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Systemic treatments for metastatic cutaneous melanoma

  • Review
  • Intervention

Authors


Abstract

Background

The prognosis of people with metastatic cutaneous melanoma, a skin cancer, is generally poor. Recently, new classes of drugs (e.g. immune checkpoint inhibitors and small-molecule targeted drugs) have significantly improved patient prognosis, which has drastically changed the landscape of melanoma therapeutic management. This is an update of a Cochrane Review published in 2000.

Objectives

To assess the beneficial and harmful effects of systemic treatments for metastatic cutaneous melanoma.

Search methods

We searched the following databases up to October 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers and the ASCO database in February 2017, and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs).

Selection criteria

We considered RCTs of systemic therapies for people with unresectable lymph node metastasis and distant metastatic cutaneous melanoma compared to any other treatment. We checked the reference lists of selected articles to identify further references to relevant trials.

Data collection and analysis

Two review authors extracted data, and a third review author independently verified extracted data. We implemented a network meta-analysis approach to make indirect comparisons and rank treatments according to their effectiveness (as measured by the impact on survival) and harm (as measured by occurrence of high-grade toxicity). The same two review authors independently assessed the risk of bias of eligible studies according to Cochrane standards and assessed evidence quality based on the GRADE criteria.

Main results

We included 122 RCTs (28,561 participants). Of these, 83 RCTs, encompassing 21 different comparisons, were included in meta-analyses. Included participants were men and women with a mean age of 57.5 years who were recruited from hospital settings. Twenty-nine studies included people whose cancer had spread to their brains. Interventions were categorised into five groups: conventional chemotherapy (including single agent and polychemotherapy), biochemotherapy (combining chemotherapy with cytokines such as interleukin-2 and interferon-alpha), immune checkpoint inhibitors (such as anti-CTLA4 and anti-PD1 monoclonal antibodies), small-molecule targeted drugs used for melanomas with specific gene changes (such as BRAF inhibitors and MEK inhibitors), and other agents (such as anti-angiogenic drugs). Most interventions were compared with chemotherapy. In many cases, trials were sponsored by pharmaceutical companies producing the tested drug: this was especially true for new classes of drugs, such as immune checkpoint inhibitors and small-molecule targeted drugs.

When compared to single agent chemotherapy, the combination of multiple chemotherapeutic agents (polychemotherapy) did not translate into significantly better survival (overall survival: HR 0.99, 95% CI 0.85 to 1.16, 6 studies, 594 participants; high-quality evidence; progression-free survival: HR 1.07, 95% CI 0.91 to 1.25, 5 studies, 398 participants; high-quality evidence. Those who received combined treatment are probably burdened by higher toxicity rates (RR 1.97, 95% CI 1.44 to 2.71, 3 studies, 390 participants; moderate-quality evidence). (We defined toxicity as the occurrence of grade 3 (G3) or higher adverse events according to the World Health Organization scale.)

Compared to chemotherapy, biochemotherapy (chemotherapy combined with both interferon-alpha and interleukin-2) improved progression-free survival (HR 0.90, 95% CI 0.83 to 0.99, 6 studies, 964 participants; high-quality evidence), but did not significantly improve overall survival (HR 0.94, 95% CI 0.84 to 1.06, 7 studies, 1317 participants; high-quality evidence). Biochemotherapy had higher toxicity rates (RR 1.35, 95% CI 1.14 to 1.61, 2 studies, 631 participants; high-quality evidence).

With regard to immune checkpoint inhibitors, anti-CTLA4 monoclonal antibodies plus chemotherapy probably increased the chance of progression-free survival compared to chemotherapy alone (HR 0.76, 95% CI 0.63 to 0.92, 1 study, 502 participants; moderate-quality evidence), but may not significantly improve overall survival (HR 0.81, 95% CI 0.65 to 1.01, 2 studies, 1157 participants; low-quality evidence). Compared to chemotherapy alone, anti-CTLA4 monoclonal antibodies is likely to be associated with higher toxicity rates (RR 1.69, 95% CI 1.19 to 2.42, 2 studies, 1142 participants; moderate-quality evidence).

