Refining Combination Strategies in Metastatic RCC - Episode 3

The Phase 3 CLEAR Study in Metastatic RCC


Robert J. Motzer, MD, of the Memorial Sloan Kettering Cancer Center, discusses the rationale for studying lenvatinib plus pembrolizumab or everolimus for frontline metastatic renal cell carcinoma treatment and reacts to outcomes of the phase 3 CLEAR study as presented at ASCO GU 2021.

Robert J. Motzer, MD: More recently, at the American Society of Clinical Oncology Genitourinary Cancers Symposium and in The New England Journal of Medicine, the results of the CLEAR trial were presented. This was a very important trial because it was a 3-arm study comparing lenvatinib/pembrolizumab to lenvatinib/everolimus to sunitinib in first-line therapy for patients with clear cell carcinoma. Both of the comparisons of the lenvatinib-containing arms statistically were made to sunitinib and not to each other.

The outcome of the trial showed that there was a powerful effect on progression-free survival [PFS] with lenvatinib/pembrolizumab, with a median PFS of over 23 months, compared to that with sunitinib. There was a high response rate of now over 70%. It’s the first time we’ve crossed that margin, and also notable, a 16% complete response rate by an independent review. Very few, about 5% of patients, had overt progression through that program, and there was a benefit in overall survival as well. The efficacy data looked quite extraordinary with the lenvatinib/[pembrolizumab] combination compared to sunitinib. Now, that is not yet FDA approved. The hope is that it will be soon, so it can be another tool in our medications for advanced RCC [renal cell carcinoma].

Lenvatinib/everolimus, in that study, the outcome was different, and it did show a benefit in progression-free survival, meeting its primary end point, and also a higher response. But the margin wasn’t as high as that with lenvatinib/[pembrolizumab] compared to sunitinib, and it didn’t show an improvement in overall survival. It’s the first of these trials to have more of a contemporary control arm in the study that does not include an immunotherapy [IO] or PD-1 agent. The significance of that study shows a proof of principle about the importance of IO therapy in first-line RCC treatment to achieve that overall survival benefit. A benefit in progression-free survival, and a benefit in response rate was seen as well, but you need that immunotherapy there to push it into a benefit in overall survival for patients. It served as proof of principle for that whole approach of IO in first-line therapy for RCC.

Transcript edited for clarity.