Perioperative Lenvatinib Plus Pembrolizumab Is Safe and Effective in Advanced ccRCC

Lenvatinib (Lenvima) plus pembrolizumab (Keytruda) was safe and generated preliminary efficacy signals as perioperative therapy in patients with locally advanced, nonmetastatic clear cell renal cell carcinoma (ccRCC), according to findings from a phase 2 study (NCT04393350), which were presented at the 2025 Genitourinary Cancers Symposium.1

In those who were evaluable for efficacy, the combination produced partial responses (PRs) in 17.6% (n = 3/17); stable disease occurred in 82.4% (n = 14/17). Treatment elicited a median primary renal tumor size reduction of 21.8% (range, 3.4%-37.0%). There were no instances of disease progression during the time when patients were receiving pembrolizumab plus lenvatinib before surgery.

Of those who completed the neoadjuvant treatment course, 16 (94%) underwent surgery as planned. One patient did not receive surgery due to cognitive decline, proteinuria, and a potential requirement for postoperative hemodialysis.

“Further data, including long-term outcomes, correlative studies, quality-of-life [QOL] assessments, and frailty/sarcopenia indices, will be reported,” Mehmet A. Bilen, MD, an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and director of the Genitourinary Medical Oncology Program at Winship Cancer Institute of Emory University in Atlanta, Georgia, and coauthors wrote in the poster.

Trial Design

In this phase 2 study, patients with biopsy-proven ccRCC and a clinical stage of at least T3Nx or TanyN+ or unresectable disease were assigned to receive 4 cycles of pembrolizumab plus lenvatinib at a starting dose of 20 mg daily over 12 weeks. Following neoadjuvant therapy, patients underwent surgery and then 13 cycles of pembrolizumab alone in the adjuvant setting.

The trial’s primary end point was objective response rate at week 12 per independent radiological review using RECIST 1.1 criteria. Secondary end points included safety and tolerability, disease-free survival, overall survival, surgical outcomes, and QOL.

Patients 18 years and older with an ECOG performance status of 0 or 1 and adequate absolute neutrophil counts, platelet counts, and hemoglobin levels were eligible for enrollment on the trial.2 Those with evidence of metastatic disease via pretreatment imaging, prior treatment with lenvatinib, or an active infection requiring systemic therapy were ineligible to enroll.

Patient Characteristics

Of 18 patients assessed at baseline, the median age was 64.5 years (range, 28-84), and most were male (66.7%) and White (66.7%).1 Additionally, most patients had a clinical TNM stage of T3N0M0 (94.4%) and an ECOG performance status of 1 (61.1%). The median tumor size at baseline was 77.3 mm (range, 50.0-180.1).

One patient did not complete neoadjuvant therapy and was not evaluable due to immune-related adverse effects (IRAEs) consisting of grade 4 rhabdomyolysis and hepatitis; this patient underwent surgery following IRAE management.

Safety Findings

Any-grade treatment-related AEs (TRAEs) included fatigue (83.3%), hypertension (55.6%), hypothyroidism (55.6%), palmar-plantar erythrodysesthesia (50.0%), and diarrhea (44.4%). The most common grade 3 or higher TRAEs were hypertension (38.9%), nausea (11.1%), and proteinuria (11.1%).

Treatment-related serious AEs included 1 thromboembolic event (5.6%) and 1 instance (5.6%) of autoimmune rhabdomyolysis. Additionally, 50% (n = 9) of patients required lenvatinib dose reductions to 14 mg due to TRAEs.

Data showed no intraoperative complications; no postoperative complications were associated with lenvatinib plus pembrolizumab. Six patients were still receiving adjuvant pembrolizumab at the time of analysis. Disease recurrence was highlighted in 2 patients, and 1 patient died following progressive disease.

References

1. Bilen M, Liu Y, Davarpanah A, et al. Phase 2 study of perioperative lenvatinib (L) with pembrolizumab (P) in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. J Clin Oncol. 2025;43(suppl 5):555. doi:10.1200/JCO.2025.43.5_suppl.555
2. Perioperative lenvatinib with pembrolizumab in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. ClinicalTrials.gov. Updated August 14, 2024. Accessed February 15, 2025. https://clinicaltrials.gov/study/NCT04393350