ASCO GU 2022: Phase 3 Study of First-Line Treatment With Pembrolizumab + Belzutifan + Lenvatinib or Pembrolizumab/Quavonlimab + Lenvatinib Versus Pembrolizumab + Lenvatinib for Advanced RCC

( The 2022 GU ASCO Annual meeting included a renal cell carcinoma (RCC) trials in progress session featuring a phase 3 study, presented by Dr. Toni Choueiri, evaluating first-line treatment with pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib for advanced RCC. Combination therapy with the PD-1 inhibitor pembrolizumab and the vascular endothelial growth factor (VEGF) inhibitor lenvatinib showed antitumor activity as first-line treatment for advanced clear cell RCC in the phase 3 KEYNOTE-581/CLEAR study.1 Antitumor activity has also been shown with the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) in clear cell RCC and with MK-1308A (coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab) in non–small cell lung cancer. Therefore, HIF-2α or CTLA-4 inhibition with a PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in clear cell RCC. This open-label, randomized, phase 3 study (NCT04736706) will compare first-line treatment with the novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) or MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C) for advanced RCC.

Approximately 1,431 adults with metastatic clear cell RCC, measurable disease per RECIST v1.1, and KPS score ≥70% who had not previously undergone systemic therapy for advanced clear cell RCC will be enrolled. Patients will be randomly assigned 1:1:1 to:

  • Arm A: Belzutifan 120 mg + lenvatinib 20 mg orally once daily (QD) + pembrolizumab 400 mg IV every 6 weeks (Q6W)
  • Arm B: MK-1308A (quavonlimab 25 mg + pembrolizumab 400 mg) IV (Q6W) and lenvatinib 20 mg orally QD
  • Arm C: Pembrolizumab 400 mg IV (Q6W) + lenvatinib 20 mg orally QD


The trial design of this important phase 3 trial is as follows: 



Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (~2 years). Stratification factors are International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, Q6W through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival for arm A or arm B versus arm C in patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. The full efficacy and safety analysis plan is as follows: 


 The study is recruiting patients at sites across, Africa, Asia, Australia, Europe, North America, and South America: 



Presented By: Toni K. Choueiri, MD, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Co-Authors: Elizabeth R. Plimack, Thomas Powles, Martin H Voss, Howard Gurney, Rachel Kloss Silverman, Rodolfo F. Perini, Karla Rodriguez-Lopez, Brian I. Rini

Affiliations: Fox Chase Cancer Center, Philadelphia, PA, Barts Health NHS Trust and the Royal Free NHS Foundation Trust, Barts Cancer Institute, and Queen Mary University of London, London, United Kingdom, Memorial Sloan Kettering Cancer Center, New York, NY, Westmead Hospital and Macquarie University Hospital, Sydney, NSW, Australia, Merck & Co., Inc., Kenilworth, NJ, Vanderbilt-Ingram Cancer Center, Nashville, TN


Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022

1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300.


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