Compared to chemotherapy, anti-PD1 monoclonal antibodies (immune checkpoint inhibitors) improved overall survival (HR 0.42, 95% CI 0.37 to 0.48, 1 study, 418 participants; high-quality evidence) and probably improved progression-free survival (HR 0.49, 95% CI 0.39 to 0.61, 2 studies, 957 participants; moderate-quality evidence). Anti-PD1 monoclonal antibodies may also result in less toxicity than chemotherapy (RR 0.55, 95% CI 0.31 to 0.97, 3 studies, 1360 participants; low-quality evidence).

Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival (HR 0.63, 95% CI 0.60 to 0.66, 1 study, 764 participants; high-quality evidence) and progression-free survival (HR 0.54, 95% CI 0.50 to 0.60, 2 studies, 1465 participants; high-quality evidence). Anti-PD1 monoclonal antibodies may result in better toxicity outcomes than anti-CTLA4 monoclonal antibodies (RR 0.70, 95% CI 0.54 to 0.91, 2 studies, 1465 participants; low-quality evidence).

Compared to anti-CTLA4 monoclonal antibodies alone, the combination of anti-CTLA4 plus anti-PD1 monoclonal antibodies was associated with better progression-free survival (HR 0.40, 95% CI 0.35 to 0.46, 2 studies, 738 participants; high-quality evidence). There may be no significant difference in toxicity outcomes (RR 1.57, 95% CI 0.85 to 2.92, 2 studies, 764 participants; low-quality evidence) (no data for overall survival were available).

The class of small-molecule targeted drugs, BRAF inhibitors (which are active exclusively against BRAF-mutated melanoma), performed better than chemotherapy in terms of overall survival (HR 0.40, 95% CI 0.28 to 0.57, 2 studies, 925 participants; high-quality evidence) and progression-free survival (HR 0.27, 95% CI 0.21 to 0.34, 2 studies, 925 participants; high-quality evidence), and there may be no significant difference in toxicity (RR 1.27, 95% CI 0.48 to 3.33, 2 studies, 408 participants; low-quality evidence).

Compared to chemotherapy, MEK inhibitors (which are active exclusively against BRAF-mutated melanoma) may not significantly improve overall survival (HR 0.85, 95% CI 0.58 to 1.25, 3 studies, 496 participants; low-quality evidence), but they probably lead to better progression-free survival (HR 0.58, 95% CI 0.42 to 0.80, 3 studies, 496 participants; moderate-quality evidence). However, MEK inhibitors probably have higher toxicity rates (RR 1.61, 95% CI 1.08 to 2.41, 1 study, 91 participants; moderate-quality evidence).

Compared to BRAF inhibitors, the combination of BRAF plus MEK inhibitors was associated with better overall survival (HR 0.70, 95% CI 0.59 to 0.82, 4 studies, 1784 participants; high-quality evidence). BRAF plus MEK inhibitors was also probably better in terms of progression-free survival (HR 0.56, 95% CI 0.44 to 0.71, 4 studies, 1784 participants; moderate-quality evidence), and there appears likely to be no significant difference in toxicity (RR 1.01, 95% CI 0.85 to 1.20, 4 studies, 1774 participants; moderate-quality evidence).

Compared to chemotherapy, the combination of chemotherapy plus anti-angiogenic drugs was probably associated with better overall survival (HR 0.60, 95% CI 0.45 to 0.81; moderate-quality evidence) and progression-free survival (HR 0.69, 95% CI 0.52 to 0.92; moderate-quality evidence). There may be no difference in terms of toxicity (RR 0.68, 95% CI 0.09 to 5.32; low-quality evidence). All results for this comparison were based on 324 participants from 2 studies.

Network meta-analysis focused on chemotherapy as the common comparator and currently approved treatments for which high- to moderate-quality evidence of efficacy (as represented by treatment effect on progression-free survival) was available (based on the above results) for: biochemotherapy (with both interferon-alpha and interleukin-2); anti-CTLA4 monoclonal antibodies; anti-PD1 monoclonal antibodies; anti-CTLA4 plus anti-PD1 monoclonal antibodies; BRAF inhibitors; MEK inhibitors, and BRAF plus MEK inhibitors. Analysis (which included 19 RCTs and 7632 participants) generated 21 indirect comparisons.

