Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Oncologist. 2018 Jun;23(6):740-745. doi: 10.1634/theoncologist.2017-0642. Epub 2018 Feb 7.
On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B, = 57) or were treatment-naïve (Cohort C, = 36). All patients received dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily. In Cohort B, overall response rate (ORR) was 63% (95% confidence interval [CI] 49%-76%) with response durations ≥6 months in 64% of responders. In Cohort C, ORR was 61% (95% CI 44%-77%) with response durations ≥6 months in 59% of responders. Results were evaluated in the context of the Intergroupe Francophone de Cancérologie Thoracique registry and a chart review of U.S. electronic health records at two academic sites, characterizing treatment outcomes data for patients with metastatic NSCLC with or without BRAF V600E mutations. The treatment effect of dabrafenib 150 mg twice daily was evaluated in 78 patients with previously treated BRAF mutant NSCLC, yielding an ORR of 27% (95% CI 18%-38%), establishing that dabrafenib alone is active, but that the addition of trametinib is necessary to achieve an ORR of >40%. The most common adverse reactions (≥20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough, and dyspnea.
The approvals of dabrafenib and trametinib, administered concurrently, provide a new regimen for the treatment of a rare subset of non-small cell lung cancer (NSCLC) and demonstrate how drugs active for treatment of -mutant tumors in one setting predict efficacy and can provide supportive evidence for approval in another setting. The FDA also approved the first next-generation sequencing oncology panel test for simultaneous assessment of multiple actionable mutations, which will facilitate selection of optimal, personalized therapy. The test was shown to accurately and reliably select patients with NSCLC with the V600E mutation for whom treatment with dabrafenib and trametinib is the optimal treatment.
2017 年 6 月 22 日，美国食品药品监督管理局（FDA）扩大了达拉非尼联合曲美替尼的适应证范围，纳入治疗携带 BRAF V600E 突变的转移性非小细胞肺癌（NSCLC）患者。此次批准基于国际多中心、多队列、非对照、开放标签临床试验 BRF113928 的结果，该研究先后纳入 93 例既往接受过晚期 NSCLC 系统治疗的患者（队列 B，n=57）或初治患者（队列 C，n=36）。所有患者均接受达拉非尼 150 mg，每日口服 2 次，以及曲美替尼 2 mg，每日口服 1 次。在队列 B 中，总缓解率（ORR）为 63%（95%置信区间[CI]：49%76%），应答持续时间≥6 个月的比例为 64%。在队列 C 中，ORR 为 61%（95% CI：44%77%），应答持续时间≥6 个月的比例为 59%。结果在法国胸科肿瘤协作组（IFCT）登记处和两个学术机构的美国电子病历图表回顾中进行了评估，对携带 BRAF V600E 突变或不携带 BRAF V600E 突变的转移性 NSCLC 患者的治疗结局数据进行了特征描述。在 78 例既往接受过 BRAF 突变 NSCLC 治疗的患者中评估了达拉非尼 150 mg 每日 2 次的治疗效果，ORR 为 27%（95% CI：18%~38%），证实了达拉非尼单药治疗有效，但联合曲美替尼治疗可使 ORR 超过 40%。最常见的不良反应（≥20%）为发热、疲乏、恶心、呕吐、腹泻、皮肤干燥、食欲下降、水肿、皮疹、寒战、出血、咳嗽和呼吸困难。
达拉非尼联合曲美替尼的批准为治疗一种罕见的非小细胞肺癌（NSCLC）亚型提供了一种新的治疗方案，并展示了在一种治疗环境中对治疗 - 突变肿瘤有效的药物如何能够预测疗效，并为在另一种治疗环境中获得批准提供支持性证据。FDA 还批准了首个用于同时评估多个可操作突变的下一代测序肿瘤panel 检测，这将有助于选择最佳的个体化治疗方案。该检测方法已被证明能够准确可靠地选择出 V600E 突变的 NSCLC 患者，这些患者接受达拉非尼联合曲美替尼治疗是最佳选择。
