Phase 2 study of perioperative lenvatinib (L) with pembrolizumab (P) in patients with locally advanced nonmetastatic clear cell renal cell carcinoma.
Authors: Bilen Mehmet Asim , Liu Yuan , Davarpanahfakhr Amir , Nazha Bassel , Brown Jacqueline T , Osunkoya Adeboya O. , Thomson Sierra , Session Wilena , Hartman Caitlin , McClintock Greta Russler , Caulfield Sarah , Joshi Shreyas , Narayan Vikram M. , Ogan Kenneth , Kucuk Omer , Carthon Bradley Curtis , Kissick Haydn T. , Master Viraj A. 
Published: February 2025

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Background:
L is an oral multi-kinase inhibitor targeting vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor α, RET, and KIT. P is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity for binding to the programmed cell death 1 receptor. The combination of P+L was approved for the treatment of advanced renal cell carcinoma (RCC). The enhanced response rates in metastatic RCC with this combination, along with emerging neoadjuvant data, support its potential use in the neoadjuvant setting.
Methods:
Patients with biopsy-confirmed clear cell RCC of clinical stage ≥ T3Nx, TanyN+, or those deemed unresectable by an experienced surgical team were eligible for this study. They received 4 cycles of P+L (starting dose: 20 mg daily) over 12 weeks, followed by surgery and 13 cycles of adjuvant P monotherapy. The primary endpoint was the objective response rate (ORR) at week 12, assessed per RECIST v1.1 by independent radiological review, including complete and partial responses. Secondary endpoints included safety, tolerability, disease-free survival (DFS), overall survival (OS), surgical outcomes, and quality of life.
Results:
At the time of analysis, 2 patients were still receiving neoadjuvant treatment. Of the 15 patients who completed the 12-week neoadjuvant regimen, 14 (93%) proceeded to surgery as planned without delay following a minimum 7-day washout period. One patient is awaiting surgery. One patient was not evaluable due to incomplete neoadjuvant treatment caused by concurrent immune-related adverse events (irAEs) rhabdomyolysis and hepatitis (grade 4), though surgery was performed after irAE management. Among evaluable patients, 3/15 (20%) exhibited a partial response, while 12/15 (80%) had stable disease. No patients experienced disease progression while on pembrolizumab+lenvatinib. The median reduction in primary renal tumor size was 21% (range: 3-37%).The most common adverse events (AEs) were fatigue (n=14), palmar-plantar erythrodysesthesia syndrome (n=9), hypertension (n=8), mucositis (n=8), and proteinuria (n=8). Intraoperative complications were not observed, and no postoperative complications related to the drug were noted. No other treatment related grade 4or 5 AEs related to lenvatinib or surgery occurred except for the unevaluable participant. At the time of analysis, two patients had disease recurrence, and one patient had died due to disease progression.
Conclusions:
The combination of P+L demonstrated clinical activity and a favorable safety profile in the perioperative setting for patients with locally advanced, non-metastatic clear cell RCC. Further data, including long-term outcomes, correlative studies, quality of life assessments, and frailty/sarcopenia indices, will be reported (NCT04393350). Clinical trial information:
NCT04393350
.