The best evidence (moderate-quality evidence) for progression-free survival was found for the following indirect comparisons:
• both combinations of immune checkpoint inhibitors (HR 0.30, 95% CI 0.17 to 0.51) and small-molecule targeted drugs (HR 0.17, 95% CI 0.11 to 0.26) probably improved progression-free survival compared to chemotherapy;
• both BRAF inhibitors (HR 0.40, 95% CI 0.23 to 0.68) and combinations of small-molecule targeted drugs (HR 0.22, 95% CI 0.12 to 0.39) were probably associated with better progression-free survival compared to anti-CTLA4 monoclonal antibodies;
• biochemotherapy (HR 2.81, 95% CI 1.76 to 4.51) probably lead to worse progression-free survival compared to BRAF inhibitors;
• the combination of small-molecule targeted drugs probably improved progression-free survival (HR 0.38, 95% CI 0.21 to 0.68) compared to anti-PD1 monoclonal antibodies;
• both biochemotherapy (HR 5.05, 95% CI 3.01 to 8.45) and MEK inhibitors (HR 3.16, 95% CI 1.77 to 5.65) were probably associated with worse progression-free survival compared to the combination of small-molecule targeted drugs; and
• biochemotherapy was probably associated with worse progression-free survival (HR 2.81, 95% CI 1.54 to 5.11) compared to the combination of immune checkpoint inhibitors.

The best evidence (moderate-quality evidence) for toxicity was found for the following indirect comparisons:
• combination of immune checkpoint inhibitors (RR 3.49, 95% CI 2.12 to 5.77) probably increased toxicity compared to chemotherapy;
• combination of immune checkpoint inhibitors probably increased toxicity (RR 2.50, 95% CI 1.20 to 5.20) compared to BRAF inhibitors;
• the combination of immune checkpoint inhibitors probably increased toxicity (RR 3.83, 95% CI 2.59 to 5.68) compared to anti-PD1 monoclonal antibodies; and
• biochemotherapy was probably associated with lower toxicity (RR 0.41, 95% CI 0.24 to 0.71) compared to the combination of immune checkpoint inhibitors.

Network meta-analysis-based ranking suggested that the combination of BRAF plus MEK inhibitors is the most effective strategy in terms of progression-free survival, whereas anti-PD1 monoclonal antibodies are associated with the lowest toxicity.

Overall, the risk of bias of the included trials can be considered as limited. When considering the 122 trials included in this review and the seven types of bias we assessed, we performed 854 evaluations only seven of which (< 1%) assigned high risk to six trials.

Authors' conclusions

We found high-quality evidence that many treatments offer better efficacy than chemotherapy, especially recently implemented treatments, such as small-molecule targeted drugs, which are used to treat melanoma with specific gene mutations. Compared with chemotherapy, biochemotherapy (in this case, chemotherapy combined with both interferon-alpha and interleukin-2) and BRAF inhibitors improved progression-free survival; BRAF inhibitors (for BRAF-mutated melanoma) and anti-PD1 monoclonal antibodies improved overall survival. However, there was no difference between polychemotherapy and monochemotherapy in terms of achieving progression-free survival and overall survival. Biochemotherapy did not significantly improve overall survival and has higher toxicity rates compared with chemotherapy.

There was some evidence that combined treatments worked better than single treatments: anti-PD1 monoclonal antibodies, alone or with anti-CTLA4, improved progression-free survival compared with anti-CTLA4 monoclonal antibodies alone. Anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies in terms of overall survival, and a combination of BRAF plus MEK inhibitors was associated with better overall survival for BRAF-mutated melanoma, compared to BRAF inhibitors alone.

The combination of BRAF plus MEK inhibitors (which can only be administered to people with BRAF-mutated melanoma) appeared to be the most effective treatment (based on results for progression-free survival), whereas anti-PD1 monoclonal antibodies appeared to be the least toxic, and most acceptable, treatment.

Evidence quality was reduced due to imprecision, between-study heterogeneity, and substandard reporting of trials. Future research should ensure that those diminishing influences are addressed. Clinical areas of future investigation should include the longer-term effect of new therapeutic agents (i.e. immune checkpoint inhibitors and targeted therapies) on overall survival, as well as the combination of drugs used in melanoma treatment; research should also investigate the potential influence of biomarkers.

