PracticeUpdate: Oncology - Winter 2018

EDITOR’S PICKS 12

Sunitinib Alone or After Nephrectomy in Renal Cell Carcinoma The New England Journal of Medicine Take-home message • This phase III trial assessed the role of nephrectomy in 450 patients with confirmed intermediate- or poor-risk metastatic clear- cell renal-cell carcinoma at presentation who either underwent nephrectomy and then sunitinib or sunitinib alone. The median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy/sunitinib group with regard to overall survival (stratified HR for death, 0.89). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy/sunitinib group. No significant differences in response rate or progression-free were observed. • The authors concluded that sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor-risk disease. Jeffrey Wiisanen MD Abstract

COMMENT By Bradley G Somer MD

BACKGROUND Cytoreductive nephrectomy has been the standard of care in metastatic renal-cell carcinoma for 20 years, supported by randomized trials and large, retrospective studies. However, the efficacy of targeted therapies has challenged this standard. We assessed the role of nephrectomy in patients with metastatic renal-cell carcinoma who were receiving targeted therapies. METHODS In this phase III trial, we randomly assigned, in a 1:1 ratio, patients with confirmed metastatic clear-cell renal-cell carcinoma at presentation who were suitable candidates for nephrectomy to undergo nephrectomy and then receive sunitinib (standard therapy) or to receive sunitinib alone. Randomization was stratified according to prognostic risk (intermediate or poor) in the Memorial Sloan Kettering Cancer Center prognostic model. Patients received sunitinib at a dose of 50 mg daily in cycles of 28 days on and 14 days off every 6 weeks. The primary end point was overall survival. RESULTS A total of 450 patients were enrolled fromSeptember 2009 to September 2017. At this planned interim analysis, the median follow-up was 50.9 months, with 326 deaths observed. The results in the sunitinib-alone group were noninferior to those in the nephrectomy-su- nitinib group with regard to overall survival (stratified hazard ratio for death, 0.89; 95% confi- dence interval, 0.71 to 1.10; upper boundary of the 95% confidence interval for noninferiority, ≤1.20). The median overall survival was 18.4 months in the sunitinib-alone group and 13.9 months in the nephrectomy-sunitinib group. No significant dif- ferences in response rate or progression-free survival were observed. Adverse events were as anticipated in each group. CONCLUSIONS Sunitinib alone was not inferior to nephrectomy followed by sunitinib in patients with metastatic renal-cell carcinoma who were classified as having intermediate-risk or poor- risk disease. Sunitinib Alone or After Nephrectomy in Met- astatic Renal-Cell Carcinoma. N Engl J Med 2018 Jun 03;[EPub Ahead of Print], A Méjean, A Ravaud, S Thezenas, et al. www.practiceupdate.com/c/69138

Cytoreductive Nephrectomy – The Important CARMENA Trial F or decades, based on antiquated data in patients receiving interferon alfa, we have been performing cytoreductive nephrectomy in patients with metastatic disease almost routinely despite multiple new therapies emerging, which have had an enormous impact on outcome for patients with metastatic RCC. The ques- tion remained whether cytoreductive nephrectomy worked to extend survival even in the modern era of metastatic RCC. Until now, there was no evidence to direct us one way or another. There have been numerous large retrospective series emerging, showing that those who received cytoreductive nephrectomy did better, reinforcing the mantra that this treatment works to extend survival in the setting of metastases. Yet, despite voluminous data, it was suspected that there was some selection bias for surgery within the retrospective datasets. So, many argued that, except for those who need treatment emergently, generally speaking, cytoreductive nephrectomy remained a standard. Moreover, for many years, clinical trials for patients with meta- static disease excluded patients who didn’t have a nephrectomy. However, with the prospective CARMENA data presented at ASCO 2018 by Dr. Méjean and with publi- cation in NEJM , this thinking has changed overnight. CARMENA is a phase III trial of patients with metastatic clear cell carcinoma, with MSKCC intermediate- and poor-risk disease who were randomized to sunitinib alone vs cytoreductive nephrectomy followed by sunitinib (standard dosing). A total of 450 patients were enrolled, with a median follow-up of 50.9 months. Sunitinib alone was noninferior to nephrectomy followed by sunitinib. Median OS was 18.4 months with sunitinib alone and 13.4 months with nephrectomy followed by sunitinib. This clearly means that, for those in this risk group who are going on treatment, cytoreductive nephrectomy is inappropriate. This calls to question, what about good-risk patients? That remains unanswered. Additionally, what if a checkpoint inhibitor or combination therapy is used in the front line? Likely, the principle should stand, and cytoreductive nephrectomy should be abandoned in that setting. The importance of this trial is that we can now definitively say that cytoreductive nephrectomy is inappropriate in most clinical settings of metastatic RCC.

Dr. Somer is an Assistant Professor of Hematology/Oncology at the University of Tennessee Health Science Center, and Senior Partner at the West Clinic in Memphis, Tennessee.

PRACTICEUPDATE ONCOLOGY