaccine used in the prevention of tuberculosis. However, it is also a form of cancer immunotherapy with established effects in superficial (non‐muscle invading) bladder cancer
Bevacizumab	Bevacizumab (Avastin) is an angiogenesis inhibitor approved for use for people with various metastatic cancers. Bevacizumab acts through blockade of vascular endothelial growth factor A (VEGF‐A) that prevents development of new vessels necessary for tumours to grow
Bleomycin	An antineoplastic agent used in chemotherapy regimens for various tumours. Belomycin acts through cleavage of DNA within cells
Biochemotherapy	A combination of chemotherapy plus immunostimulating cytokines, such as interleukin‐2 and interferon‐alpha
Bosentan	An endothelin receptor inhibitor that causes reduced DNA synthesis and promotes apoptosis through competitive antagonism with the anti‐apoptotic factor endothelin‐1, often secreted by cancer cells in an autocrine or paracrine manner
BRAF	A gene that makes a protein called B‐Raf. BRAF is involved in sending signals within cells that direct their growth. In some cancers, this gene has mutated (Melanoma Institute Australia 2017)
Carmustine	An alkylating agent that prevents DNA replication and cell proliferation used in chemotherapy for various cancers
Cobimetinib	An inhibitor of MAPK kinase (MEK) approved for use in metastatic melanoma with BRAF V600E/K mutation usually in combination with a BRAF inhibitor
Corynebacterium parvum	C parvum is an aerobic, gram positive bacterium that has been reported to have antineoplastic potential
Cyclophosphamide	An alkylating agent used in auto‐immune diseases and various tumours as a chemotherapy drug
Cytokine	Small proteins produced by a broad range of cells that are important in cell signalling; they are immunostimulating agents
Cytotoxic	Cell killing
CTLA4 (cytotoxic T‐cell lymphocyte‐associated antigen‐4)	CTLA4 is a receptor located on the surface of T‐cells that down regulates the immune system (an immune checkpoint). The inhibition of this receptor with monoclonal antibodies, such as ipilimumab and tremelimumab, 'unleashes' the immune response to fight against malignant cells
Dabrafenib	An inhibitor of the BRAF kinase that has been approved for people with advanced melanoma carrying the BRAF V600E mutation
Dacarbazine	A chemotherapy drug that belongs to the family of alkylating agents that is used in the treatment of various cancers, including melanoma
Dendritic cell	These are antigen‐presenting cells that link the innate to the adaptive immune systems via processing antigens and presenting them to T‐lymphocytes. Their role is crucial for proper functioning of vaccines, including cancer vaccines
Elesclomol	A drug that causes the accumulation of reactive oxygen species to trigger apoptosis in cancer cells via oxidative stress. It is approved for use for people with metastatic melanoma
Endostar	A modified recombinant human endostatin that acts as an anti‐angiogenic agent to prevent the formation of new blood vessels that are necessary for tumour growth and survival
Fotemustine	A chemotherapy drug that belongs to the family of alkylating agents and has been approved for the treatment of metastatic melanoma
G3 and G4	G3 (grade 3) and G4 (grade 4) toxicity refers to the highest degree of adverse events due to a systemic treatment. This system grades the toxicity related to a given system or organ (e.g. hepatic, cardiac, haematologic)
gp100	A known melanoma antigen that can be applied to develop a cancer vaccine through processing and presentation by dendritic cells to lymphocytes
Granulocyte macrophage ‐ colony‐stimulating factor (GM‐CSF)	A cytokine that stimulates stem cells to give rise to granulocytes and monocytes and boosts the immune system
Hydroxyurea	A chemotherapy agent that acts through reducing the generation of deoxyribonucleotides, the building blocks of DNA, to inhibit adequate synthesis of DNA. It is used as a chemotherapy drug for people with myeloproliferative disorders
Immune checkpoints	Signalling proteins that protect against auto‐immunity and regulate the immune response; these checkpoints can be hijacked by cancer cells to evade T‐cell‐mediated death, i.e. stopping an immune response to the tumour. CTLA4 and PD1 are both immune checkpoints
Immune checkpoint inhibitors	Drugs that override the signalling/activation of immune checkpoints to encourage cytotoxic T‐cell recognition of cancer (i.e. an immune response). These are monoclonal antibodies blocking either CTLA4 or PD1 (two immune checkpoints), known as anti‐CTLA4 and anti‐PD1 monoclonal antibodies
Immunomodulating	Stimulates or suppresses the immune system
Immunostimulating	Stimulates an immune response
Interferon‐alpha	Interferon‐alpha is used for the postoperative treatment of people with AJCC TNM stages II (primary tumour at high risk of disease progression with negative lymph nodes) and III (positive lymph nodes) and to enhance the efficacy of chemotherapy in those who have metastatic melanoma