Plain language summary

Systemic treatments (tablets or injections) taken for metastatic melanoma (expanded from its starting point to other parts of the body)

Background

Melanoma is the most dangerous common skin cancer. Early diagnosis offers the best chance of cure. People affected by early stage melanoma represent about 70% to 80% of all those with melanoma and can be treated by surgical removal of the original tumour (known as the primary tumour). However, when a primary melanoma is detected at a later stage, there is a risk of disease spreading to the nearest lymph nodes (glands that are part of the body's immune system) and distant sites, such as the lungs, liver, bone and brain. In this case, systemic chemotherapy (giving drugs that kill cells throughout the body) and biochemotherapy (chemotherapy combined with substances that can improve the immune response, known as immunostimulating cytokines, such as interleukin-2 and interferon-alpha) have been the main treatments for over three decades. However, only few people experience tumour regression, and the chance of being cured is lower than 10% after five years from diagnosis of cancer that has spread beyond the primary tumour (metastatic disease).

Over the past few years, new classes of drugs have been used with promising results. We aimed to look at how new systemic treatments compare with older therapies, as well as with each other, in terms of survival, acceptability, tumour response, and quality of life. We assessed these outcomes in people with metastatic melanoma (AJCC TNM stage IV).

Review question

We aimed to assess the effects of systemic treatments for people with metastatic cutaneous melanoma (melanoma of skin tissue). We searched for relevant trials up to October 2017 and included 122 studies.

We summarised the results of melanoma treatments (delivered systemically), such as conventional chemotherapy, biochemotherapy, as well as newer drug classes, such as immune checkpoint inhibitors (anti-CTLA4 and anti-PD1 monoclonal antibodies, which increase the anti-tumour activity of the immune system), small-molecule targeted drugs (BRAF inhibitors, which are used only for melanomas containing specific BRAF gene mutations that promote tumour progression, and MEK inhibitors, which work on the same molecular pathway), and anti-angiogenic drugs (which reduce blood supply to cancer cells). We compared these treatments with conventional chemotherapy.

Study characteristics

All 122 studies were randomised controlled trials that enrolled participants with metastatic cutaneous melanoma and compared different systemic treatments (28,561 participants). Study participants were adults of either sex, with a mean age of 57.5 years. There were 29 studies that included people whose cancer had spread to the brain, which is important because the detection and treatment of brain metastases often present unique challenges. Most treatments were compared with chemotherapy, and all studies were set in hospitals. Frequently, the pharmaceutical company who produced a tested drug also sponsored the study in which it was assessed, especially in the case of new classes of drugs, such as immune checkpoint inhibitors and small-molecule targeted drugs.

Key results

Compared to conventional chemotherapy, several treatments can improve the progression-free survival of people with metastatic melanoma. These include biochemotherapy (high-quality evidence), anti-CTLA4 monoclonal antibodies plus chemotherapy (moderate-quality evidence), anti-PD1 monoclonal antibodies (moderate-quality evidence), BRAF inhibitors (high-quality evidence), MEK inhibitors (moderate-quality evidence), and anti-angiogenic drugs (moderate-quality evidence). However, no difference was found for use of a combination of several chemotherapy agents (polychemotherapy) (high-quality evidence). Moreover, the combination of immune checkpoint inhibitors (anti-PD1 plus anti-CTLA4 monoclonal antibodies) performed better than anti-CTLA4 monoclonal antibodies alone (high-quality evidence), but anti-PD1 monoclonal antibodies performed better than anti-CTLA4 monoclonal antibodies (high-quality evidence). The combination of small-molecule inhibitors (BRAF plus MEK inhibitors) lead to better results than BRAF inhibitors alone (moderate-quality evidence), for people with melanoma that has a BRAF gene change .

Anti-PD1 monoclonal antibodies improved patients' overall survival compared with either standard chemotherapy (high-quality evidence) or anti-CTLA4 monoclonal antibodies (high-quality evidence). Compared to chemotherapy alone, both BRAF inhibitors (high-quality evidence), and anti-angiogenic agents combined with chemotherapy (moderate-quality evidence) also prolong overall survival, but anti-CTLA4 monoclonal antibodies plus chemotherapy (low-quality evidence), MEK inhibitors (low-quality evidence), combined multiple chemotherapeutic agents (polychemotherapy) (high-quality evidence), or biochemotherapy (high-quality evidence) did not lead to significantly improved overall survival. WE also found that the combination of small-molecule inhibitors performed better than BRAF inhibitors alone (high-quality evidence). No data on overall survival were available for anti-CTLA4 monoclonal antibodies alone compared with the combination of anti-CTLA4 plus anti-PD1 monoclonal antibodies.

