Pembrolizumab plus lenvatinib in first-line metastatic renal cell carcinoma: a single-institution experience and a case of severe treatment-related toxicity with durable tumour control

Abstract

Background: Pembrolizumab plus lenvatinib is a standard first-line treatment for metastatic renal cell carcinoma (mRCC) based on the phase III CLEAR trial. Real- world data are needed to assess effectiveness and toxicity management in routine practice. We report a retrospective single-institution experience and a case of grade 4 immune-related pancreatitis followed by sustained tumour control after treatment discontinuation. Methods: We retrospectively analysed consecutive patients with mRCC treated with first-line pembrolizumab plus lenvatinib at IRCCS Regina Elena from March 2024 through March 2026, with clinical follow-up updated through September 2026. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety outcomes, including dose modifications and permanent treatment discontinuations. Survival was estimated by the Kaplan–Meier method. Results: Thirty-eight patients were treated, and all were evaluable for response. ORR was 78.9% (4 complete responses and 26 partial responses). At a median follow- up of 11.7 months (95% CI 10.8–18.7), median PFS was not reached (95% CI 19.0–NR) and median OS was not reached (95% CI NR–NR). The estimated 12-month PFS and OS rates were 75.1% and 91.7%, respectively. Grade ≥3 adverse events occurred in 39.5% of patients. Lenvatinib was temporarily interrupted in 71.1% and dose-reduced in 60.5%. Permanent discontinuation due to toxicity occurred in 5.3% for lenvatinib and 15.8% for pembrolizumab; both agents were permanently discontinued in 2 (5.3%) patients. A representative case involved a 37-yearold woman who achieved an early partial response but developed grade 4 immune-related pancreatitis requiring high-dose corticosteroids (2 mg/kg) and second-line immunosuppression with mycophenolate mofetil and everolimus. Despite permanent discontinuation of both agents, partial response persisted at the August 2026 data cutoff. Conclusions: In this real-world cohort, pembrolizumab plus lenvatinib demonstrated high response rates and manageable toxicity consistent with pivotal trial data. Proactive dose modulation allowed treatment continuation in most patients, underscoring the importance of effective management of severe treatment-related toxicity in combination regimens to ensure optimal clinical outcomes in routine clinical settings. Download the Plain Language Summary of this article: https://www.drugsincontext.com/plain-language-summaries/plain-language-summary-pembrolizumab-plus-lenvatinib-in-first-line-metastatic-renal-cell-carcinoma-a-single-institution-experience-and-a-case-of-severe-treatment-related-toxicity-with-durable-tumour This article is part of the Special Issue From evidence to the individual patient: pembrolizumab plus lenvatinib in real-world metastatic renal cell carcinoma: https://www.drugsincontext.com/special_issues/from-evidence-to-the-individual-patient-pembrolizumab-plus-lenvatinib-in-real-world-metastatic-renal-cell-carcinoma