From Memorial Sloan Kettering Cancer Center, New York (P.K.P.); the Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (E.F.), and Dr. Rosell Oncology Institute, Dexeus University Hospital, Quirónsalud Group (S.V.), Barcelona; Centre Hospitaliere Universitaire (CHU) Bordeaux, Service des Maladies Respiratoires, Bordeaux (R.V.), Université de Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de Lille, UMR9020-UMR-S 1277-Canther, Lille (A.B.C.), CHU de Toulouse, Institut Universitaire du Cancer de Toulouse, Université Paul Sabatier, Toulouse (J.M.), and Institut de Cancérologie de l'Ouest Rene Gauducheau Centre, Saint-Herblain (H. Senellart) - all in France; Saitama Cancer Center, Saitama (H. Sakai), and the Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama (T.K.) - both in Japan; the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.C.G.), and the Department of Surgery, Oncology and Gastroenterology, University of Padua and Oncologia Medica 2, Istituto Oncologico Veneto, IRCCS, Padua (P.C.) - both in Italy; Antwerp University Hospital, Edegem, Belgium (J.V.M., J.R.); Asklepios Lung Clinic, Munich-Gauting (N.R.), Pius Hospital Oldenburg, University Medicine Oldenburg, Oldenburg (F.G.), Translational Medicine, Department of Bioinformatics (D.J.), Translational Innovation Platform, Oncology (C.S.), the Department of Biostatistics (R.B.), Translational Medicine, Department of Clinical Biomarkers and Companion Diagnostics (J. Straub), and Global Clinical Development (A.J., J. Scheele), Merck, Darmstadt - all in Germany; the Department of Lung Cancer and Thoracic Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (D.K.); Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), the Center for Lung Cancer, National Cancer Center, Goyang (J.-Y.H.), and Chonnam National University Medical School and Hwasun Hospital, Hwasun (Y.-C.K.) - all in South Korea; Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago (J.D.P.); the Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville (L.H.); the Faculty of Medicine, School of Medicine, National Yang-Ming University (G.-C.C.), the Division of Chest Medicine, Department of Internal Medicine, Tri-service General Hospital, National Defense Medical Center (C.-L.T.), National Taiwan University Hospital (J.C.-H.Y.), and the Department of Chest Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University (Y.-M.C.), Taipei, and the Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung (G.-C.C.) - both in Taiwan; the Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam (E.F.S.), and the Department of Pulmonology, University of Groningen and University Medical Center Groningen, Groningen (A.J.W.) - both in the Netherlands; and M.D. Anderson Cancer Center, University of Texas, Houston (J.V.H., X.L.).
N Engl J Med. 2020 Sep 3;383(10):931-943. doi: 10.1056/NEJMoa2004407. Epub 2020 May 29.
A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver 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 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 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 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.).
导致致癌驱动基因 外显子 14 转录缺失的剪接位点突变发生在 3%至 4%的非小细胞肺癌（NSCLC）患者中。我们评估了高度选择性 MET 抑制剂 tepotinib 对此类患者人群的疗效和安全性。
在这项开放标签、2 期研究中，我们对经证实存在 外显子 14 跳跃突变的晚期或转移性 NSCLC 患者每日一次给予 tepotinib（剂量为 500mg）。主要终点是在至少随访 9 个月的患者中，由独立评审确定的客观缓解率。根据液体活检或组织活检中是否检测到 外显子 14 跳跃突变，对缓解情况进行了分析。
截至 2020 年 1 月 1 日，共有 152 例患者接受了 tepotinib 治疗，99 例患者的随访时间至少为 9 个月。独立评审的缓解率为 46%（95%置信区间[CI]：36%至 57%），联合活检组的中位缓解持续时间为 11.1 个月（95%CI：7.2 至无法估计）。液体活检组 66 例患者的缓解率为 48%（95%CI：36%至 61%），组织活检组 60 例患者的缓解率为 50%（95%CI：37%至 63%）；27 例患者两种方法均为阳性。研究者评估的缓解率为 56%（95%CI：45%至 66%），与晚期或转移性疾病先前接受的治疗无关。研究者认为与 tepotinib 治疗相关的 3 级或更高等级的不良事件在 28%的患者中发生，包括 7%的外周水肿。不良事件导致 11%的患者永久性停止 tepotinib 治疗。在基线和治疗期间有匹配液体活检样本的患者中，67%观察到循环游离 DNA 中的分子应答。
在确认为 外显子 14 跳跃突变的晚期 NSCLC 患者中，使用 tepotinib 治疗约一半患者出现部分缓解。3 级或更高等级的主要毒性作用是外周水肿。（由德国默克公司[达姆施塔特]资助；VISION 临床试验.gov 编号，NCT028
