Are Combinations the Answer in Metastatic RCC? - Episode 2

Strong Efficacy and Favorable Safety From CLEAR for RCC

A comprehensive review of the efficacy and safety data from the phase 3 CLEAR trial (Study 307/KEYNOTE-581) for the frontline treatment of advanced renal cell carcinoma.

Robert J. Motzer, MD: Lenvatinib plus pembrolizumab is a combination that was recently studied and shown to produce a high level of efficacy in patients with advanced clear-cell carcinoma in first-line therapy. Lenvatinib is a very potent tyrosine kinase inhibitor [TKI] that targets VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, among other kinases. It showed a high level of activity in combination with everolimus in second-line therapy and was approved as a combination in this fashion. Pembrolizumab, a PD-1 inhibitor that has activity across many malignancies, has also shown single-agent activity for advanced renal cell carcinoma [RCC]. There’s a strong rationale for combining the 2; it appears that the tyrosine kinase inhibitor prepares and betters the environment around the tumor for the immunotherapy to work. And so this particular combination, lenvatinib plus pembrolizumab, is particularly promising for this disease based on this strong rationale.

Recently, the results of the CLEAR phase 3 trial were reported at the ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] and published simultaneously in the New England Journal of Medicine. This was a 3-arm trial that was conducted in patients who were treatment-naïve. That is, they had not received prior systemic therapy, had advanced clear-cell RCC, and otherwise met eligibility criteria. It was a 3-arm trial in which patients were randomized to lenvatinib 20 mg per day plus pembrolizumab at a standard 200-mg IV [intravenous] every 3 weeks. Lenvatinib 18 mg daily plus everolimus at 5 mg per day was the second arm. The third arm was sunitinib, given at the standard 4-weeks-on, 2-weeks-off dosing. The primary end point of the trial was progression-free survival by independent review for each lenvatinib-containing arm, compared with sunitinib. The key secondary end points included overall survival and response rate as well as safety. The trial accrued over 1100 patients equally among the 3 arms. At the time of the analysis, the primary end points were met for improvement of lenvatinib plus pembrolizumab, compared with sunitinib, as well as improvement in progression-free survival by independent review for lenvatinib plus everolimus through sunitinib. The hazard ratio for lenvatinib plus pembrolizumab compared with sunitinib was 0.39, which is really a profound benefit for this combination vs sunitinib, which was statistically significant. The median progression-free survival was nearly 24 months compared with 9 months with sunitinib, which is the longest progression-free survival we’ve seen in any of these phase 3 trials. Lenvatinib plus everolimus also showed a benefit compared with sunitinib. But the margin was not as great as what we’ve seen with lenvatinib plus pembrolizumab. In addition, there was a survival benefit that was found with lenvatinib plus pembrolizumab, compared with sunitinib. The hazard ratio was 0.66 and the P value was .005, showing a benefit in overall survival for lenvatinib plus pembrolizumab, compared with sunitinib. Benefit and survival were not seen for the other combination, for lenvatinib plus everolimus, compared with sunitinib. This really speaks to the profound efficacy of the lenvatinib-pembrolizumab combination. To me, it serves as proof of principle that, inclusion of an immunotherapy or a PD-1 inhibitor in the first-line regimen is important for producing a benefit and survival. We also saw a very high response rate with that combination, 71%, which is a new bar for these combinations in renal cell cancer, compared with 36% for response rate to sunitinib. They’ve been most remarkable; there was a complete response of 16% in patients with lenvatinib-pembrolizumab. Also, these responses were quite durable with lenvatinib plus pembrolizumab. The median duration of response was 25.8 months for lenvatinib plus pembrolizumab, compared with 14.6 months with sunitinib. So the long progression-free survival, the benefit and the overall survival, the doubling of response rate, and the 16% complete response rate really speak to the efficacy of this particular regimen. The safety profile was with other TKI–I/O [immuno-oncology] combinations and was largely driven by the tyrosine kinase inhibitor, via the adverse events associated with lenvatinib. Most notably, however, there was a relative lack of hepatotoxicity of high-grade myelosuppression and of high-grade hand-foot syndrome—with the lymphatic-containing arm—which speaks to the good choice as lenvatinib as a combination with pembrolizumab.

Transcript edited for clarity.