Robert J. Motzer, MD, on a Phase 3 Trial Evaluating MK-6482 Plus Lenvatinib Versus Cabozantinib for Advanced ccRCC

March 4, 2021
Robert J. Motzer, MD

The medical oncologist at Memorial Sloan Kettering Cancer Center highlighted what clinicians treating patients with advanced ccRCC should understand about this trial in progress.

A phase 3 trial (NCT04586231) evaluating the efficacy and safety of belzutifan (MK-6482) plus lenvatinib (Lenvima) compared with cabozantinib (Cabometyx) in patients with advanced clear cell renal cell carcinoma (ccRCC) who have progressed on prior anti–PD-1/L1 therapy was announced at the American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium.

The randomized, open-label, active-controlled, multicenter trial will include adults with histologically confirmed, unresectable, locally advanced or metastatic ccRCC with progressive disease on or after first- or second-line systemic treatment with an anti–PD-1/L1 therapy. Approximately 708 patients will be randomly assigned 1:1 to receive either MK-6482 plus lenvatinib or cabozantinib. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent.

The co-primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Key secondary end points include objective response rate, duration of response per RECIST v1.1 as assessed by BICR, and safety.

In an interview with CancerNetwork®, Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed what he believes clinicians should understand about this trial in progress.


This is a trial that looks at patients who have progressed on an [immuno-oncology; IO] therapy and compares cabozantinib, a standard therapy, to a standard [tyrosine kinase inhibitor; TKI], lenvatinib. [Lenvatinib] is also a standard TKI in the second-line [when its] combined with everolimus, but substituting for everolimus [in this combination] is MK-6482, which is a new HIF inhibitor that there’s been a lot of excitement around. It looks like it’s particularly effective in heavily pretreated patients or in patients that have resistant tumors. And so, with the advent of these new IO therapies in first-line, we’re grappling for what’s the best treatment in second or third line and I think this particular trial is really a priority. It looks to identify what’s the best treatment now that the paradigm has changed in first line. It brings in this new novel drug MK-6482, a HIF inhibitor, and it looks at the question as to whether that HIF plus TKI gives additional efficacy. I’m really excited about that trial. I think it’s going to be a priority global trial and a very good option for patients.


Motzer RJ, Liu Y, Perini RF, Zhang Y, Heng DYC. Phase III study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy. J Clin Oncol. 2021;39(suppl 6):TPS372. doi: 10.1200/JCO.2021.39.6_suppl.TPS372