Commentary
The results of the current phase 3 CLEAR trial highlight the efficacy and safety of lenvatinib plus pembrolizumab as a first-line treatment in advanced ccRCC. This trial adds to the rapidly growing body of literature supporting the notion that the combination of anti-PD-1 based therapy with either CTLA-4 antibodies or VEGF receptor tyrosine kinase inhibitors (TKI) improves outcomes in previously untreated patients with advanced ccRCC. Previously presented data from Keynote-426 (pembrolizumab plus axitinib), Checkmate-214 (nivolumab plus ipilimumab), and Javelin Renal 101 (Avelumab plus axitinib) have also shown improved outcomes with combination therapy in the frontline setting.1-4 While the landscape of therapeutic options in the frontline setting continues to grow, there remains lack of clarity as to how to tailor our therapeutic decisions for specific patient populations. The exception would be nivolumab and ipilimumab, which are currently indicated for IMDC intermediate- or poor-risk patients.
The combination of VEGFR TKI therapy and PD-1 antibodies provides rapid disease control, with a median time to response in the current study of 1.9 months, and, generally speaking, a low risk of progression in the first 6 months of therapy. While cross-trial comparisons are always problematic, the PFS reported in this study and others with VEGFR TKI and PD-1 antibody combinations is quite impressive and surpasses that noted in Checkmate 214.3 While the median OS survival has not yet been reached, the long duration of PFS and complete response rate of 16% in this study certainly make this an attractive frontline option for newly diagnosed patients with advanced ccRCC. Longer follow-up is needed to confirm the survival benefit noted.
Applications for Clinical Practice
The current data support the use VEGFR TKI and anti-PD1 therapy in the frontline setting. How to choose between such combination regimens or combination immunotherapy remains unclear, and further biomarker-based assessments are needed to help guide therapeutic decisions for our patients.