Background: PD-1/L1-based combination regimens are the standard of care for first-line treatment of advanced clear cell RCC (ccRCC); however, there is no standard of care in the postimmunooncology/post-VEGF patient population, resulting in a high-unmet need. This umbrella platform study is an open-label, rolling-arm, multicenter phase 1b/2 trial in advanced ccRCC with an adaptive design that will evaluate safety and efficacy of experimental combinations of investigational agents targeting various mechanisms of action such as CTLA-4 (quavonlimab [MK-1308]), HIF-2α (belzutifan [MK-6482]), LAG-3 (MK-4280), ILT4 (MK-4830), PD-1 (pembrolizumab) and VEGF-TKI (lenvatinib). Substudy 03B (NCT04626518) will evaluate patients who progressed on PD-1/L1 inhibitors and VEGF-TKIs. Given the promising results of the phase 1b/2 KEYNOTE-146 study, pembrolizumab (400 mg IV Q6W) in combination with lenvatinib (20 mg orally QD) will be used as the reference arm.

Methods: Patients will be aged ≥18 years with histologically confirmed diagnosis of ccRCC and KPS ≥70, and experience progression on or after having received treatment with a PD-1/L1 inhibitor and a VEGF-TKI (in sequence or in combination), as defined by RECIST v1.1). Progression on PD-1/L1 inhibitors is defined as receiving 2 doses of treatment, demonstrating radiographic disease progression per RECIST v1.1, and having documented disease progression within 12 weeks of last dose. The study will comprise a safety lead-in phase for experimental combinations with investigational agents without an established recommended phase 2 dose (RP2D) followed by an efficacy phase. Patients will be randomized 1:1 to an experimental arm (approximately 50 pts per arm) or the reference arm. If more than 1 experimental arm is open for enrollment, the pts in the reference arm can be shared. Experimental arms are pembrolizumab (400 mg Q6W IV) + belzutifan (MK-6482, 120 mg orally QD); lenvatinib (20 mg orally QD) + belzutifan (120 mg orally QD); MK-1308A (coformulation of quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W); MK-4280A (coformulation of MK-4280 800 mg and pembrolizumab 200 mg IV Q3W); and pembrolizumab (200 mg IV Q3W) + MK-4830 (800 mg IV Q3W). Treatments will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors are IMDC risk group (favorable, intermediate, or poor) and use of a CTLA-4 inhibitor (yes vs no). Primary end points for safety lead-in phase (if applicable) are safety and tolerability to establish an RP2D; co-primary end points for efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival, and clinical benefit rate per RECIST v1.1 (BICR), and overall survival.

Citation Format: Hans Hammers, Toni Choueiri, Elizabeth Plimack, Brian Rini, Robert Motzer, Lina Yin, Rodolfo Perini, Jaqueline Willemann-Rogerio, Laurence Albiges. A phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced renal cell carcinoma (RCC) who progressed on PD-1/L1 and VEGF inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT243.