晚期BRAF突变型黑色素瘤疗法的安全性比较-小柯机器人-科学网

晚期BRAF突变型黑色素瘤疗法的安全性比较

2020-10-11 21:27

瑞士苏黎世大学Reinhard Dummer等研究人员报道了PD-1、BRAF和MEK联合抑制在晚期BRAF突变型黑色素瘤中的安全性和生物标志物临床试验结果。2020年10月5日，《自然—医学》杂志发表了这一研究结果。

研究人员从抗PD-1抗体spartalizumab与BRAF抑制剂dabrafenib和MEK抑制剂曲美替尼联用的试验（NCT02967692）的随机、安慰剂对照、第3期COMBI-组中的单臂安全run-in（第1部分； n=9）和生物标志物（第2部分； n=27）队列中报告了功效、安全性和生物标志物分析。患者（n=36）以前未接受过BRAF V600突变的不可切除或转移性黑色素瘤的治疗。在第1部分中，根据剂量限制性毒性（DLT；主要终点）的发生率，确定了推荐的第3期方案：每4周一次400毫克司帕他珠单抗加150毫克达布拉非尼每天两次，再加2毫克曲美替尼每天一次。

第2部分描述了治疗后（主要终点）PD-L1水平和CD8⁺细胞的变化，并分析了其他生物标志物。疗效和安全性评估是主要的次要终点（中位随访24.3个月）。Spartalizumab加上dabrafenib和trametinib的客观缓解率（ORR）为78％，其中包括44％的完全缓解（CR）。72％的患者经历了≥3级的治疗相关不良事件（TRAE）。所有患者均进行了临时剂量调整，并且17％的患者因TRAE永久停用了所有三种研究药物。早期无进展生存（PFS）事件与基线时低的肿瘤突变负担/ T细胞发炎的基因表达特征（GES）或高免疫抑制性肿瘤微环境（TME）GES水平相关；免疫抑制性TME也可能排除CR。

总体而言，与spartalizumab加dabrafenib和曲美替尼相关的功效、安全性和治疗中生物标志物调节前景看好，并已鉴定出可预测长期获益的生物标志物。

据介绍，免疫和靶向疗法可在转移性黑色素瘤中实现长期生存，但是，需要新的治疗策略来改善患者的治疗效果。

附：英文原文

Title: Combined PD-1, BRAF and MEK inhibition in advanced BRAF -mutant melanoma: safety run-in and biomarker cohorts of COMBI-i

Author: Reinhard Dummer, Celeste Lebb, Victoria Atkinson, Mario Mandal, Paul D. Nathan, Ana Arance, Erika Richtig, Naoya Yamazaki, Caroline Robert, Dirk Schadendorf, Hussein A. Tawbi, Paolo A. Ascierto, Antoni Ribas, Keith T. Flaherty, Neha Pakhle, Catarina D. Campbell, Daniel Gusenleitner, Aisha Masood, Jan C. Brase, Eduard Gasal, Georgina V. Long

Issue&Volume: 2020-10-05

Abstract: Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients’ outcomes1,2. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n=9) and biomarker (part 2; n=27) cohorts of the randomized, placebo-controlled, phase3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n=36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part1, the recommended phase3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400mg of spartalizumab every 4weeks plus 150mg of dabrafenib twice daily plus 2mg of trametinib once daily. Part2 characterized changes in PD-L1 levels and CD8+ cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell–inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified.

DOI: 10.1038/s41591-020-1082-2

Source: https://www.nature.com/articles/s41591-020-1082-2

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex

本期文章：《自然—医学》：Online/在线发表

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