In terms of toxicity (defined as occurrence of high-grade side effects), biochemotherapy (high-quality evidence), anti-CTLA4 monoclonal antibodies (moderate-quality evidence), polychemotherapy (moderate-quality evidence), and MEK inhibitors (moderate-quality evidence) were associated with worse toxicity compared to chemotherapy. In contrast, anti-PD1 monoclonal antibodies appear to be better tolerated than chemotherapy alone. Anti-PD1 monoclonal antibodies also appeared to be better tolerated than anti-CTLA4 monoclonal antibodies. However, evidence quality supporting these findings was assessed as low. Furthermore, the frequency of side effects did not differ significantly between anti-PD1 plus anti-CTLA4 monoclonal antibodies versus anti-CTLA4 monoclonal antibodies alone (low-quality evidence), anti-angiogenic drugs combined with chemotherapy versus chemotherapy (low-quality evidence), BRAF inhibitors versus chemotherapy (low-quality evidence), and BRAF plus MEK inhibitors versus BRAF inhibitors alone (moderate-quality evidence).

We also conducted an analysis that compared treatments that had not been directly compared in a study. This is known as a network meta-analysis. For the outcome of progression-free survival, looking at only the best evidence available, we found the following results (please note that because the highest quality level was moderate, the following results can only be deemed probable):
• both combination of immune checkpoint inhibitors and combination of small-molecule targeted drugs were favoured compared to chemotherapy;
• both BRAF inhibitors and combination of small-molecule targeted drugs were favoured compared to anti-CTLA4 monoclonal antibodies;
• biochemotherapy led to less favourable results than BRAF inhibitors;
• the combination of small-molecule targeted drugs was favoured compared to anti-PD1 monoclonal antibodies;
• both biochemotherapy and MEK inhibitors led to less favourable results than the combination of small-molecule targeted drugs; and
• biochemotherapy led to less favourable results than the combination of immune checkpoint inhibitors

For the outcome of toxicity, looking at only the best evidence available, we found the following results (again, evidence quality was no higher than moderate):
• combination of immune checkpoint inhibitors led to less favourable results than chemotherapy;
• combination of immune checkpoint inhibitors led to less favourable results than BRAF inhibitors;
• the combination of immune checkpoint inhibitors led to less favourable results than anti-PD1 monoclonal antibodies; and
• biochemotherapy was favoured compared to the combination of immune checkpoint inhibitors.

Our results suggest that the combination of small-molecule targeted drugs (BRAF plus MEK inhibitors) is the most effective treatment strategy, for people with melanoma that has a BRAF gene change, at least in terms of progression-free survival; however, this combination therapy is burdened by a higher rate of severe toxicity compared to effects observed among people treated with anti-PD1 monoclonal antibodies, which can be used in all melanoma types, and rank highest in terms of tolerability.

These results need long-term analysis from randomised trials to be confirmed, with special attention to effects on patients' overall survival.

Quality of the evidence

GRADE findings showed that most evidence was high- to moderate-quality for three (overall survival, progression-free survival and tumour response) out of four outcomes (toxicity). Evidence quality was reduced due to small numbers of participants in some comparisons, differences between the studies, and poor reporting of trials.

平易な要約

転移性メラノーマ(原発部位から他の部位に広がったメラノーマ)に対する全身療法(錠剤あるいは注射剤)

背景

メラノーマ(悪性黒色腫)は、よくみられる最も危険な皮膚がんであり、早期の診断が治癒への要となる。早期メラノーマ患者が全メラノーマ患者の約70~80%を占め、最初に発生した腫瘍(原発腫瘍)の外科的切除による治療が可能である。しかし、原発腫瘍が進行した状態で発見された場合は、近接するリンパ節(免疫系の一部である腺)や肺、肝臓、骨、脳などの遠隔(原発巣から離れた)部位に病巣が広がる危険がある。この場合、全身化学療法(全身にある細胞を殺傷する薬を投与する)や生物化学療法(インターロイキン-2やインターフェロン-αなど、免疫賦活性サイトカインとして知られる免疫反応を改善する物質を併用する化学療法)が30年以上にわたり主要な治療法とされてきた。しかしこれらの治療法では、少数の患者でしか腫瘍が縮小せず、原発腫瘍からがんが広がっている状態(転移性メラノーマ)と診断されてから5年後に治癒している可能性は10%未満である。

