In a trial with a modified primary endpoint due to slow accrual reported in JAMA Oncology,1 Axel Bex, MD, PhD, and colleagues found that deferred cytoreductive nephrectomy after sunitinib did not improve the 28-week progression-free rate vs immediate nephrectomy followed by sunitinib in patients with metastatic renal cell carcinoma (RCC).
Axel Bex, MD, PhD
Study Details
The trial was begun as a phase III trial in July 2010 and continued until March 2016, with a clinical cutoff date for the current report in May 2017. Patients with clear-cell metastatic RCC with resectable primary tumor and ≤ 3 surgical risk factors from 19 sites in the Netherlands, Belgium, the United Kingdom, and Canada were randomly assigned to immediate cytoreductive nephrectomy followed by sunitinib therapy or 3 cycles of sunitinib followed by cytoreductive nephrectomy in the absence of progression followed by sunitinib therapy.
The primary endpoint was progression-free survival, with analysis requiring a target population of approximately 458 patients. Due to poor accrual, the independent data monitoring committee endorsed the reporting of intention-to-treat analysis of 28-week progression-free rate, instead of progression-free survival, for the 50 patients assigned to immediate cytoreductive nephrectomy and 49 patients assigned to delayed surgery.
“The independent data monitoring committee endorsed the reporting of intention-to-treat analysis of 28-week progression-free rate....”— Axel Bex, MD, PhD
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Progression-Free Rate at 28 Weeks
Median follow-up was 3.3 years. The 28-week progression-free rate was 43% in the deferred surgery group vs 42% in the immediate surgery group (P = .61). The progression-free survival hazard ratio for deferred vs immediate surgery was 0.88 (P = .57). On intention-to-treat analysis, median overall survival was 32.4 months in the deferred surgery group vs 15.0 months in the immediate surgery group (hazard ratio = 0.57, P = .03). The per-protocol population (excluding patients ineligible or not receiving the allocated treatment) consisted of 38 patients in the deferred surgery group and 35 patients in the immediate surgery group; on per-protocol analysis, the difference in overall survival for the deferred vs immediate surgery group was no longer significant (HR= 0.71, P = .23).
Sunitinib treatment was received by 48 (98%) of 49 patients in the deferred cytoreductive nephrectomy group vs 40 (80%) of 50 patients in the immediate surgery group. Systemic progression prior to planned cytoreductive nephrectomy in the deferred surgery group resulted in per-protocol recommendation against nephrectomy in 14 patients (29%).
The investigators concluded, “Deferred [cytoreductive nephrectomy] did not improve the 28-week [progression-free rate]. With the deferred approach, more patients received sunitinib and [overall survival] results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned [cytoreductive nephrectomy]. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell metastatic RCC requiring sunitinib.”
Axel Bex, MD, PhD, of the Division of Surgical Oncology, The Netherlands Cancer Institute, is the corresponding author for the JAMA Oncology article. ■
DISCLOSURE: This study was supported by Pfizer and Kankerbestrijding/KWF from the Netherlands through the Cancer Research Fund of the European Organisation for Research and Treatment of Cancer. Dr. Bex reported receiving grants from Pfizer during the conduct of the study; receiving personal fees from Pfizer, Eisai Co., Ipsen, EUSA, and Bristol-Myers Squibb; and serving as a member of the steering committee of the IMMotion 010 adjuvant trial in renal cell carcinoma from Roche outside the submitted work. For disclosure information of all authors, see jamanetwork.com.
REFERENCE
1. 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. JAMA Oncol 5(2):164-170, 2019.