Interleukin‐2	Interleukin‐2 is a protein that regulates the activities of leucocytes (particularly lymphocytes) that are responsible for immunity. The receptor for interleukin‐2 is expressed by lymphocytes. A recombinant form of human interleukin‐2 has been approved by the FDA for the treatment of melanoma and renal cell cancer
Lomustine	An oral alkylating chemotherapeutic agent used mainly to treat brain tumours because it crosses the blood‐brain barrier
MEK	Mitogen‐activated protein kinase (MEK) is part of the MAPK signalling pathway (see 'RAS‐RAF‐MEK‐ERK pathway' below), which is activated in melanoma
Monoclonal antibodies	Monoclonal antibodies are a type of targeted drug therapy; they work by recognising and finding specific proteins on cancer cells (they work in different ways depending on the protein they are targeting) (Cancer Research UK 2017)
Oblimersen	A bcl‐2 antisense oligodeoxynucleotide that reduces cancer cell survival and proliferation by blocking the generation of the anti‐apoptotic protein bcl‐2 thus promoting programmed cell death in cancer cells
Oncogene	A gene thats activation or over expression favours cancer growth
Paclitaxel	A chemotherapy agent targeting the protein tubulin. The drug interferes with the dynamics of microtubule formation and breakdown leading to problems during cell division and triggering of apoptosis. DHA‐ and nab‐paclitaxel are modified forms of the drug
PD1 (programmed cell death protein‐1)	PD1 is a receptor located on the surface of the T‐cells that down regulates the immune system (an immune checkpoint). The inhibition of this receptor with monoclonal antibodies, such as nivolumab and pembrolizumab, 'unleashes' immune response to fight against malignant cells
PF‐3512676	An synthetic oligonucleotide that acts as a Toll‐like receptor‐9 (TLR‐9) agonist. It is used as an immunomodulatory agent alone, or in combination with chemotherapy, to boost anti‐tumour effects by enhancing B‐cell proliferation and antigen‐specific antibody production and cytokine secretion
Polychemotherapy	A combination of multiple chemotherapeutic agents
Procarbazine	An alkylating agent used as an antineoplastic chemotherapy drug in various tumours such as glioblastoma multiforme and Hodgkin's lymphoma
Programmed death‐1 (PD‐1)	PD‐1 is an inhibitory receptor located on the surface of the T‐cells that down regulates the immune system when bound by its ligands (PD‐L1 and PD‐L2, often found on cancer cells). The inhibition of this receptor with monoclonal antibodies, such as pembrolizumab and nivolumab, releases the brake on immune cells thus allowing them to freely fight malignant cells
Ramucirumab	A human monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR2) to block VEGF binding and thus inhibit angiogenesis. It is approved for use in advanced gastric adenocarcinoma and metastatic non‐small cell lung carcinoma
RAS‐RAF‐MEK‐ERK pathway	This is also known as 'MAPK/ERK pathway', which is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the nucleus of the cell (where DNA is located). When one of the proteins in the pathway is mutated, it can be stuck in the 'on' or 'off' position, which is a necessary step in the development of many cancers, including melanoma. Drugs, such as BRAF and MEK inhibitors, can reverse this switch
Small‐molecule inhibitors	Low molecular weight drugs targeting molecules mutated or overexpressed in tumours; examples include BRAF inhibitors (which block the BRAF protein) or MEK inhibitors (which block the MEK protein)
Sorafenib	An inhibitor of various tyrosine protein kinases including RAF
Selumetinib	An inhibitor of the MAPK kinase (MEK) downstream of BRAF
T‐cell	A white blood cell type, which plays a key role in immunity
Tasisulam	A small‐molecule agent that induces apoptosis through the intrinsic mitochondrial pathway
Tamoxifen	A cytostatic hormonal therapeutic agent used mainly as a treatment for oestrogen receptor positive breast cancer. Tamoxifen acts through competing with oestrogen for its receptor thus reducing oestrogen‐related effects in breast tissue such as DNA synthesis and cell proliferation
Temozolomide	An oral alkylating agent that can be used in chemotherapy regimens for various cancers such as glioblastoma multiforme
Trametinib	An inhibitor of MAPK kinase (MEK) 1 and 2 approved for use in people with V600E‐mutated metastatic melanoma
Vemurafenib	A small‐molecule inhibitor of mutated BRAF, an oncogene involved in cell survival or proliferation
Vincristine	An anti‐mitotic agent that binds tubulin thus preventing cell proliferation and triggering apoptosis
Vindesine	An anti‐mitotic agent that acts by targeting microtubules and preventing cell division thus useful as a chemotherapy drug in various cancers
Vitespen	A tumour‐derived heat shock protein that is used as an adjuvant in cancer immunotherapy

