By Sumanta K. Pal, MD, and Nicholas Vogelzang, MD, FASCO
For years now, we have had a raging debate in the renal cell carcinoma (RCC) community regarding the use of adjuvant therapy. In a patient with no evidence of metastatic disease following surgery, the standard of care has been observation, with scans done at regular intervals for several years. In essence, RCC has lagged behind tumor types such as breast cancer and colon cancer, in which a risk-adapted approach is used to deliver systemic therapy following resection of localized disease.
The possibility of adjuvant therapy emerged just over a decade ago, with the approval of effective targeted therapies for metastatic RCC. Two classes of targeted therapies emerged: inhibitors of vascular endothelial growth factor (VEGF) and its cognate receptor, and inhibitors of the mammalian target of rapamycin (mTOR). Collectively, these classes include a total of seven agents approved by the U.S. Food and Drug Administration. Five of these agents are being examined in the context of adjuvant clinical trials for RCC.
A critical blow to adjuvant therapy in this disease was delivered roughly two weeks ago at the 2015 Genitourinary Cancers Symposium. Dr. Naomi Haas, of the University of Pennsylvania, delivered results from Eastern Cooperative Oncology Group (ECOG) 2805 (ASSURE), a randomized, phase III study comparing sunitinib, sorafenib, and placebo for one year. The study included a broad range of tumor stages (pT1b-T4) and histologies (21% with non-clear cell disease). No difference was seen in overall survival (OS), and disease-free survival (DFS) was in the range of 5.6 to 5.7 years on each of the treatment arms. As one might envision, toxicities were more frequently encountered with sunitinib or sorafenib.
These results have already had an impact on discussions in the clinic. Patients are aware of the results of ASSURE, and many are thusly discouraged from pursuing adjuvant clinical trials for RCC. Two phase III studies are currently enrolling patients, ATLAS and EVEREST. The underlying differences in these study designs are critical to review with patients. ATLAS compares three years of axitinib to the same duration of placebo—presumably, three years of therapy may have a greater bearing on DFS, with many recurrence events occurring within a short window following surgery. Furthermore, axitinib represents a more potent and specific inhibitor of VEGFR2, the presumed target of the agents explored in ASSURE (sorafenib and sunitinib). EVEREST compares the mTOR inhibitor everolimus to placebo, both for a duration of one year. Everolimus is mechanistically different, and may be more tolerable than VEGF-directed therapies. Outside of EVEREST and ATLAS, a third smaller study deserves mention: E2810. This smaller study will randomly assign 126 patients who have had complete metastasectomy for RCC to either pazopanib or placebo for one year. This extremely high-risk group differs markedly from the population of patients who have been assessed in any adjuvant RCC trial to date.
Beyond underscoring variations in trial design, it is critical to note that several phase III studies have results pending. The SORCE, S-TRAC, and PROTECT studies, examining adjuvant sorafenib, sunitinib, and placebo, respectively, have completed enrollment but have yet to report on efficacy. As with EVEREST and ATLAS, these studies have key methodological differences. Any of these trials could presumably swing the pendulum back towards adjuvant therapy.
Ultimately, we will not know the true value of adjuvant therapy until all completed and ongoing studies have reported final results with respect to both DFS and OS. Notably, OS results from ASSURE are not yet mature; only 389 deaths (20%) have been recorded thus far. It is critical that the investigative community continue to support accrual to adjuvant clinical trials in RCC so that a fair and just verdict on this strategy can be rendered.
Dr. Pal is an Assistant Professor in the Department of Medical Oncology & Therapeutics Research and Co-Director of the Kidney Cancer Program at City of Hope. He has garnered numerous awards to support his work, including grants from the California Breast Cancer Research Program, the National Comprehensive Cancer Network, and the National Institutes of Health. He has more than 110 MEDLINE-cited publications, and he recently received a Young Investigator Award from the Kidney Cancer Association to recognize his outstanding research in this domain, and further received the 2012 Charles A. Coltman Translational Research Award from the Southwest Oncology Group to support his work in bladder cancer.
Dr. Vogelzang is a renowned medical oncologist and cancer researcher who has authored/co-authored numerous peer-reviewed articles, book chapters, and abstracts. He is currently the Associate Editor of the peer-reviewed journal, Clinical Genitourinary Cancer. Dr. Vogelzang joined Comprehensive Cancer Centers of Nevada as a medical oncologist in 2009, and he also serves as Chair and Medical Director of the Developmental Therapeutics Committee and Co-Chair of the Genitourinary Committee for US Oncology Research. Prior to joining CCCN, Dr. Vogelzang served as the Director of the Nevada Cancer Institute and the Director of the University of Chicago Cancer Research Center. Dr. Vogelzang has also served on numerous ASCO committees and is a current member of the Cancer Education Committee.