過去数年間、新しいタイプの薬剤が用いられ、有望な結果が得られている。そこで、生存期間、受容性、腫瘍の反応、生活の質(QOL)の観点から新旧の全身療法を比較するほか、それぞれ各治療法を比較するために、転移性メラノーマ患者(AJCC TNM病期分類に基づくステージIV)のこれらに関する転帰を評価した。

レビューの論点

転移性皮膚メラノーマ(皮膚組織のメラノーマ)患者に対する全身療法の効果を評価するために、2017年10月までの該当試験を検索し、122件を組み入れた。

メラノーマに対する従来の化学療法や生物化学療法、および新しいタイプの薬剤による治療(いずれも全身療法)の結果を要約した。新しいタイプの薬剤とは、免疫チェックポイント阻害薬(抗CTLA4モノクローナル抗体および抗PD1モノクローナル抗体:免疫系の抗腫瘍作用を増強する)、低分子性分子標的薬(BRAF阻害薬:腫瘍の増殖を促進する特定のBRAF遺伝子変異を有するメラノーマのみに用いられる。MEK阻害薬:BRAF阻害薬と同じ分子経路に作用する)、血管新生阻害薬(がん細胞への血液供給を減少させる)である。その後、これらの新しい治療法と従来の化学療法とを比較した。

試験の特性

試験122件はすべて、転移性皮膚メラノーマ患者(28,561例)を組み入れ、異なる全身療法を比較したランダム化比較試験であった。試験参加患者は成人男女、平均年齢は57.5歳であった。脳に転移のある患者を組み入れていた試験が29件あったが、脳転移の発見と治療には特有の難題が伴うことが多いため、これらの患者の組み入れは重要である。ほとんどの治療法の比較対象は化学療法であり、試験はすべて病院で実施された。免疫チェックポイント阻害薬、低分子性分子標的薬などの新しいタイプの薬剤を評価した試験では特に、被験薬を開発した製薬会社が資金提供している場合が多かった。

主要な結果

いくつかの治療法で、従来の化学療法よりも転移性メラノーマ患者の無増悪生存期間を改善する可能性が認められた。それらは、生物化学療法(高い質のエビデンス)、抗CTLA4モノクローナル抗体と化学療法の併用(中等度の質のエビデンス)、抗PD1モノクローナル抗体(中等度の質のエビデンス)、BRAF阻害薬(高い質のエビデンス)、MEK阻害薬(中等度の質のエビデンス)、血管新生阻害薬(中等度の質のエビデンス)である。しかし、化学療法薬同士の併用療法(多剤併用化学療法)の間では、差は認められなかった(高い質のエビデンス)。さらに、免疫チェックポイント阻害薬同士の併用(抗PD1モノクローナル抗体と抗CTLA4モノクローナル抗体の併用)は、抗CTLA4モノクローナル抗体単独よりも良好に作用した(高い質のエビデンス)。しかし、抗PD1モノクローナル抗体は、抗CTLA4モノクローナル抗体よりも良好に作用した(高い質のエビデンス)。BRAF遺伝子変異のあるメラノーマ患者では、低分子阻害薬同士の併用(BRAF阻害薬とMEK阻害薬の併用)は、BRAF阻害薬単独よりも良好な転帰につながっていた(中等度の質のエビデンス)。

抗PD1モノクローナル抗体は、標準化学療法あるいは抗CTLA4モノクローナル抗体のいずれかと比較したとき、全生存期間を改善した(いずれも高い質のエビデンス)。化学療法単独と比較して、BRAF阻害薬は、全生存期間を延長した(高い質のエビデンス)。また、血管新生阻害薬と化学療法の併用も、全生存期間を延長した(中等度の質のエビデンス)。しかし、以下のいずれにおいても全生存期間の有意な改善にはつながらなかった;抗CTLA4モノクローナル抗体と化学療法の併用(低い質のエビデンス)、MEK阻害薬(低い質のエビデンス)、複数の化学療法薬の併用(多剤併用化学療法)(高い質のエビデンス)、生物化学療法(高い質のエビデンス)。さらに、低分子阻害薬同士の併用はBRAF阻害薬単独よりも良好に作用した(高い質のエビデンス)。全生存期間に関し、抗CTLA4モノクローナル抗体単独と、抗CTLA4モノクローナル抗体と抗PD1モノクローナル抗体の併用とを比較したデータは入手できなかった。