Table 1. Glossary of terms used

Table 2. Reasons for excluding 39 studies from meta‐analysis

Study ID	Reason for exclusion from meta‐analysis
Hamid 2014	Single study investigating tasisulam
Kefford 2010	Single study investigating bosentan
Hofmann 2011	Single study comparing dacarbazine and best supportive care
Schadendorf 2006	Single study investigating dendritic cells therapy
Agarwala 2002	Single study investigating histamine with interleukin‐2
Bajetta 1985	Different polychemotherapy regimens not compared in other studies
Beretta 1976	Different polychemotherapy regimens not compared in other studies
Cocconi 1992	Different polychemotherapy regimens not compared in other studies
Dummer 2006	Different PEG‐interferon schedules tested
Flaherty 2001	Inpatient and outpatient interleukin‐2‐based regimens not compared in other studies
Glaspy 2009	Different lenalidomide schedules not compared in other studies
Jelic 2002	Different polychemotherapy regimens not compared in other studies
Keilholz 1997	Study comparing biochemotherapy versus biotherapy
Legha 1996	Study comparing alternating and sequential biochemotherapy and chemotherapy
Miller 1989	Single study investigating Indomethacine with interferon
Moon 1975	Different single‐agent chemotherapy regimens not compared in other studies
Presant 1982	Different polychemotherapy regimens not compared in other studies
Richtig 2004	Different temozolomide and interferon schedules tested
Wittes 1978	Different polychemotherapy regimens not compared in other studies
Vuoristo 2005	Different interferon‐based regimens not compared in other studies
Punt 2006	Different biochemotherapy regimens not compared in other studies
Reichle 2007	Single study investigating chemotherapy and COX‐2 inhibitor
Sparano 1993	Single study comparing interleukin‐2 with versus without interferon‐alpha
Wolchok 2010	Different ipilimumab schedules tested
Avril 2004	Single study comparing fotemustine and dacarbazine
O'Day 2011	Single study testing Intetumumab
Ranson 2007	Single study testing lomeguatrib
Hersh 2015	Single study testing nab‐paclitaxel
Bedikian 2006	Single study testing oblimersen
Bedikian 2011	Single study testing DHA‐paclitaxel
Weber 2009	Single study testing PF‐3512676
Carvajal 2014	Single study testing ramucirumab
Balch 1984	Single study testing dacarbazine and C parvum after surgery
Eigentler 2008	Single study testing vindesine after surgery
Lawson 2015	Single study testing GM‐CSF and a polypeptide vaccination after surgery
Eisen 2010	Single study testing lenalidomide
Middleton 2015	Single study testing veliparib
Testori 2008	Single study testing vetaspen

