Abstract 717TiP
Background
Combination therapy with the PD-1 inhibitor pembro and the VEGF inhibitor lenvatinib showed activity in patients (pts) with advanced ccRCC in the phase III KEYNOTE-581/CLEAR trial. The HIF-2α inhibitor belzutifan (MK-6482) and MK-1308A, a coformulation of pembro and the CTLA-4 inhibitor quavonlimab, have each shown antitumor activity in phase I/II trials. HIF-2α or CTLA-4 inhibition with PD-1 and VEGF inhibition backbone combination may provide additional benefit as 1L treatment in ccRCC.
Trial design
This open-label, phase III study (NCT04736706) is currently enrolling patients and will compare 2 new combination therapies with pembro + lenvatinib (control): pembro + belzutifan + lenvatinib (HIF arm) or MK-1308A + lenvatinib (CTLA arm). Eligible pts are adults with metastatic ccRCC, measurable disease per RECIST v1.1, KPS ≥70%, and no prior systemic therapy for advanced ccRCC. Pts will be stratified by IMDC score (0, 1/2, or 3-6) and region (North America, Western Europe, or rest of the world). The study will enroll ∼1431 pts, randomly assigned 1:1:1 to the HIF arm (belzutifan 120 mg + lenvatinib 20 mg oral QD + pembro 400 mg IV Q6W), CTLA-4 arm (MK-1308A [quavonlimab 25 mg + pembro 400 mg] IV Q6W and lenvatinib 20 mg oral QD), or control (pembro 400 mg IV Q6W + lenvatinib 20 mg oral QD). Treatment will be given until documented disease progression, withdrawal of consent, or other discontinuation event; pembro and MK-1308A will be limited to 18 infusions (∼2 years). Response will be evaluated per RECIST v1.1 by BICR with CT/MRI imaging at week 12 from randomization through week 78, and Q12W thereafter. Adverse events (AEs) and serious AEs will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 and overall survival. Primary end points will be assessed in the HIF arm vs control and in the CTLA arm vs control for pts with IMDC intermediate/poor status and in all pts regardless of IMDC status. Secondary end points are objective response rate, duration of response, patient-reported outcomes, and safety.
Clinical trial identification
NCT04736706, February 3, 2021.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Eisai Inc., Woodcliff Lake, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Eisai Inc., Woodcliff Lake, NJ, USA.
Disclosure
B.I. Rini: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: GNE/Roche; Financial Interests, Personal, Advisory Role: Aveo; Financial Interests, Personal, Advisory Role: Synthorx; Financial Interests, Personal, Advisory Role: Compugen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Corvus; Financial Interests, Personal, Advisory Role: Surface Oncology; Financial Interests, Personal, Advisory Role: 3DMedicines; Financial Interests, Personal, Advisory Role: Aravive; Financial Interests, Personal, Advisory Role: Alkermes; Financial Interests, Personal, Advisory Role: Arrowhead; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: Shionogi; Financial Interests, Personal, Advisory Role: Eisai; Non-Financial Interests, Personal, Leadership Role: SITC; Financial Interests, Personal, Stocks/Shares: PTC Therapeutics; Financial Interests, Personal, Other, Travel expenses: Merck; Financial Interests, Personal, Other, Travel expenses: Pfizer; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Personal, Other, Travel expenses: Aveo; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Hoffman-LaRoche; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Taris; Financial Interests, Institutional, Funding: Seattle Genetics; Financial Interests, Institutional, Funding: Arrowhead Pharmaceuticals; Financial Interests, Institutional, Funding: Immunomedics; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Mirati Therapeutics; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Surface Oncology; Financial Interests, Institutional, Funding: Dragonfly Therapeutics; Financial Interests, Institutional, Funding: Aravive; Financial Interests, Institutional, Funding: Exelixis. E.R. Plimack: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Calithera; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: MEI Pharma; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Infinity Pharma; Financial Interests, Institutional, Funding: Astellas; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: Merck; Non-Financial Interests, Personal, Member of the Board of Directors: ASCO. T.B. Powles: Financial Interests, Personal, Advisory Role, Consulting or advisory role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol-Myers Squibb; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pfizer, MSD Oncology, Ipsen; Financial Interests, Personal, Stocks/Shares: Rainier Therapeutics; Financial Interests, Personal, Other, Honoraria: UpToDate; Financial Interests, Institutional, Research