The time gained from adjuvant sunitinib therapy in disease-free survival is equivalent to time spent on treatment, implying a net zero gain. If a moderate trend toward benefit was observed, perhaps one could be more open-minded about this strategy.— Sumanta Kumar Pal, MD
In renal cell carcinoma and other cancer types, a consistent paradigm in drug development exists: Observe efficacy of a drug in the metastatic setting and move quickly to explore the agent in the adjuvant setting. In the cytokine era, there were multiple efforts to characterize whether adjuvant interferon or biochemotherapy could improve clinical outcomes in localized renal cell carcinoma. Virtually all of these studies failed to demonstrate improved clinical outcome.
Adjuvant Clinical Trials
In the targeted therapy era, we are in the midst of multiple studies that assess the role of targeted therapy as adjuvant treatment. Two broad classes of targeted therapies exist for renal cell carcinoma: (1) vascular endothelial growth factor (VEGF)-directed therapies and (2) inhibitors of the mammalian target of rapamycin (mTOR).
In the latter category, the adjuvant EVEREST study pits the oral mTOR inhibitor everolimus (Afinitor) against placebo. This study recently completed accrual, with results likely several years away. Multiple studies are at varying stages of completion in the assessment of adjuvant VEGF-directed therapies. The first study to be reported was the Eastern Cooperative Oncology Group (ECOG)-led ASSURE trial, comparing sorafenib (Nexavar), sunitinib (Sutent), and placebo. The study showed no improvement in disease-free survival, and furthermore, toxicities encountered early on in the trial led to dose reductions.
S-TRAC Results Unveiled
The disappointing results of ASSURE cast a dark shadow over similar adjuvant trials with impending results. However, a surprise came recently when a press release hinted that the adjuvant S-TRAC study had yielded a positive result. As reported by Ravaud et al1 and reviewed in this issue of The ASCO Post, S-TRAC compared 1 year of sunitinib with placebo in patients with resected localized disease. In contrast to ASSURE, the study enrolled higher-risk patients, maintained higher doses of sunitinib at treatment initiation, and utilized central radiographic review.
At the 2016 European Society for Medical Oncology (ESMO) Congress, the complete results were unveiled—an improvement in disease-free survival of approximately 1 year resulted from 1 year of sunitinib therapy. Toxicities with sunitinib in the adjuvant setting were similar to those observed in the metastatic setting. Most important, data for overall survival were immature, and survival curves to date show no hint of benefit.
Is Clinical Use of Sunitinib Justified?
Surely these results cannot justify clinical utilization. To those familiar with the agent, sunitinib is a toxic therapy, and a treatment duration of 1 year exposes patients to significant risk. Furthermore, the time gained from adjuvant sunitinib therapy in disease-free survival is equivalent to time spent on treatment, implying a net zero gain. Survival data were deceptively omitted from the presentation of S-TRAC at ESMO 2016, and the careful reader will find the survival curves buried in a supplementary appendix of The New England Journal of Medicine publication. If a moderate trend toward benefit was observed, perhaps one could be more open-minded about this strategy.
What do these data teach us? For one, the bar is high in the adjuvant setting. A statistically significant improvement in disease-free survival, as observed with sunitinib, does not necessarily imply a clinically meaningful result—the duration of disease-free survival improvement, overall survival trend, and toxicity are all factors one must consider.
Immunotherapy: Optimal Path Forward
The future of renal cell carcinoma adjuvant therapy likely rests in immunotherapeutic approaches. For example, a recently launched study will explore 1 year of adjuvant atezolizumab (Tecentriq) vs placebo. This study, supported in part by the Society of Urology Oncology–Clinical Trials Committee, uses a treatment strategy that may induce durable responses and thereby extend survival. Based on data to date with atezolizumab, one may anticipate a lower toxicity burden from this approach as well.
ECOG is also launching a trial of perioperative nivolumab (Opdivo), comparing a sequence of neoadjuvant and adjuvant nivolumab with observation. Although the trial is well poised to address correlative studies, it remains to be seen whether patients will comply with a control arm of observation. Nonetheless, unless current trials of adjuvant VEGF-directed therapies yield dramatically different results, the trials of atezolizumab and nivolumab in this setting likely represent the optimal path forward. ■
Disclosure: Dr. Pal is a consultant for Pfizer, Genentech, Exelixis, Novartis, and Bristol-Myers Squibb and has received honoraria from Genentech.
Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic ...!-->!-->