Abstract A015: Phase II trial of perioperative Lenvatinib plus Pembrolizumab in locally advanced nonmetastatic clear cell renal cell carcinoma

Abstract Lenvatinib, a multi-tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, PDGFRα, RET, and c-KIT, has demonstrated clinical activity in combination with the PD-1 inhibitor, Pembrolizumab in advanced renal cell carcinoma (RCC). When paired with immune checkpoint blockade, Lenvatinib’s vascular-normalizing and immunomodulatory effects are thought to alleviate intratumoral immune suppression and enhance anti-tumor T-cell responses. Administering this regimen in the neoadjuvant setting may therefore promote early systemic immune activation, reduce primary tumor burden, and eradicate micrometastatic disease prior to surgery, ultimately improving surgical outcomes and long-term disease control. We conducted a phase II, single-arm clinical trial (NCT04393350) evaluating neoadjuvant Lenvatinib plus Pembrolizumab in 17 patients with locally advanced, non-metastatic clear cell RCC (ccRCC). Eligible patients had biopsy-confirmed ccRCC of clinical stage ≥T3Nx, TanyN+, or disease considered unresectable by an experienced surgical team. Participants received 4 cycles of Lenvatinib plus Pembrolizumab over 12 weeks, followed by nephrectomy after a 7-day washout period and adjuvant Pembrolizumab monotherapy for 13 cycles. The primary endpoint was objective response rate (ORR) at week 12 per RECIST v1.1. Secondary endpoints included safety, tolerability, surgical outcomes, and quality of life. Correlative immune analyses assessed functional and phenotypic changes in circulating and intratumoral T cells and myeloid populations. All 17 patients underwent nephrectomy as planned without surgical delay. At week 12, 3/17 (18%) achieved a partial response and 14/17 (82%) had stable disease, with no disease progression occurred during neoadjuvant therapy. The median reduction in primary tumor size was 21.8% (range: 3.4-37.1%). Treatment was well tolerated, with no grade 4 or 5 toxicities or perioperative complications. Correlative analyses demonstrated robust immune activation. After 1-2 cycles of therapy (C1D8 and C2D1), peripheral CD4+ and CD8+ T cells showed significant increases in Ki-67 expression and co-expression of HLA-DR/CD38, markers associated with recent activation and responsiveness to immunotherapy. Tumor analyses revealed increased CD8+ T-cell infiltration following neoadjuvant treatment. At the time of reporting, two patients had experienced disease recurrence, and one patient had died from disease progression. Collectively, these findings indicate that perioperative Lenvatinib plus Pembrolizumab is safe, clinically active, and immunologically stimulatory in patients with locally advanced ccRCC. The results support further evaluation of this combination in the curative-intent setting and provide a framework for future neoadjuvant immunotherapy strategies in RCC. Citation Format: BaoHan T. Vo, Mehmet A. Bilen, Paris E. Davey, Yuan Liu, Amir H. Davarpanah, Bassel Nazha, Jacqueline T. Brown, Sierra Williams, Wilena Session, Caitlin Hartman, Adriana Boyanton, Rachel Greenwald, Greta R. McClintock, Sarah Caulfield, Shreyas S. Joshi, Vikram M. Narayan, Kenneth Ogan, Omer Kucuk, Bradley C. Carthon, Adeboye O. Osunkoya, Haydn T. Kissick, Viraj A. Master. Phase II trial of perioperative Lenvatinib plus Pembrolizumab in locally advanced nonmetastatic clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A015.