Table 2. Reasons for excluding 39 studies from meta‐analysis

Table 3. Studies included in meta‐analysis

Comparison	Experimental (class of) drug	Study ID
Polychemotherapy versus single agent chemotherapy	Polychemotherapy	Bellett 1976
		Carter 1975
		Chapman 1999
		Chauvergne 1982
		Chiarion Sileni 2001
		Costanza 1977
		Luikart 1984
		Ringborg 1989
		Zimpfer‐Rechner 2003
		Bafaloukos 2005
		Glover 2003
		Costanza 1972
		Kogoniia 1981
		Lopez 1984
Biochemotherapy versus chemotherapy	Interferon‐alpha	Bajetta 1994
		Bajetta 2006
		Dorval 1999
		Falkson 1991
		Falkson 1995
		Gorbonova 2000
		Kaufmann 2005
		Thomson 1993
		Vorobiof 1994
		Young 2001
		Kirkwood 1990
		Daponte 2013
		Falkson 1998
		Danson 2003
		Maio 2010
	Interleukin‐2	Keilholz 2005
		Sertoli 1999
		Hauschild 2001
	Interleukin‐2 plus interferon‐alpha	Atkins 2008
		Atzpodien 2002
		Eton 2002
		Johnston 1998
		Middleton 2007
		Ridolfi 2002
		Rosenberg 1999
Immune checkpoint inhibitors versus chemotherapy (or other immune checkpoint inhibitors)	Anti‐CTLA4 monoclonal antibodies	Hodi 2010
		Hodi 2014
		Ribas 2013
		Robert 2011
	Anti‐PD1 monoclonal antibodies	Ribas 2015
		Robert 2015a
		Weber 2015
		Robert 2015b
	Anti‐CTLA4 plus anti‐PD1 monoclonal antibodies	Larkin 2015
	Anti‐CTLA4 plus anti‐PD1 monoclonal antibodies	Postow 2015
Small‐molecule targeted drugs versus chemotherapy (or other small‐molecule targeted drugs)	BRAF inhibitors	Hauschild 2012
	BRAF inhibitors	McArthur 2014
	MEK inhibitors	Flaherty 2012b
		Gupta 2014
		Robert 2013
	BRAF plus MEK inhibitors	Flaherty 2012a
		Larkin 2014
		Long 2015
		Robert 2015
Chemotherapy with versus without other agents	Bacille Calmette‐Guérin (BCG)	Costanzi 1982
		Mastrangelo 1979
		Newlands 1976
		Ramseur 1978
		Verschraegen 1993
		Veronesi 1984
	Corynebacterium parvum	Clunie 1980
		Gough 1978
		Presant 1979
		Robidoux 1982
		Thatcher 1986
		Kokoschka 1978
	Tamoxifen	Agarwala 1999
		Cocconi 1992
		Rusthoven 1996
	Anti‐angiogenic drugs	Cui 2013
	Anti‐angiogenic drugs	Kim 2012
	Sorafenib	Flaherty 2013
		Hauschild 2009
		McDermott 2008
	Elesclomol	O'Day 2009
	Elesclomol	O'Day 2013
Single agent chemotherapy versus other single agent chemotherapy	Temozolomide	Chiarion‐Sileni 2011
		Middleton 2000
		Patel 2011
Hodi 2010a; Hodi 2014; Maio 2010; Schwartzentruber 2011a were included in a meta‐analysis of immunostimulating agents.

