Phase 2 open-label study of pembrolizumab plus lenvatinib and belzutifan in patients with advanced solid tumors.
Authors: Kelley Robin Kate , Van Cutsem Eric , Lee Michael S. , Wolf Ido , Fakih Marwan , de Vos-Geelen Judith , Lee Valerie , Vogel Arndt , Wu Xi Lawrence , Jin Fan , Naik Girish S. , O'Reilly Eileen Mary 
Published: January 2022

TPS669 Background: There is an unmet medical need in patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and biliary tract cancer (BTC), that progresses after standard therapy. The combination of pembrolizumab (pembro; anti–PD-1 antibody) and lenvatinib (len; anti-angiogenic multikinase inhibitor) demonstrated antitumor activity and manageable toxicity in many tumor types. Hypoxia-inducible factor-2 alpha (HIF-2α) acts on multiple pathways including cell survival and proliferation, angiogenesis, genomic instability and treatment resistance. Monotherapy with the HIF-2α inhibitor belzutifan (MK-6482) impairs hypoxic signaling in cancer cells and has antitumor activity in clear cell renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease associated non-RCC tumors such as pancreatic neuroendocrine tumors. Based on the potential role of hypoxia signaling and HIF-2α in tumorigenesis and tumor progression, the combination of belzutifan with pembro and len may improve antitumor activity further in the selected tumor types. Methods: This phase 2, single-arm, open-label, multicenter study (NCT04976634) is evaluating pembro 400 mg IV Q6W + oral len 20 mg QD (8 or 12 mg QD for body weight < 60 or ≥60 kg, respectively, for pts with HCC) + oral belzutifan 120 mg QD. Eligible pts: ≥18 y old with histologically confirmed unresectable HCC (Child-Pugh A; 1L); previously treated unresectable, metastatic non–MSI-H/mismatch repair deficient CRC (3L+); metastatic PDAC (2L/3L); or locally advanced/metastatic BTC (includes intra/extrahepatic cholangiocarcinoma and gall bladder cancer; 2L+) with progressive disease (PD); measurable disease per RECIST v1.1 (verified by blinded independent central review [BICR]); ECOG PS ≤1 and archival/new tumor sample for biomarker analysis. All pts should be naïve to prior immune checkpoint inhibitor therapy, len or any HIF-2α inhibitor. The safety lead-in phase is based on the modified toxicity probability interval design with a target dose-limiting toxicity (DLT) rate of 30% and DLT-evaluable period of 21 days (3 wk/1 cycle) in ≤10 HCC pts and ≤15 pts with CRC, PDAC and BTC pooled for each dose level. The study will enroll 120 pts (30/tumor type) to receive triplet therapy for up to 2 y (for pembro) or until PD or discontinuation criteria are met. Enrollment may be expanded by an additional 70 pts/tumor type at the chosen dose level after safety and efficacy review with ≥6 mo follow-up. Primary endpoints are safety (DLTs [safety lead-in], AEs, and treatment discontinuation due to AEs) and ORR per RECIST v1.1 by BICR. Secondary endpoints include DOR, disease control rate and PFS per RECIST v1.1 (and mRECIST for HCC) by BICR, and OS. Efficacy analyses will report binomial proportion or Kaplan-Meier estimates with 95% CIs. Safety analyses will be descriptive. Enrollment began August 2021. Clinical trial information: NCT04976634.