Lenvatinib and Pembrolizumab Outperform Sunitinib in Advanced RCC

Jaime Merchan, MD

Treatment with lenvatinib (Lenvima) and pembrolizumab (Keytruda) led to significantly longer rates of progression-free survival (PFS) and overall survival (OS) in the phase 3 CLEAR study (NCT02811861) for the treatment of patients with advanced renal cell carcinoma (RCC).¹

Data come from a biomarker analysis of the CLEAR trial in which investigators compared 3 treatments for advanced RCC: lenvatinib plus pembrolizumab, lenvatinib plus everolimus, and sunitinib (Sutent). Compared with sunitinib, the lenvatinib and pembrolizumab combination was more effective in this patient population, regardless of the tested markers. This included gene expression signatures related to cell growth, blood vessel formation, and immune response.

“This confirms the value, importance, and the relevance of this combination in advanced renal cell carcinoma, regardless of any genomic transcriptomics or biomarker characteristics,” Jaime Merchan, MD, told Targeted Oncology_^TM in an interview.

This analysis shows that biomarkers do not impact the superiority of lenvatinib plus pembrolizumab compared with sunitinib when used as a first-line therapy in patients with advanced RCC.

In the interview, Merchan, professor, co-leader of the Translational and Clinical Oncology Research Program and director of the phase 1 clinical trials program at the Sylvester Comprehensive Cancer Center at the University of Miami, explained the background and data from a biomarker analysis of the CLEAR trial in advanced RCC.

Human kidney on science background: © Rasi - stock.adobe.com

Targeted Oncology: What was the CLEAR trial evaluating?

Merchan: The CLEAR trial was a randomized, phase 3, controlled trial of a triplet for patients with treatment-naive metastatic clear cell renal carcinoma that compared 3 regimens: pembrolizumab and lenvatinib, everolimus and lenvatinib, and sunitinib. In a nutshell, this trial, which was published several years ago in The New England Journal of Medicine, shows that the combination of lenvatinib and pembrolizumab was superior to the control of sunitinib in patients with advanced disease, with an improvement in median progression-free survival and overall survival.

What were some of the findings from the most recent analysis?

This study was a biomarker analysis of the CLEAR trial trying to determine a correlation between a progression-free survival in the pembrolizumab and lenvatinib vs sunitinib group in correlation with different biomarkers including PD-L1 expression, gene expression signatures, and genomic abnormalities.

Did you observe any differences depending on biomarkers or on tumor characteristics?

The results of the study showed that regardless of any biomarkers, the combination of pembrolizumab and lenvatinib was superior or associated with a better median progression-free survival compared with sunitinib in both expression of PD-L1, different genomic signatures or gene expression analyses, and also a genomic alterations, specifically mutations [in] the common renal cell carcinoma gene alterations. The study showed no clear correlation of any benefit with any of these biomarkers.

What are the potential clinical implications or takeaways for colleagues based on these findings?

The takeaway from this study is that the combination of lenvatinib and pembrolizumab is an excellent combination that is associated with high response rates, including a good number of complete responses and high median progression-free survival compared with sunitinib. This confirms the value, importance, and relevance of this combination in advanced renal cell carcinoma, regardless of any genomic transcriptomics or biomarker characteristics.

Are there any further steps or more analyses planned from this data?

There will be further analysis. In my opinion, there needs to be a new type of analysis that may be independent of the classical current gene signatures that are validated in renal cell carcinoma. Hopefully, in the near future, an analysis using different levels of gene expression or different signatures in RCC will be conducted.

REFERENCE:

Motzer RJ, Porta C, Eto M, et al. Biomarker analyses in patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial. J Clin Oncol. 2024;42(suppl 16):4504. doi:10.1200/JCO.2024.42.16_suppl.4504