Phase 2 study of pembrolizumab plus lenvatinib and belzutifan in patients with metastatic esophageal squamous cell carcinoma.
Authors: Rojas Carlos , Ryoo Baek-Yeol , Rha Sun Young , Kelley Robin Kate , Hubert Ayala , Painemal Claudio , Wadlow Raymond Couric , Gong Jun , Fan Li , Jin Fan , Naik Girish S. , Macarulla Teresa 
Published: January 2024

TPS425 Background: Initial signal finding studies demonstrated promising antitumor activity with the anti–PD-1 antibody pembrolizumab in combination with the anti-angiogenic multikinase inhibitor lenvatinib in patients with advanced gastric cancer or head and neck squamous cell carcinoma. Because hypoxia is common in many solid tumors and is known to induce an immunosuppressive tumor microenvironment, targeting hypoxia-inducible factor-2 alpha (HIF-2α) may enhance the activity of immune checkpoint inhibitors. The ongoing phase 2 LITESPARK-016 study (NCT04976634) is evaluating the combination of pembrolizumab plus lenvatinib and the HIF-2α inhibitor belzutifan (MK-6482) in multiple solid tumors. LITESPARK-016 includes 2 esophageal squamous cell carcinoma cohorts: one enrolling patients with immunotherapy-naive and the other enrolling patients with immunotherapy-resistant esophageal squamous cell carcinoma, cohorts F and G, respectively. We report the methodology for these cohorts. Methods: In this phase 2, open-label, multicenter study, eligible patients in the esophageal squamous cell carcinoma cohorts have histologically or cytologically confirmed metastatic disease and have tumors that are either immunotherapy-naive with disease progression on 1 prior line of standard systemic therapy (cohort F) or immunotherapy-resistant with disease progression during or after 1 prior line of treatment that contained an anti–PD-1/PD-L1 therapy (cohort G). Patients must be aged at least 18 years, have measurable disease per RECIST v1.1 (verified by BICR) with no radiographic evidence of major blood vessel encasement or intratumoral cavitation, ECOG PS of 0 to 1, and an archival/new tumor sample for biomarker analysis. Patients in cohort F receive triple therapy with pembrolizumab plus lenvatinib plus belzutifan; patients in cohort G are randomized 1:1 to receive either the same triple therapy or doublet therapy with pembrolizumab plus lenvatinib. The planned starting doses are pembrolizumab 400 mg given intravenously every 6 weeks, lenvatinib 20 mg orally once daily, and belzutifan 120 mg orally once daily. Treatment will continue for up to 2 years (for pembrolizumab) or until PD or discontinuation criteria are met. Approximately 30 patients will be enrolled in cohort F and in each arm of cohort G (approximately 90 total patients), with potential expansion of up to 70 additional patients in cohort F and each treatment arm of cohort G after safety/efficacy review with at least 6 months follow-up. The primary endpoints in cohorts F and G are safety (AEs, treatment discontinuation due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints are duration of response, disease control rate, and PFS per RECIST v1.1 by BICR, and OS. Assessment of biomarkers is an exploratory objective. Enrollment for this study began in September 2022 and is ongoing across 48 global sites. Clinical trial information: NCT04976634 .