267 - Neoadjuvant Pembrolizumab and Stereotactic Radiotherapy Prior to Nephrectomy for Renal Cell Carcinoma (NAPSTER): A Phase II Randomized Clinical Trial
Presenter(s)
M. Ali1,2, D. I. Pryor3,4, S. Wood3,5, M. Bressel1,6, D. Moon7, A. A. Azad1,8, L. Au1,8, L. Spain1,8, C. Mitchel1,9, D. Murphy10, N. Hardcastle11,12, R. Eapen13, M. Perera13, B. Thomas14, L. M. Wong7,15, K. Cuff16, W. Ranasinghe17, C. DSouza18, P. Neeson1,18, and S. Siva1,2; 1Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia, 2Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, 3Princess Alexandra Hospital, Brisbane, QLD, Australia, 4Queensland University of Technology, Brisbane, QLD, Australia, 5Metro South Hospital and Health Service, Brisbane, QLD, Australia, 6Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia, 7Deapartment of surgery, The University of Melbourne, Melbourne, VIC, Australia, 8Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, 9Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, 10Department of Surgery, Peter MacCallum Cancer Center, Melbourne, VIC, Australia, 11Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, 12University of Wollongong, Wollongong, Australia, 13Department of Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, 14Department of Urology, Royal Melbourne Hospital, Melbourne, VIC, Australia, 15Department of Urology, St Vincent’s health, Melbourne, VIC, Australia, 16Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, QLD, Australia, 17Department of Urology, Monash Health, Melbourne, VIC, Australia, 18Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Purpose/Objective(s): In a first-in-human trial, we hypothesize that neoadjuvant SABR with or without pembrolizumab before nephrectomy will result in an immune response in the presence of an extensive reserve of tumor-associated antigens in the intact primary, resulting in better clinical outcomes
Materials/Methods: NAPSTER is a multi-institutional prospective, open-label, phase II, randomized, non-comparative clinical trial of adult patients with biopsy-confirmed clear-cell RCC stage T1B-T3, N0 or N1, M0 or low volume M1 planned for nephrectomy. Patients were randomized 1:1 to receive neoadjuvant SABR 42 Gy in 3 fractions to the primary RCC (Neo. SABR) or SABR and three cycles of pembrolizumab (Neo. SABR+IO), followed by radical nephrectomy (RN). The co-primary endpoints were pathological response and changes in tumor-responsive T-cells. Safety was assessed with common terminology criteria for adverse events (CTCAE) version 5.0 and the Clavin-Dindo (CD) grading system for neoadjuvant treatment and nephrectomy, respectively.
Results: From April 2022 to October 2024, 20 patients with a median age of 66 years (IQR: 57 – 74) were randomized (9 to Neo. SABR and 11 to Neo. SABR+IO). Nine had T1b disease, 4 had T2, and 7 had T3. Three patients had low volume M1 disease treated with metastasis-directed therapy (radiotherapy/surgery). Median (IQR) for maximum dimension was 62 mm (50-82) in Neo. SABR and 60 mm (47-90) in Neo. SABR+IO. All patients completed neoadjuvant treatment as per protocol. One patient experienced an infusion reaction with pembrolizumab and received a reduced dose in cycle 2. Two patients (both in Neo. SABR+IO) did not undergo nephrectomy after completing neoadjuvant treatment (patient choice [n=1]; unanticipated anesthetic contraindication [n=1]). Of the 18 patients undergoing nephrectomy, all surgical margins were negative, and four (22%) showed features of tumor necrosis and fibrosis in histopathology specimens. The incidence of treatment-related CTCAE-grade 2 and 3 events was 3/9 and 2/9 with Neo. SABR, respectively and 4/11 and 1/11 in Neo. SABR+IO, respectively. There were no grade 4-5 events. For all cases, operating surgeons did not report any significant additional technical difficulties during RN. One patient experienced a CD grade-2 wound complication with Neo. SABR. In the Neo SABR+IO arm, one patient developed CD grade 2 and 3 wound infection and hematoma, respectively, and another one experienced grade 2 retroperitoneal hematoma.
Conclusion: Neoadjuvant SABR +/- pembrolizumab is well tolerated, technically feasible and does not result in increased surgical complications. Post-nephrectomy histopathology specimens demonstrated neoadjuvant treatment effect. The final results of cytological and tumor-responsive T-cell changes are awaited and will may guide us for future prospective randomized trials in this space. (NCT05024318)