Mariano Ponz-Sarvise, Sun Young Rha, Carlos Gomez‐Roca, Laura Ortega Morán, Sanjeev Gill, Giampaolo Tortora, Ravit Geva, Esma Saada-Bouzid, A. Santoro, Tae Won. Kim, Daniel Heudobler, Corina E. Dutcus, Chinyere E. Okpara, Razi Ghori, Yiwei Zhang, Amir Vajdi, EJ Dettman, Fan Jin, Roman Groisberg, Ronnie Shapira-Frommer
PURPOSE: Patients with gastric cancer, biliary tract cancer (BTC), and pancreatic ductal adenocarcinoma (PDAC) have poor survival outcomes and limited second- or later-line treatment options. Certain drugs targeting vascular endothelial growth factor (VEGF) or programmed cell death protein 1 (PD-1) signaling pathways are currently used in these cancers in specific circumstances; however, there remains a need for novel treatment combinations. LEAP-005 is a multicohort, open-label, phase II study that evaluated lenvatinib (multitargeted inhibitor of tyrosine kinases, including VEGF) plus pembrolizumab (anti-PD-1 monoclonal antibody) in select previously treated solid tumors. PATIENTS AND METHODS: Participants with previously treated, advanced gastric cancer, BTC, and PDAC were enrolled in cohorts C, F, and G of LEAP-005, respectively, and received lenvatinib 20 mg/day orally plus pembrolizumab 200 mg i.v. every 3 weeks. Primary endpoints were objective response rate (ORR) and safety. RESULTS: Of 99, 102, and 103 total participants enrolled in cohorts C, F, and G, respectively, median times from first dose of study treatment to data cutoff (February 6, 2023) were 23.7, 24.2, and 19.5 months. ORRs (95% confidence interval) by blinded independent central review were 15.2% (8.7%-23.8%) in cohort C, 17.6% (10.8%-26.4%) in cohort F, and 7.8% (3.4%-14.7%) in cohort G. Grade 3 to 5 treatment-related adverse events occurred in 54.5% of participants in cohort C, and grade 3 to 4 (no grade 5) occurred in 60.8% and 59.2% of participants in cohorts F and G, respectively. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated modest antitumor activity and a manageable safety profile in previously treated, advanced gastric cancer, BTC, and PDAC. SIGNIFICANCE: In the phase II LEAP-005 study, lenvatinib plus pembrolizumab showed modest antitumor activity and a manageable safety profile in participants with previously treated gastrointestinal-related cancers. Exploratory analyses in participants with BTC indicated higher ORRs in participants with targetable alterations versus those without.