The Phase 3 CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma - Episode 1

Current Therapies for Advanced RCC: Options and Challenges

Robert J. Motzer, MD, gives a background on the current first-line therapy options for advanced renal cell carcinoma, including challenges and unmet needs.

Robert J. Motzer, MD: My name is Robert Motzer. I am from Memorial Sloan Kettering Cancer Center, and today our perspective focus is on the phase 3 CLEAR trial, which was a randomized phase 3 trial of lenvatinib plus pembrolizumab or lenvatinib plus everolimus versus sunitinib for patients with advanced RCC [renal cell carcinoma]. There has been really dramatic progress in first-line options for patients with advanced RCC over the last 3 to 4 years. Prior to that time, single-agent tyrosine kinase inhibitors [TKIs] with sunitinib or pazopanib comprised the mainstay of our treatment. With the study of nivolumab, a checkpoint inhibitor, compared to everolimus, a mTOR [mechanistic target of rapamycin] inhibitor, in second- or third-line therapy in patients who progressed on those TKIs, and the overall survival benefit that was seen in the CheckMate 025 study. Since that time, checkpoint inhibitors have been studied in combination and incorporated into first-line therapy for clear cell RCC, the predominant cell type. The first study that showed a benefit over sunitinib was a phase 3 trial with 2 checkpoint inhibitors, ipilimumab and nivolumab, and that showed a benefit over sunitinib primarily in intermediate- and poor-risk patients. Since that time, there have been a number of phase 3 trials of tyrosine kinase inhibitor plus checkpoint inhibitor combinations compared to sunitinib which have also shown benefit in response rate, progression-free survival, and overall survival compared to sunitinib. The initial one which established a new standard of care was with axitinib plus pembrolizumab. More recently, trials with cabozantinib plus nivolumab and lenvatinib plus pembrolizumab compared to sunitinib showed striking improvements in efficacy and are now first-line options for patients with RCC. One of the challenges really is in terms of patient selection for a first-line regimen—which patient is best served by each regimen and whether there is a benefit of 1 particular regimen over the other. Now we have multiple options. It has been referred to as an “embarrassment of riches,” and I think one of the challenges moving forward will really be in terms of the choice of regimen for a patient. This largely depends on the patient characteristics and the individual preference of the treating physician and his experience with the particular program. We are also doing studies looking at underlying biology to see if we can identify biomarkers that would predict which regimen would be best for which patient.

This transcript has been edited for clarity.