(UroToday.com) The 2023 AUA annual meeting included an advanced kidney cancer session, featuring a presentation by Dr. Eric Singer discussing the assessment of surgical complications in patients with metastatic clear cell RCC receiving perioperative cabozantinib and nivolumab in the Cyto-KIK clinical trial. In the era of interferon-based therapy, radical nephrectomy improved survival in patients with metastatic RCC and became the standard of care.
The CARMENA trial showed sunitinib alone is non-inferior to nephrectomy followed by sunitinib, however, follow-up analysis showed that there may be some benefit from nephrectomy in favorable risk patients.1 The SURTIME trial, which examined immediate versus deferred cytoreductive nephrectomy with sunitinib, was closed due to poor accrual but the deferred approach led to more patients receiving systemic therapy and longer overall survival.2 Importantly, 60%-80% of patients in the first-line IO+IO and IO+VEGFR TKI trials had prior nephrectomies.
Currently, there is no prospective data to determine the benefit of cytoreductive nephrectomy with the current immunotherapy-based standard of care. Pre-clinical and clinical data show that neoadjuvant immunotherapy is superior to adjuvant immunotherapy in eradicating metastatic disease, and CheckMate 9ER established that cabozantinib and nivolumab is an effective frontline regimen in metastatic RCC.3 The perioperative safety of cabozantinib and nivolumab in metastatic clear cell RCC, and the optimal timing to hold cabozantinib prior to surgery, are unknown. At the AUA 2023 annual meeting, Dr. Singer and colleagues presented results from the Cyto-KIK clinical trial.
In this phase 2 trial, patients with metastatic clear cell RCC are given cabozantinib (40 mg daily) and nivolumab (480 mg q4 weeks) for 12 weeks prior to cytoreductive nephrectomy. Post-operatively, patients resume treatment with cabozantinib and nivolumab until disease progression. The predicted terminal half-life of cabozantinib is approximately 99 hours. Thus, a 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabozantinib and nephrectomy. Evaluable patients completed at least 10 of 14 cabozantinib doses prior to the pre-specified period of stopping pre-operative cabozantinib. The primary objective was to evaluate complete response rate in patients receiving combination cabozantinib and nivolumab followed by nephrectomy and subsequent continuation of double systemic therapy. Surgical complications assessed using the Clavien-Dindo classification system is a secondary endpoint of this study. The trial design is as follows:
Overall, 16 patients enrolled, and 14 completed nephrectomy to date. There were 12 (75%) male patients, 4 (25%) female, ages 44-77 years old with median age at diagnosis 58.5 years old. BMIs ranged from 17.8 kg/m2 to 39.3 kg/m2 with median BMI of 28.7 kg/m2. There were 63% of patients classified by IMDC as intermediate-risk and 37% as poor-risk disease. Predominant sites of disease included lung nodules, retroperitoneal adenopathy, and mediastinal adenopathy; there were no brain or bone lesions. The clinical characteristics are as follows:
Prior to nephrectomy, cabozantinib was dose reduced in 2/14 (14%) of patients who completed nephrectomy, and cabozantinib was held in 6/14 (42%) of nephrectomy patients during the course of treatment. Dose modifications were due to standard adverse events associated with cabozantinib + nivolumab, including transaminitis, fatigue, and rash. Three evaluable patients completed nephrectomy within the 21-day interval and 5 within the 14-day interval after discontinuation of cabozantinib. There were no treatment-related surgical complications in patients who completed nephrectomy in either cohort, and there were no delays in resuming combination systemic therapy after surgery.
Dr. Singer concluded his presentation by discussing the assessment of surgical complications in patients with metastatic clear cell RCC receiving perioperative cabozantinib and nivolumab in the Cyto-KIK clinical trial by highlighting that combination cabozantinib and nivolumab can be safely administered up to 14 days prior to cytoreductive nephrectomy. The target enrollment is 42 patients and the trial is ongoing.
Presented by: Eric Singer, MD, MS, FACS, FASCO, The Ohio State Comprehensive Cancer Center, Columbus, OH
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023
References:
- Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Engl J Med 2018 Aug 2;379(5):417-427.
- Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol 2019 Feb 1;5(2):164-170.
- Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841.