CLEAR Trial: Lenvatinib-Pembrolizumab Efficacy Consistent Across Biomarker Subgroups in Advanced Renal Cell Carcinoma
Key Insights
The CLEAR trial's biomarker analysis reveals that lenvatinib plus pembrolizumab (L+P) consistently improves outcomes in advanced renal cell carcinoma (search) (aRCC) regardless of RCC driver mutations, PD-L1 (search) expression, or gene expression signatures.
No significant association was found between PD-L1 (search) levels and best overall response or progression-free survival (PFS) within either the L+P or sunitinib treatment arms.
High proliferation and MYC signature scores were associated with shorter PFS in the sunitinib arm, while high angiogenesis scores correlated with longer PFS.
The Phase 3 CLEAR trial, which demonstrated the superior efficacy of lenvatinib plus pembrolizumab (L+P) over sunitinib in first-line treatment of advanced renal cell carcinoma (search) (aRCC), has now reported results from biomarker analyses. These analyses, presented in Annals of Oncology, aimed to identify predictive biomarkers for treatment response within the CLEAR trial cohort.
The study evaluated PD-L1 (search) expression via immunohistochemistry (IHC) and performed next-generation sequencing (whole exome sequencing/RNA-sequencing) on archival tumor specimens. The researchers investigated the association between PD-L1 combined positive score (CPS), gene signature scores (T-cell inflamed gene-expression profile [TcellinfGEP], non-TcellinfGEP signatures including proliferation and angiogenesis), and molecular subtypes with best overall response (BOR) and progression-free survival (PFS).
Biomarker Analysis Details
Within-arm analyses using continuous values showed no association between PD-L1 (search) levels and BOR/PFS for either treatment. PFS hazard ratios between arms were similar regardless of mutant or wildtype subgroups of RCC driver genes (VHL (search), PBRM1 (search), SETD2, BAP1 (search), KDM5C (search)). No associations between PFS and gene-signature scores were observed for L+P. With sunitinib, high proliferation and MYC signature scores showed shorter PFS; high angiogenesis and microvessel density signature scores showed longer PFS.
Six new molecular subtypes were defined. Tumors of patients with favorable/intermediate risk were enriched in angiogenesis and angiogenesis/stromal clusters; those with poor risk were enriched in proliferative and unclassified (low-TcellinfGEP/low-angiogenesis/low-proliferation) clusters. No association between molecular subtypes and PFS for L+P/sunitinib was observed (after adjustment for KPS and gene signatures that were individually associated with PFS).
Consistent Efficacy Across Subgroups
The study's findings indicate that the improvements in ORR and PFS observed with L+P compared to sunitinib in aRCC were consistent across a range of biomarker subgroups. These subgroups were defined using RCC driver mutations, PD-L1 (search) expression, gene expression signatures, and molecular subtypes. According to the authors, these results suggest that the clinical benefit of L+P is not limited to specific patient populations based on these biomarkers.
These findings reinforce the role of lenvatinib plus pembrolizumab as a first-line treatment option for advanced renal cell carcinoma (search), demonstrating consistent efficacy across diverse molecular profiles.