Table 3. Studies included in meta‐analysis

Comparison 1. Polychemotherapy versus single agent chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Overall survival Show forest plot	6	594	Hazard Ratio (IV, Random, 95% CI)	0.99 [0.85, 1.16]

1.2 Progression‐free survival Show forest plot	5	398	Hazard Ratio (IV, Random, 95% CI)	1.07 [0.91, 1.25]

1.3 Tumour response Show forest plot	14	1885	Risk Ratio (M‐H, Random, 95% CI)	1.27 [1.02, 1.58]

1.4 Toxicity (≥ G3) Show forest plot	3	514	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [1.44, 2.71]

Comparison 1. Polychemotherapy versus single agent chemotherapy

Comparison 2. Chemotherapy ± tamoxifen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Overall survival Show forest plot	4	643	Hazard Ratio (IV, Random, 95% CI)	1.03 [0.80, 1.33]

2.2 Progression‐free survival Show forest plot	2	475	Hazard Ratio (IV, Random, 95% CI)	1.06 [0.93, 1.22]

2.3 Tumour response Show forest plot	4	643	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.94, 1.89]

2.4 Toxicity (≥ G3) Show forest plot	1	271	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.38, 1.28]

Comparison 2. Chemotherapy ± tamoxifen

Comparison 3. Temozolomide versus dacarbazine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Overall survival Show forest plot	3	1313	Hazard Ratio (IV, Random, 95% CI)	0.98 [0.85, 1.12]

3.2 Progression‐free survival Show forest plot	3	1313	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.74, 1.03]

3.3 Tumour response Show forest plot	3	1313	Risk Ratio (M‐H, Random, 95% CI)	1.21 [0.85, 1.73]

3.4 Toxicity (≥ G3) Show forest plot	2	1164	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.98, 1.35]

Comparison 3. Temozolomide versus dacarbazine

Comparison 4. Chemotherapy ± interferon‐alpha

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Overall survival Show forest plot	11	1785	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.73, 1.04]

4.2 Progression‐free survival Show forest plot	6	1272	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.74, 1.01]

4.3 Tumour response Show forest plot	15	2419	Risk Ratio (M‐H, Random, 95% CI)	1.36 [1.12, 1.66]

4.4 Toxicity (≥ G3) Show forest plot	3	791	Risk Ratio (M‐H, Random, 95% CI)	1.72 [0.37, 7.95]

Comparison 4. Chemotherapy ± interferon‐alpha

Comparison 5. Chemotherapy ± interleukin‐2

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Overall survival Show forest plot	2	644	Hazard Ratio (IV, Random, 95% CI)	0.95 [0.82, 1.11]

5.2 Progression‐free survival Show forest plot	1	363	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.70, 1.08]

5.3 Tumour response Show forest plot	3	735	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.64, 1.13]

Comparison 5. Chemotherapy ± interleukin‐2

Comparison 6. Chemotherapy ± interferon‐alpha and interleukin‐2

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Overall survival Show forest plot	7	1307	Hazard Ratio (IV, Random, 95% CI)	0.94 [0.84, 1.06]

6.2 Progression‐free survival Show forest plot	6	964	Hazard Ratio (IV, Random, 95% CI)	0.90 [0.83, 0.99]

6.3 Tumour response Show forest plot	7	1307	Risk Ratio (M‐H, Random, 95% CI)	1.36 [1.11, 1.67]

6.4 Toxicity (≥ G3) Show forest plot	2	657	Risk Ratio (M‐H, Random, 95% CI)	1.35 [1.14, 1.61]

Comparison 6. Chemotherapy ± interferon‐alpha and interleukin‐2

Comparison 7. Chemotherapy ± interferon‐alpha and interleukin‐2 (first line)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Overall survival Show forest plot	5	1118	Hazard Ratio (IV, Random, 95% CI)	0.96 [0.83, 1.10]

7.2 Progression‐free survival Show forest plot	4	775	Hazard Ratio (IV, Random, 95% CI)	0.86 [0.76, 0.99]

7.3 Tumour response Show forest plot	5	1118	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.15, 1.83]

7.4 Toxicity (≥ G3) Show forest plot	1	241	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.12, 1.87]

Comparison 7. Chemotherapy ± interferon‐alpha and interleukin‐2 (first line)

Comparison 8. Chemotherapy ± Bacille Calmette‐Guérin (BCG)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Overall survival Show forest plot	2	154	Hazard Ratio (IV, Random, 95% CI)	0.87 [0.61, 1.25]

