Real-World Effectiveness and Safety of Pembrolizumab-Lenvatinib Versus Axitinib-Based Regimens in Metastatic Clear Cell Renal Cell Carcinoma: A Multicenter Retrospective Study.

[OBJECTIVES] To compare the real-world effectiveness and safety of pembrolizumab plus lenvatinib with axitinib-based regimens (avelumab plus axitinib or pembrolizumab plus axitinib) as first-line therapy for metastatic clear cell renal cell carcinoma.

[METHODS] We retrospectively analyzed 107 patients treated with immuno-oncology plus vascular endothelial growth factor inhibitor combinations between 2017 and 2025. Propensity score matching (1:1, 0.2 caliper) generated 42 matched pairs. Objective response rate, progression-free survival, overall survival, and adverse events were assessed. Multivariable logistic regression and Cox regression analyses were performed in the overall cohort, and conditional logistic regression and stratified Cox regression analyses were applied in the matched cohort.

[RESULTS] In the matched cohort, pembrolizumab plus lenvatinib demonstrated a significantly higher objective response rate than axitinib-based regimens. The incidence of any-grade and grade ≥ 3 adverse events was similar between regimens. However, pembrolizumab plus lenvatinib was associated with higher rates of hypertension (including grade ≥ 3 hypertension), fatigue, appetite loss, and rash in the full-dose subgroup. Progression-free and overall survival did not differ significantly. Multivariate analyses identified pembrolizumab plus lenvatinib treatment as an independent predictor of objective response, whereas survival outcomes were associated with clinical factors rather than the regimen type.

[CONCLUSIONS] Pembrolizumab plus lenvatinib achieved a superior tumor response to axitinib-based regimens, whereas survival outcomes were comparable. Treatment selection should balance enhanced antitumor activity with differences in toxicity profiles.