Grant: Millennium, Sanofi, Pfizer/EMO Serono. M.H. Voss: Financial Interests, Personal, Advisory Role: Aveo; Financial Interests, Personal, Advisory Role: Calithera Biosciences; Financial Interests, Personal, Advisory Role: Corvus Pharmaceuticals; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Onquality Pharmaceuticals; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Funding: Bristol-Myers Squibb; Financial Interests, Personal, Funding: Pfizer; Financial Interests, Personal, Funding: Genentech/Roche; Financial Interests, Personal, Other, Travel expenses: AstraZeneca; Financial Interests, Personal, Other, Travel expenses: Eisai; Financial Interests, Personal, Other, Travel expenses: Novartis; Financial Interests, Personal, Other, Travel expenses: Takeda; Financial Interests, Institutional, Funding: Bristol-Myers Squibb; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: Genentech/Roche. H.P. Gurney: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: MSD. R. Silverman: Financial Interests, Personal, Full or part-time Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck. R. Perini: Financial Interests, Personal, Full or part-time Employment: MSD; Financial Interests, Personal, Stocks/Shares: MSD. K. Rodriguez-Lopez: Financial Interests, Personal, Full or part-time Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck. T.K. Choueiri: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Foundation Medicine; Financial Interests, Personal, Advisory Role: Cerulean Pharma; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Prometheus; Financial Interests, Personal, Advisory Role: alligent; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Corvus Pharmaceuticals; Financial Interests, Personal, Advisory Role: Lpath; Financial Interests, Personal, Advisory Role: Axelon Pharmaceuticals; Financial Interests, Personal, Advisory Role: Sanofi/Aventis; Financial Interests, Personal, Advisory Role: Peloton Therapeutics; Financial Interests, Personal, Advisory Role: UpToDate; Financial Interests, Personal, Advisory Role: NCCN; Financial Interests, Personal, Advisory Role: Michael J. Hennessy Associates; Financial Interests, Personal, Advisory Role: Analysis Group; Financial Interests, Personal, Advisory Role: Kidney Cancer Association; Financial Interests, Personal, Advisory Role: Clinical Care Options; Financial Interests, Personal, Advisory Role: PlatformQ Health; Financial Interests, Personal, Advisory Role: Navinata Health; Financial Interests, Personal, Advisory Role: Harborside Press; Financial Interests, Personal, Advisory Role: ASCO; Financial Interests, Personal, Advisory Role: The New England Journal of Medicine; Financial Interests, Personal, Advisory Role: Lancet Oncology; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: HERON; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: ESMO; Financial Interests, Personal, Full or part-time Employment: Dana Farber Cancer Hospital; Financial Interests, Personal, Leadership Role: Dana Farber Cancer Hospital; Financial Interests, Personal, Leadership Role: NCCN; Financial Interests, Personal, Leadership Role: ASCO; Financial Interests, Personal, Leadership Role: KidneyCan; Financial Interests, Personal, Other, Travel, accommodations, expenses: Pfizer; Financial Interests, Personal, Other, Travel, accommodations, expenses: Bayer; Financial Interests, Personal, Other, Travel, accommodations, expenses: Novartis; Financial Interests, Personal, Other, Travel, accommodations, expenses: GlaxoSmithKline; Financial Interests, Personal, Other, Travel, accommodations, expenses: Merck; Financial Interests, Personal, Other, Travel, accommodations, expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, accommodations, expenses: Roche/Genentech; Financial Interests, Personal, Other, Travel, accommodations, expenses: Eisai; Financial Interests, Personal, Other, Travel, accommodations, expenses: Foundation Medicine; Financial Interests, Personal, Other, Travel, accommodations, expenses: Cerulean Pharma; Financial Interests, Personal, Other, Travel, accommodations, expenses: AstraZeneca; Financial Interests, Personal, Other, Travel, accommodations, expenses: Exelixis; Financial Interests, Personal, Other, Travel, accommodations, expenses: Prometheus; Financial Interests, Personal, Other, Travel, accommodations, expenses: alligent; Financial Interests, Personal, Other, Travel, accommodations, expenses: Ipsen; Financial Interests, Personal, Other, Travel, accommodations, expenses: Corvus Pharmaceuticals; Financial Interests, Personal, Other, Travel, accommodations, expenses: Lpath; Financial Interests, Personal, Other, Travel, accommodations, expenses: Alexion Pharmaceuticals; Financial Interests, Personal, Other, Travel, accommodations, expenses: Sanofi/Aventis; Financial