美国纪念斯隆·凯特林癌症中心Paul K. Paik团队探讨了Tepotinib治疗MET外显子14跳跃突变的非小细胞肺癌的疗效。2020年5月29日，该论文发表在《新英格兰医学杂志》上。

在非小细胞肺癌（NSCLC）患者中，有3%至4%的患者发生了剪接位点突变，导致癌基因驱动因子MET的第14外显子转录丢失。研究组评估了高选择性MET抑制剂Tepotinib在该患者群体中的疗效和安全性。

在这项开放标签的临床2期研究中，研究组对确诊MET外显子14跳跃突变的晚期或转移性NSCLC患者给予tepotinib进行治疗，每日一次。主要终点为，经过至少9个月随访后，患者通过独立评估的客观缓解率。

截至2020年1月1日，共有152例患者接受了tepotinib治疗，其中99例接受了至少9个月的随访。在联合活检组中，独立评估的缓解率为46％，中位缓解期为11.1个月。液体活检组中66例患者的缓解率为48％，组织活检组中60例患者的缓解率为50％，有27例患者经两种方法评估病情均缓解。

研究组评估的缓解率为56％，与患者先前是否接受治疗无关。与tepotinib有关的3级及以上不良事件发生率为28％，包括7％的外周水肿。不良事件导致11％的患者永久停用tepotinib。在基线检查和治疗期间，67%的患者其液体活检样本中观察到循环游离DNA的分子反应。

总之，对于确诊MET外显子14跳跃突变的晚期NSCLC患者，使用tepotinib治疗可使半数患者获得部分缓解。周围水肿是3级及以上的主要毒副作用。

附：英文原文

Title: Tepotinib in Non–Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations | NEJM

Author: Paul K. Paik, M.D.,, Enriqueta Felip, M.D., Ph.D.,, Remi Veillon, M.D.,, Hiroshi Sakai, M.D.,, Alexis B. Cortot, M.D., Ph.D.,, Marina C. Garassino, M.D.,, Julien Mazieres, M.D., Ph.D.,, Santiago Viteri, M.D.,, Helene Senellart, M.D.,, Jan Van Meerbeeck, M.D., Ph.D.,, Jo Raskin, M.D.,, Niels Reinmuth, M.D., Ph.D.,, Pierfranco Conte, M.D.,, Dariusz Kowalski, M.D., Ph.D.,, Byoung Chul Cho, M.D., Ph.D.,, Jyoti D. Patel, M.D.,, Leora Horn, M.D.,, Frank Griesinger, M.D., Ph.D.,, Ji-Youn Han, M.D., Ph.D.,, Young-Chul Kim, M.D., Ph.D.,, Gee-Chen Chang, M.D., Ph.D.,, Chen-Liang Tsai, M.D.,, James C.-H. Yang, M.D., Ph.D.,, Yuh-Min Chen, M.D., Ph.D.,, Egbert F. Smit, M.D., Ph.D.,, Anthonie J. van der Wekken, M.D., Ph.D.,, Terufumi Kato, M.D.,, Dilafruz Juraeva, Ph.D.,, Christopher Stroh, Ph.D.,, Rolf Bruns, M.Sc.,, Josef Straub, Ph.D.,, Andreas Johne, M.D.,, Jürgen Scheele, M.D., Ph.D.,, John V. Heymach, M.D., Ph.D.,, and Xiuning Le, M.D., Ph.D.

Issue&Volume: 2020-05-29

Abstract: Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

DOI: 10.1056/NEJMoa2004407

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2004407