毒性(重度の副作用の発生率と定義される)について、以下の治療法は化学療法よりも高い毒性に関連していた;生物化学療法(高い質のエビデンス)、抗CTLA4モノクローナル抗体(中等度の質のエビデンス)、多剤併用化学療法(中等度の質のエビデンス)、MEK阻害薬(中等度のエビデンス)。それとは対照的に、抗PD1モノクローナル抗体は化学療法単独よりも忍容性が良好と考えられる。抗PD1モノクローナル抗体はまた、抗CTLA4モノクローナル抗体よりも忍容性が良好と考えられた。しかし、これらの知見を裏付けるエビデンスの質は低いと評価された。さらに、副作用の頻度に関し、以下の比較において有意差は認められなかった。抗PD1モノクローナル抗体と抗CTLA4モノクローナル抗体の併用と抗CTLA4モノクローナル抗体単独(低い質のエビデンス)、血管新生阻害薬と化学療法の併用と化学療法(低い質のエビデンス)、BRAF阻害薬と化学療法(低い質のエビデンス)、BRAF阻害薬とMEK阻害薬の併用とBRAF阻害薬単独(中等度の質のエビデンス)。

試験では直接比較されなかった治療法間の比較解析も行った。これをネットワークメタ解析という。無増悪生存期間に関する転帰について、得られた中で最良のエビデンスのみに着目したところ、以下の結果が見出された(エビデンスの質は中等度が最高であり、以下の結果は推測の域を出ないことに留意されたい)。
・免疫チェックポイント阻害薬同士の併用および低分子性分子標的薬同士の併用は、いずれも化学療法よりも良好であった。
・BRAF阻害薬および低分子性分子標的薬同士の併用は、いずれも抗CTLA4モノクローナル抗体よりも良好であった。
・生物化学療法による転帰は、BRAF阻害薬よりも不良であった。
・低分子性分子標的薬同士の併用は、抗PD1モノクローナル抗体よりも良好であった。
・生物化学療法およびMEK阻害薬のいずれによる転帰も、低分子性分子標的薬同士の併用よりも不良であった。
・生物化学療法による転帰は、免疫チェックポイント阻害薬同士の併用よりも不良であった。

毒性に関する転帰について、得られた中で最良のエビデンスのみに着目したところ、以下の結果が見出された(ここでもエビデンスの質は中等度が最高であった)。
・免疫チェックポイント阻害薬同士の併用による転帰は、化学療法よりも不良であった。
・免疫チェックポイント阻害薬同士の併用による転帰は、BRAF阻害薬よりも不良であった。
・免疫チェックポイント阻害薬同士の併用による転帰は、抗PD1モノクローナル抗体よりも不良であった。
・生物化学療法では、免疫チェックポイント阻害薬同士の併用よりも良好であった。

以上の結果から、BRAF遺伝子変異のあるメラノーマ患者では、少なくとも無増悪生存期間に関し、低分子性分子標的薬同士の併用(BRAF阻害薬とMEK阻害薬の併用)が最も有効な治療戦略であることが示唆される。しかし、BRAF阻害薬とMEK阻害薬の併用は、抗PD1モノクローナル抗体による治療を受けた患者に認められた影響と比較すると、重度の毒性の発生率が高いという難点がある。抗PD1モノクローナル抗体は、全メラノーマに使用可能であり、忍容性は最高ランクである。

今回得られた結果を確かめるには、特に患者の全生存期間に着目し、ランダム化試験後も長期にわたり解析していく必要がある。

エビデンスの質

GRADEに基づく評価の結果、全生存期間、無増悪生存期間、腫瘍縮小、毒性の4項目のうち前者3項目の転帰に関するエビデンスのほとんどが中等度~高い質であると示された。エビデンスの質を下げた要因は、一部の比較試験で症例数が少なかったこと、試験間の相違、試験に関する報告が不十分であったことであった。

訳注

《実施組織》一般社団法人 日本癌医療翻訳アソシエイツ(JAMT:ジャムティ)『海外癌医療情報リファレンス』(https://www.cancerit.jp/)八木佐和子 翻訳、東光久(福島県立医科大学 白河総合診療アカデミー)監訳 [2018.06.02] 《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、コクラン・ジャパンまでご連絡ください。 なお、2013年6月からコクラン・ライブラリーのNew review、Updated reviewとも日単位で更新されています。最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。《CD011123》