8.2 Tumour response Show forest plot	6	770	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.65, 1.12]

Comparison 8. Chemotherapy ± Bacille Calmette‐Guérin (BCG)

Comparison 9. Chemotherapy ± Corynebacterium parvum

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Overall survival Show forest plot	4	242	Hazard Ratio (IV, Random, 95% CI)	0.95 [0.74, 1.22]

9.2 Tumour response Show forest plot	7	537	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.77, 1.38]

Comparison 9. Chemotherapy ± Corynebacterium parvum

Comparison 10. Anti‐CTLA4 monoclonal antibodies (first line)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Overall survival Show forest plot	2	1157	Hazard Ratio (IV, Random, 95% CI)	0.81 [0.65, 1.01]

10.2 Progression‐free survival Show forest plot	1	502	Hazard Ratio (IV, Random, 95% CI)	0.76 [0.63, 0.92]

10.3 Tumour response Show forest plot	2	1157	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.92, 1.77]

10.4 Toxicity (≥ G3) Show forest plot	2	1142	Risk Ratio (M‐H, Random, 95% CI)	1.69 [1.19, 2.42]

Comparison 10. Anti‐CTLA4 monoclonal antibodies (first line)

Comparison 11. Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Overall survival Show forest plot	2	784	Hazard Ratio (IV, Random, 95% CI)	0.83 [0.52, 1.33]

11.2 Progression‐free survival Show forest plot	2	785	Hazard Ratio (IV, Random, 95% CI)	1.06 [0.75, 1.51]

11.3 Tumour response Show forest plot	2	785	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.38, 1.47]

11.4 Toxicity (≥ G3) Show forest plot	2	785	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.69, 1.11]

Comparison 11. Anti‐CTLA4 monoclonal antibodies ± other immunostimulating agents (second line)

Comparison 12. Anti‐PD1 monoclonal antibodies versus chemotherapy

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Overall survival Show forest plot	1	418	Hazard Ratio (IV, Random, 95% CI)	0.42 [0.37, 0.48]

12.2 Progression‐free survival Show forest plot	2	957	Hazard Ratio (IV, Random, 95% CI)	0.49 [0.39, 0.61]

12.3 Tumour response Show forest plot	3	1367	Risk Ratio (M‐H, Random, 95% CI)	3.42 [2.38, 4.92]

12.4 Toxicity (≥ G3) Show forest plot	3	1360	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.31, 0.97]

Comparison 12. Anti‐PD1 monoclonal antibodies versus chemotherapy

Comparison 13. Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Overall survival Show forest plot	1	834	Hazard Ratio (IV, Random, 95% CI)	0.63 [0.60, 0.66]

13.2 Progression‐free survival Show forest plot	2	1465	Hazard Ratio (IV, Random, 95% CI)	0.54 [0.50, 0.60]

13.3 Tumour response Show forest plot	2	1465	Risk Ratio (M‐H, Random, 95% CI)	2.47 [2.01, 3.04]

13.4 Toxicity (≥ G3) Show forest plot	2	1435	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.54, 0.91]

Comparison 13. Anti‐PD1 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies

Comparison 14. Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Progression‐free survival Show forest plot	2	738	Hazard Ratio (IV, Random, 95% CI)	0.40 [0.35, 0.46]

14.2 Tumour response Show forest plot	2	738	Risk Ratio (M‐H, Random, 95% CI)	3.50 [2.07, 5.92]

14.3 Toxicity (≥ G3) Show forest plot	2	764	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.85, 2.92]

Comparison 14. Anti‐PD1 monoclonal antibodies and anti‐CTLA4 monoclonal antibodies versus anti‐CTLA4 monoclonal antibodies alone

Comparison 15. Chemotherapy ± sorafenib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Overall survival Show forest plot	3	1194	Hazard Ratio (IV, Random, 95% CI)	1.00 [0.88, 1.14]