Interests, Personal, Other, Travel, accommodations, expenses: UpToDate; Financial Interests, Personal, Other, Travel, accommodations, expenses: Peloton Therapeutics; Financial Interests, Personal, Other, Travel, accommodations, expenses: NCCN; Financial Interests, Personal, Other, Travel, accommodations, expenses: Michael J. Hennessy Associates; Financial Interests, Personal, Other, Travel, accommodations, expenses: Analysis Group; Financial Interests, Personal, Other, Travel, accommodations, expenses: Kidney Cancer Association; Financial Interests, Personal, Other, Travel, accommodations, expenses: Clinical Care Options; Financial Interests, Personal, Other, Travel, accommodations, expenses: PlatformQ Health; Financial Interests, Personal, Other, Travel, accommodations, expenses: Harborside Press; Financial Interests, Personal, Other, Travel, accommodations, expenses: Navinata Health; Financial Interests, Personal, Other, Travel, accommodations, expenses: The New England Journal of Medicine; Financial Interests, Personal, Other, Travel, accommodations, expenses: Lancet Oncology; Financial Interests, Personal, Other, Travel, accommodations, expenses: EMO Serono; Financial Interests, Personal, Other, Travel, accommodations, expenses: HERON; Financial Interests, Personal, Other, Travel, accommodations, expenses: Lilly; Financial Interests, Personal, Other, Travel, accommodations, expenses: ESMO; Financial Interests, Personal, Other, Patent PCT/US2018/058430: Patents, royalties, other intellectual property; Financial Interests, Personal, Other, Patent PCT/US2018/12209: Patents, royalties, other intellectual property; Financial Interests, Personal, Stocks/Shares: Pionyr; Financial Interests, Personal, Stocks/Shares: Tempest Therapeutics; Financial Interests, Personal, Other, Honoraria: NCCN; Financial Interests, Personal, Other, Honoraria: UpToDate; Financial Interests, Personal, Other, Honoraria: Michael J. Hennessy Associates; Financial Interests, Personal, Other, Honoraria: ASCO; Financial Interests, Personal, Other, Honoraria: Harborside Press; Financial Interests, Personal, Other, Honoraria: Analysis Group; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Alexion Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: Sanofi/Aventis; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Genentech/Roche; Financial Interests, Personal, Other, Honoraria: GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Peloton Therapeutics; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Corvus Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Personal, Other, Honoraria: Foundation Medicine; Financial Interests, Personal, Other, Honoraria: Eisai; Financial Interests, Personal, Other, Honoraria: PlatformQ Health; Financial Interests, Personal, Other, Honoraria: Clinical Care Options; Financial Interests, Personal, Other, Honoraria: Navinata Health; Financial Interests, Personal, Other, Honoraria: Kidney Cancer Association; Financial Interests, Personal, Other, Honoraria: Exelixis; Financial Interests, Personal, Other, Honoraria: Prometheus; Financial Interests, Personal, Other, Honoraria: Lpath; Financial Interests, Personal, Other, Honoraria: The New England Journal of Medicine; Financial Interests, Personal, Other, Honoraria: Lancet Oncology; Financial Interests, Personal, Other, Honoraria: Cerulean Pharma; Financial Interests, Personal, Other, Honoraria: alligent; Financial Interests, Personal, Other, Honoraria: EMD Serono; Financial Interests, Personal, Other, Honoraria: HERON; Financial Interests, Personal, Other, Honoraria: Lilly; Financial Interests, Personal, Other, Honoraria: Janssen Oncology; Financial Interests, Personal, Other, Honoraria: IQvia; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: Exelixis; Financial Interests, Institutional, Funding: TRACON Pharma; Financial Interests, Institutional, Funding: GlaxoSmithKline; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Peloton Therapeutics; Financial Interests, Institutional, Funding: Roche/Genentech; Financial Interests, Institutional, Funding: Celldex; Financial Interests, Institutional, Funding: Agensys; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Institutional, Funding: Prometheus; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Funding: Corvus Pharmaceuticals; Financial Interests, Institutional, Funding: Cerulean Pharma; Financial Interests, Institutional, Funding: Seattle Genetics/Astellas; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Foundation Medicine; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Calithera Biosciences; Financial Interests, Institutional, Funding: Analysis Group; Financial Interests, Institutional, Funding: NCI; Financial Interests, Institutional, Funding: Congressionally Directed Medical Research Programs (DOD).