Lenvatinib's efficacy in heavily pre-treated metastatic renal cell carcinoma: Insights from a European multicenter study.

510 Background: Lenvatinib-based therapy has shown efficacy in the frontline treatment of metastatic renal cell carcinoma (mRCC). However, there is uncertainty about the role of Lenvatinib (LEN) in subsequent lines of treatment, particularly after immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). This study aimed to describe the real-world clinical outcomes of patients (pts) with mRCC treated with LEN-based therapies beyond first-line treatment. Methods: Retrospective multicenter study including all pts with mRCC treated with LEN-based therapies beyond first-line at seven European centers from October 2020 to August 2024. Data on patient characteristics, treatments, and outcomes were collected. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included disease control rate (DCR), overall survival (OS), and safety. This study was approved by a centralized institutional review board (Gustave Roussy). Results: A total of 115 pts were included, 80% males, with a median age of 60.0 years. Of them, 80.9% had clear-cell subtype. Lenvatinib was mainly used after a median of 3 previous lines of treatment (range 2-8), either alone (41.7%) or in combination with everolimus (35.7%), pembrolizumab (PEM) (20.0%), or investigational agents (2.6%). Most of the pts had previously received ICI (88.7%) or TKI (96.5%), including cabozantinib (89.6%). The ORR was 28.2% and DCR was 65.5%. With a median follow-up time of 13.5 months (mo), the median PFS was 6.0 mo (95% CI 4.3-8.4 mo). Previous Cabozantinib (HR 4.3, p=0.02), bone metastases (HR 2.1, p=0.002) and the intermediate (HR 3.4, p=0.009) or poor IMDC risk (HR 7.7, p<0.001) significantly impacted PFS in the multivariate analysis. Median OS was 10.1 mo (95% CI 6.9-12.4 mo). Multivariate Cox models identified poor IMDC risk (HR 7.4, p<0.001) and bone metastases (HR 2.3, p=0.002) as negative independent prognostic factors for OS. On the contrary, LEN-PEM treatment (HR 0.3, p=0.017) had a positive impact on OS. Up to 38.3% of the pts started LEN with a dose adjustment (<18mg per day). On treatment, dose modifications were required in 33.9% of pts, with 9.6% discontinuing due to toxicities. Conclusions: In our cohort, LEN demonstrated meaningful clinical activity in heavily pretreated mRCC pts. The safety profile was manageable. These findings provide evidence to support its utilization in pretreated pts with mRCC.