Efficacy and safety of lenvatinib plus everolimus in metastatic renal cell carcinoma after immune checkpoint and VEGFR tyrosine kinase inhibitors.

Abstract

489 Background: Limited studies have investigated the real-world effectiveness and safety of Lenvatinib (LEN) combined with everolimus (EVE) in metastatic renal cell carcinoma (mRCC), particularly after failure of immune checkpoint inhibitors (ICIs) and VEGFR tyrosine kinase inhibitors (TKIs). This study aimed to evaluate the efficacy and safety of LEN plus EVE in patients who had progressed after these prior therapies. Methods: This single-center retrospective study included mRCC patients at Asan Medical Center, Korea, who initiated LEN plus EVE as second-line or later therapy between September 2017 and June 2024. We reviewed electronic medical records for dosage, dose reductions, discontinuation, response, progression, and survival outcomes. The primary objectives were objective response rate (ORR) and progression-free survival (PFS), with secondary objectives including overall survival (OS), adverse events, and prognostic factors. Results: Eighty-two eligible patients were included, predominantly with clear cell type (n=74, 90.2%). ECOG performance status was 1 in 54 patients, and 2 in 26. At treatment initiation, the IMDC risk distribution was favorable (n=6, 7.3%), intermediate (n=48, 58.5%), and poor (n=28, 34.1%). The median number of prior therapies was four (range, 1-7), with 80.5% receiving LEN plus EVE as fourth-line or later therapy. All patients had prior anti-angiogenic TKI exposure, 86.6% had been treated with ICIs, and 37.8% had prior mTOR inhibitor therapy. The ORR was 39.0% (n=32/82), with a disease control rate (DCR) of 81.7% (n=67/82). The median follow-up duration was 21.8 months. The median time to progression (TTP) was 6.4 months (95% Confidence Interval [CI], 5.4-9.7), while the median PFS was 5.4 months (95% CI, 4.3-6.4), and the median OS was 7.7 months (95% CI, 6.2-12.1). Subgroup analyses indicated comparable ORR and PFS for patients treated beyond the fourth line (ORR 36.4%, PFS 5.3 months), those previously exposed to mTOR inhibitors (ORR 29.0%, PFS 5.5 months), and those who had progressed after both ICI and TKIs (ORR 38.0%, PFS 5.3 months). The median treatment duration was 6.8 months. Adverse events were significant: 54.9% required dose reductions of LEN, and 25.6% experienced treatment interruptions. For EVE, 17.1% required dose reductions, and 25.6% had interruptions due to toxicities. Notably, 31 patients (37.8%) developed proteinuria, with 18 experiencing grade 3 or higher. Conclusions: LEN plus EVE shows promising efficacy and disease control in heavily pretreated mRCC patients after failure of ICIs and VEGFR TKIs, even beyond the fourth line and in those previously treated with mTOR inhibitors. The safety profile aligns with known adverse effects, but the high incidence of proteinuria is notable. Further studies are warranted to optimize treatment protocols in this patient population.