メラノーマに対する有望な新併用療法（Abstract # 8510）

進行メラノーマ患者に対する2つの分子標的治療薬併用は毒性が少なく有望な作用を示した
Combining two targeted drugs shows encouraging activity with fewer toxicities for patients with advanced melanoma
第48回American Society of Clinical Oncology学会で発表されたexpanded IBトライアルの結果、治験段階にある2つの分子標的治療薬―BRAF阻害薬dabrafenibおよびMEK阻害薬trametinib―は、がんの進行を停止し、現在の標準単剤BRAF標的治療薬のスタディで公表されたよりも皮膚副作用レベルが低いことが示された。この解析ではV600 BRAF変異を有しBRAF標的治療を受けたことのない進行メラノーマ患者を対象とした。トライアル全体では、様々な用量のdabrafenib および trametinibを投与された患者125人が含まれ、今回の解析では過去にBRAF標的治療を受けたことのない（化学療法などの前治療は許可された）、したがってBRAF標的治療抵抗歴のないサブグループの77人に焦点が当てられた。この77人の患者の無増悪生存期間中央値は7.4か月であり、過去のvemurafenib単剤スタディでみられた結果と同等であった。生存期間に関するデータは今年後半に得られる予定である。トライアル全体の125人中扁平上皮がんが発症したのはわずか2%であり、他の2%において日光角化症が発症した。一般的な、しかし制御可能なその他の副作用は発熱、倦怠感および脱水などであった。
Full Text

Results from an expanded Phase IB trial presented at the American Society of Clinical Oncology's 48th Annual Meeting, show that combination therapy with two investigational targeted drugs – the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib – stalls cancer progression and with a lower level of skin side effects than published studies of the current standard single-agent BRAF-targeted therapy, vemurafenib, have shown. The analysis included patients with advanced melanoma who had a V600 BRAF mutation and who had no previous BRAF-targeted treatment.

Approximately half of all melanomas harbor a V600E mutation in the BRAF gene; in those patients, the nearby MEK pathway is also highly active. While the approval of vemurafenib last year represented a major research achievement, most patients eventually develop resistance to the drug. It is hoped that simultaneously targeting the two active pathways – BRAF and MEK – will provoke a stronger anti-cancer response and prevent, or further delay, treatment resistance.

"It's fascinating to find such promising effects with this combination regimen. Not only are the two drugs causing shrinkage of the cancer, but we're seeing that a second anti-cancer therapy may actually suppress the side effects of the first," said Jeffrey Weber, M.D., Ph.D., a senior member at H. Lee Moffitt Cancer Center and director of the Donald A. Adam Comprehensive Melanoma Research Center.

While the overall trial included 125 patients who received varying doses of dabrafenib and trametinib, the current analysis focuses on a sub-group of 77 patients who received no prior BRAF-targeted therapy (other prior therapies, such as chemotherapy, were permitted), and thus had no prior resistance to BRAF-targeted therapy. Among these 77 patients, median progression-free survival was 7.4 months, which is comparable to what was observed in past single-agent vemurafenib studies. Survival data is expected later this year.

Skin lesions are a well-known side effect of vemurafenib therapy, occurring in up to one-quarter of patients. In this trial, such toxicities were far less common: just 2 percent of the 125 patients in the overall trial developed squamous cell carcinomas and another two percent developed actinic keratoses. Additional common, but manageable, side effects included fever, fatigue and dehydration.