Annals of Oncology | Lenvatinib plus Pembrolizumab versus Sunitinib as First-line Treatment for Advanced Renal Cell Carcinoma: A Biomarker Analysis

This article systematically evaluates the efficacy of Lenvatinib combined with Pembrolizumab compared to Sunitinib in advanced renal cell carcinoma (aRCC) through the CLEAR clinical trial and analyzes the predictive roles of multiple biomarkers. The study finds that Lenvatinib plus Pembrolizumab consistently demonstrates superior objective response rates and progression-free survival across all PD-L1 expression levels, RCC driver gene mutation statuses, and molecular subtypes, providing critical insights for personalized treatment of aRCC.

Literature Overview
This article, titled 'Biomarker analyses from the phase 3 randomized CLEAR trial: Lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma', published in the journal 'Annals of Oncology', reviews and summarizes the biomarker analysis results from the CLEAR phase 3 trial. The study compares the efficacy of Lenvatinib plus Pembrolizumab and Sunitinib as first-line treatments for advanced renal cell carcinoma (aRCC), evaluating efficacy differences based on multiple dimensions including PD-L1 expression, RCC driver gene mutations, gene expression profiles, and molecular subtypes, while exploring potential biomarker associations.

Background Knowledge
Advanced renal cell carcinoma (aRCC) is a highly heterogeneous tumor, and its treatment strategy has evolved in recent years from single-targeted therapy to combination immunotherapy and targeted therapy. Although PD-L1 and VEGF pathway inhibitors have shown clinical efficacy, their predictive biomarkers remain controversial. Previous studies suggest that different molecular subtypes and gene expression features (e.g., T-cell inflammation, angiogenesis, proliferation) may influence treatment response, but definitions and results across trials vary. Therefore, exploring biomarkers in the CLEAR trial for Lenvatinib plus Pembrolizumab combination therapy can help elucidate its mechanism of action across subtypes and inform clinical decision-making.

Research Methods and Experimental Design
The study included patient samples from the CLEAR phase 3 trial and analyzed PD-L1 expression (Combined Positive Score, CPS, determined by IHC), RCC driver gene mutations (VHL, PBRM1, SETD2, BAP1, KDM5C), gene expression features (e.g., T-cell inflamed GEP, proliferation, MYC, angiogenesis), and molecular subtypes (e.g., angiogenesis, immune/proliferative, proliferative, unclassified). All analyses were adjusted for baseline KPS scores, and progression-free survival (PFS) and best overall response (BOR) were evaluated using Cox regression models and Harrell’s C-index. The study particularly examined the relationship between PD-L1 CPS and gene expression features, and differences in treatment efficacy across molecular subtypes.

Key Conclusions and Perspectives

• PD-L1 CPS did not show a significant association with BOR or PFS in either the Lenvatinib plus Pembrolizumab or Sunitinib treatment arms, indicating that PD-L1 expression lacks predictive value in aRCC.
• Lenvatinib plus Pembrolizumab showed superior efficacy compared to Sunitinib across all mutation and wild-type subgroups in RCC driver gene (VHL, PBRM1, SETD2, BAP1, KDM5C) analyses, suggesting that the combination therapy is effective regardless of mutational status.
• In gene expression feature analyses, patients treated with Sunitinib who exhibited high proliferation or high MYC expression had shorter PFS, whereas those with high angiogenesis or high microvessel density had prolonged PFS, consistent with Sunitinib’s anti-angiogenic mechanism.
• While Lenvatinib plus Pembrolizumab showed superior efficacy across all molecular subtypes, molecular subtype itself was not significantly associated with PFS, likely due to its dual mechanism of action (anti-angiogenic and immune checkpoint inhibition).
• The study defined six new molecular subtypes and found that different risk subgroups exhibited enrichment differences in angiogenesis and proliferation features, but these features did not influence the efficacy of combination therapy.

Conclusion
This article systematically analyzed the efficacy of Lenvatinib plus Pembrolizumab versus Sunitinib in the treatment of advanced renal cell carcinoma (aRCC) based on the CLEAR phase 3 trial, while evaluating the impact of multiple biomarkers on treatment response. The study found that Lenvatinib plus Pembrolizumab consistently demonstrated superior efficacy compared to Sunitinib, regardless of PD-L1 expression, driver gene mutation status, or gene expression features. These findings provide critical evidence for first-line treatment decision-making and suggest that PD-L1 expression and molecular subtypes may not serve as standalone predictive biomarkers in aRCC. Further studies are needed to identify more precise biomarkers to optimize personalized treatment strategies.

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