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We evaluated the efficacy and safety of a novel combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in this population. This phase 2, open-label, single-arm study enrolled patients with metastatic NSCLC with sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) or c-ROS oncogene 1 (ROS1) alteration who progressed on standard TKIs. Patients received a combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. Of the 24 patients screened, 19 were enrolled and included in the intention-to-treat population. Median follow-up time was 10.7\u00a0months (95% CI 4.4\u201311.9). ORR was 31.6% (6\/19, 95% CI 12.6%\u201356.6%; all partial responses). Median PFS was 11.9\u00a0months (95% CI 4.3\u2013not reached). Median OS was not reached. Most of the treatment-related adverse events (TRAEs) were grade 1\u20132, which occurred in 63% (12\/19) of the patients. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%) and anorexia (21.1%). The combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed showed modest efficacy and manageable toxicity in metastatic NSCLC patients with targetable genomic alterations who progressed on standard TKIs. NCT04989322.<\/jats:p>","DOI":"10.1007\/s10637-025-01589-6","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T09:18:54Z","timestamp":1762766334000},"page":"1191-1200","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in patients with metastatic non-small cell lung cancer harbouring targetable genomic alterations who progressed on standard tyrosine kinase inhibitors"],"prefix":"10.1007","volume":"43","author":[{"given":"Hoi Wai","family":"Chan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris Chun Long","family":"Tse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chung","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Leung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gin Wai","family":"Kwok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey Sum Lung","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen Hoi-Lam","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine Wing Yan","family":"Tsang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cho Wing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny Wai Yan","family":"Lo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikki","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rina","family":"Hui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Yau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James Chung Man","family":"Ho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne Wing Yan","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"issue":"3","key":"1589_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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The protocol was approved by the institutional review board of the University of Hong Kong\/Hospital Authority Hong Kong West Cluster (ref. UW 20\u2013205). The study design and conduct complied with all relevant local regulations regarding the use of human study participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}