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tokine Working Group found that one course of highdose bolus IL-2 did not produce clinically meaningful benefit when administered postoperatively to patients with resected high-risk RCC.4 The rationale followed by the Working Group was that IL-2 had produced durable response in patients with metastatic disease and therefore could be investigated in those with locoregional disease. Results are expected in 2017 from another study— SORCE, a randomized, double blind, trial of sorafenib, given for one or three years, vs placebo for patients at moderate or high-risk of disease recurrence after surgical excision of primary RCC.5 However, if the messages from ASSURE can be extrapolated, it will be a challenge for SORCE investigators to demonstrate benefit from sorafenib in this group. What’s Next? More Adjuvant Trials In the wake of results from S-TRAC questions remain on how continuing results and forthcoming studies will address unresolved issues. One of these issues is the use of various endpoints, most importantly, DFS vs overall survival. Disease-free survival is a useful surrogate endpoint, but the results from different studies have been contradictory. It does not necessarily translate to overall survival, which is the gold standard. There are expectations that additional studies will address these questions. The phase 3 ATLAS trial, for example, is currently assessing adjuvant therapy with axitinib (Inlyta) for patients with high-risk, clear cell RCC. This study enrolled 700 patients.6 Additionally, the phase 3 PROTECT study is looking at adjuvant pazopanib (Votrient) in patients with intermediate or high-risk, clear cell RCC. This large study includes 1540 patients.7 In the past several years there has been a resurgence of interest in cancer immunotherapy. The development of blocking antibodies against the inhibitory programmed death-1 (PD-1) pathway represents a clinical breakthrough in the treatment of solid tumors and these agents have shown great promise in RCC. Currently, new checkpoint inhibitor studies are ongoing to evaluate their role as adjuvant therapy. The efforts are intriguing, particularly because they may be able to offer improved side effect profiles. Genentech is conducting one of these studies 138 Kidney Cancer Journal and Bristol-Myers Squibb is examining a combination of a CTLA4 and PD1 inhibitor. Combined checkpoint blockade, to date explored with CTLA-4 and PD-1 pathway blocking agents, represents a first step in this new direction. Conclusion The pivotal S-TRAC trial has been viewed as a milestone in establishing the benefits of adjuvant sunitinib in patients with locoregional clear cell RCC at high-risk for recurrence after nephrectomy. In contrast to the ASSURE trial, in which no improvement in DFS occurred, S-TRAC is expected to reshape treatment for this subgroup of patients. Distinct patient populations, dose regimens, and trial methods were likely responsible for the different outcomes in the two trials. The safety profile in patients treated with adjuvant sunitinib revealed moderate declines in quality of life while receiving active treatment. It remains for S-TRAC and additional studies to further elucidate advantages of the regimen of sunitinib to determine if an overall survival benefit, not yet demonstrated, can be achieved. References 1.Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High- Risk Renal-Cell Carcinoma after Nephrectomy published online October 10, 2016. N Engl J Med. DOI: 10.1056/NEJMoa1611406. 2. Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol. 2015;33 (suppl 7; abstr 403). 3. Chamie K, Donin NM, Klöpfer P, et al. Adjuvant weekly girentuximab following nephrectomyfor high-risk renal cell carcinoma: the ARISER randomized clinical trial. JAMA Oncol. Published online Oct. 277, 2016. doi:10.1001. 4. Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin 2 for patients with high-risk renal cell carcinoma: a Cytokine Working Group randomized trial. J Clin Oncol.2003;213133-3140. 5. Ritchie AWS, Meade AM, Choo L, et al. MRC SORCE trial: analysis of patients presenting characteristics, tumor staging, and surgical approach. J Clin Oncol. 2014;32: (suppl 4; abstr 496). 6. ATLAS study: A randomized double-blind phase 3 study of adjuvant axitinib versus placebo in subjects at high risk of recurrent renal cell carcinoma (RCC). J Clin Oncol. 32:5s, 2014 (suppl; abstr TPS4595^). 7. A Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma (RCC) (PROTECT). ClinicalTrials.gov Identifier: NCT01235962 KCJ


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