Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.
Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.
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DOI：
10.1056/nejmoa2004407
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发表时间：
2020-09-03
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通讯作者：
Le X
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作者：
Paik PK;Felip E;Veillon R;Sakai H;Cortot AB;Garassino MC;Mazieres J;Viteri S;Senellart H;Van Meerbeeck J;Raskin J;Reinmuth N;Conte P;Kowalski D;Cho BC;Patel JD;Horn L;Griesinger F;Han JY;Kim YC;Chang GC;Tsai CL;Yang JC;Chen YM;Smit EF;van der Wekken AJ;Kato T;Juraeva D;Stroh C;Bruns R;Straub J;Johne A;Scheele J;Heymach JV;Le X
在3%到4%的非小细胞肺癌(NSCLC)患者中，会发生导致致癌驱动基因MET第14外显子转录缺失的剪接点突变。我们评估了替波替尼的有效性和安全性，替波替尼是一种高度选择性的MET抑制剂，用于该患者群体。在这项开放标签的第二阶段研究中，我们对确诊为MET外显子14跳过突变的晚期或转移性非小细胞肺癌患者给予替波替尼(500 Mg)，每天一次。主要终点是经过至少9个月随访的患者通过独立回顾得出的客观反应。根据是否在液体活检或组织活检中检测到MET外显子14跳跃突变的存在来分析反应。截至2020年1月1日，共有152名患者接受替波替尼治疗，99名患者至少随访9个月。经独立回顾，联合活检组的有效率为46%(95%可信区间，36~57)，中位有效时间为11.1个月(95%可信区间，7.2~无法估计)。液体活检组66例，有效率48%(95%CI，36~61)，组织活检组60例，有效率50%(95%CI，37~63)，两种方法均阳性27例。研究人员评估的应答率为56%(95%可信区间，45至66)，无论先前接受的是晚期或转移性疾病的治疗，情况相似。研究人员认为与替波替尼治疗有关的3级或更高级别的不良事件在28%的患者中报告，包括7%的周围水肿。不良事件导致11%的患者永久停止使用替波替尼。在基线和治疗期间，67%的患者在匹配的液体活检样本中观察到了在循环游离DNA中测量到的分子反应。在确诊为MET第14外显子跳跃突变的晚期非小细胞肺癌患者中，替波替尼的使用与大约一半的患者的部分反应有关。3级及以上的毒性反应主要为外周水肿。(由默克[德国达姆施塔特]资助；Vision ClinicalTrials.gov编号，NCT02864992。)
A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.)