• Yi-Long Wu, Valentina Guarneri, Pei Jye Voon, Boon Khaw Lim, Jin-Ji Yang, Marie Wislez, Cheng Huang, Chong Kin Liam, Julien Mazieres, Lye Mun Tho, Hidetoshi Hayashi, Nguyen Viet Nhung, Puey Ling Chia, Filippo de Marinis, Jo Raskin, Qinghua Zhou, Giovanna Finocchiaro, Anh Tuan Le, Jialei Wang, Christophe Dooms, Terufumi Kato, Ernest Nadal, How Soon Hin, Egbert F Smit, Martin Wermke, Daniel Tan, Masahiro Morise, Aurora O'Brate, Svenja Adrian, Boris M Pfeiffer, Christopher Stroh, Dilafruz Juraeva, Rainer Strotmann, Kosalaram Goteti, Karin Berghoff, Barbara Ellers-Lenz, Niki Karachaliou, Xiuning Le, Tae Min Kim, and INSIGHT 2 investigators.
• Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China. Electronic address: wuyilong@gdph.org.cn.
• Lancet Oncol. 2024 Aug 1; 25 (8): 9891002989-1002.

BackgroundPatients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population.MethodsThis open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete).FindingsBetween Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea.InterpretationTepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated.FundingMerck (CrossRef Funder ID: 10.13039/100009945).Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

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