15.2 Progression‐free survival Show forest plot	3	1194	Hazard Ratio (IV, Random, 95% CI)	0.89 [0.73, 1.09]

15.3 Tumour response Show forest plot	3	1194	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.91, 1.50]

15.4 Toxicity (≥ G3) Show forest plot	3	1194	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.93, 1.26]

Comparison 15. Chemotherapy ± sorafenib

Comparison 16. Chemotherapy ± elesclomol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Overall survival Show forest plot	1	651	Hazard Ratio (IV, Random, 95% CI)	1.10 [0.92, 1.32]

16.2 Progression‐free survival Show forest plot	2	732	Hazard Ratio (IV, Random, 95% CI)	0.75 [0.50, 1.13]

16.3 Tumour response Show forest plot	2	732	Risk Ratio (M‐H, Random, 95% CI)	1.86 [0.98, 3.50]

16.4 Toxicity (≥ G3) Show forest plot	1	651	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.00, 1.50]

Comparison 16. Chemotherapy ± elesclomol

Comparison 17. Chemotherapy ± anti‐angiogenic drugs

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 Overall survival Show forest plot	2	324	Hazard Ratio (IV, Random, 95% CI)	0.60 [0.45, 0.81]

17.2 Progression‐free survival Show forest plot	2	324	Hazard Ratio (IV, Random, 95% CI)	0.69 [0.52, 0.92]

17.3 Tumour response Show forest plot	2	324	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.96, 3.03]

17.4 Toxicity (≥ G3) Show forest plot	2	324	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.09, 5.32]

Comparison 17. Chemotherapy ± anti‐angiogenic drugs

Comparison 18. Single agent BRAF inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 Overall survival Show forest plot	2	925	Hazard Ratio (IV, Random, 95% CI)	0.40 [0.28, 0.57]

18.2 Progression‐free survival Show forest plot	2	925	Hazard Ratio (IV, Random, 95% CI)	0.27 [0.21, 0.34]

18.3 Tumour response Show forest plot	2	925	Risk Ratio (M‐H, Random, 95% CI)	6.78 [4.84, 9.49]

18.4 Toxicity (≥ G3) Show forest plot	2	925	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.48, 3.33]

Comparison 18. Single agent BRAF inhibitor

Comparison 19. Single agent MEK inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
19.1 Overall survival Show forest plot	3	496	Hazard Ratio (IV, Random, 95% CI)	0.85 [0.58, 1.25]

19.2 Progression‐free survival Show forest plot	3	496	Hazard Ratio (IV, Random, 95% CI)	0.58 [0.42, 0.80]

19.3 Tumour response Show forest plot	3	496	Risk Ratio (M‐H, Random, 95% CI)	2.01 [1.35, 2.99]

19.4 Toxicity (≥ G3) Show forest plot	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [1.08, 2.41]

Comparison 19. Single agent MEK inhibitor

Comparison 20. Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
20.1 Overall survival Show forest plot	4	1784	Hazard Ratio (IV, Random, 95% CI)	0.70 [0.59, 0.82]

20.2 Progression‐free survival Show forest plot	4	1784	Hazard Ratio (IV, Random, 95% CI)	0.56 [0.44, 0.71]

20.3 Tumour response Show forest plot	4	1784	Risk Ratio (M‐H, Random, 95% CI)	1.32 [1.20, 1.46]

20.4 Toxicity (≥ G3) Show forest plot	4	1774	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.85, 1.20]

Comparison 20. Combination of BRAF and MEK inhibitors versus single agent BRAF inhibitor

Comparison 21. Immunostimulating agents

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
21.1 Overall survival Show forest plot	4	1458	Hazard Ratio (IV, Random, 95% CI)	0.82 [0.67, 0.99]

21.2 Progression‐free survival Show forest plot	4	1458	Hazard Ratio (IV, Random, 95% CI)	0.92 [0.74, 1.14]

21.3 Tumour response Show forest plot	4	1451	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.60, 2.50]

21.4 Toxicity (≥ G3) Show forest plot	4	1458	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.77, 1.08]

Comparison 21. Immunostimulating agents