There are 3 completed trials that have resulted in the last few years: ASSURE, PROTECT, and S-TRAC. ASSURE evaluated 1900 patients with both ccRCC and non-ccRCC after nephrectomy, randomized to sunitinib vs. sorafenib vs. placebo. Patients belonged to modified UISS-intermediate + very high risk prognostic groups. Due to a high attrition rate from treatment intolerability, dose reductions were necessary during study. Ultimately, the study was negative, and no differences were seen between the 3 treatment arms.
PROTECT also evaluated intermediate and high risk individuals. 1500 patients were randomized to pazopanib vs. placebo, and again, many required dose reduction due to high attrition rates. This study was also negative. S-TRAC accrued 615 UISS very high risk patients that were randomized to 1 year of sunitinib (dose reductions built in) vs. placebo. S-TRAC, unlike ASSURE and PROTECT, did show a significant PFS advantage to TKI treatment. This was ultimately the basis for the FDA-approval of sunitinib in this setting.
Importantly, these studies were all evaluating the effect of these therapies on disease-free survival (DFS), and none have shown any benefit in terms of OS (secondary endpoints). Additionally, there was a ~60% Grade >=3 toxicity rate in all three trials, indicating just how intolerable these TKIs appear to be in this particular patient population.
Questions remain about which variables are most responsible for the treatment responses seen in these studies. Several post-hoc studies of these trials have been published to that end. For example, ASSURE was reassessed by stage and dosing, but no significant differences in DFS were elicited. In PROTECT, a post-hoc analysis found that there was a difference ins DFS by dose of pazopanib. Therefore, it is unclear if dose intensity is a driver of outcome. ASSURE does not support the dose-outcome hypothesis, even when analyzed using eligibility criteria and dosing similar to S-TRAC. PROTECT does support the hypothesis, which may be unique to the pharmacology of pazopanib.
Dr. Haas recommends withholding judgement on the future of TKIs in the adjuvant setting until we learn more information. Ongoing trials will give us more information about other variables that might be important when analyzing treatment outcomes. Current adjuvant RCC trials include:
-SORCE (MRC) – sorafenib for both ccRCC and non-ccRCC
-EVEREST (SWOG) – mTor inhibitor for both ccRCC and non-ccRCC
-ATLAS (SFJ Pharma) – axitinib in ccRCC
-E2810 – pazopanib used adjuvantly in the setting of resected ccRCC metastases
It is also important to wait for results of adjuvant immune-oncologic (IO) therapy trials, which may greatly impact the efficacy of adjuvant therapy for high-risk patients. Ongoing trials are studying nivolumab (PROSPER), atezolizumab (IMMotion), pembrolizumab (KEYNOTE), and nivolumab + ipilimumab (CheckMate). All of these agents have impressive clinical activity in patients with metastatic RCC, so it is hopeful that they will also impact outcomes in the adjuvant setting. Importantly, these trials are targeting high risk populations and are testing the utility of biomarkers in the treatment and prognostic modeling for patients with high-risk localized disease. And based on other data, patients may tolerate IO agents much better than TKIs.
In conclusion, there is no OS benefit in the reported adjuvant TKI trials, but there may be a DFS benefit, which appears to be modifiable based on which variables are used to stratify the data. Ongoing trials may shed light on the true utility of TKIs in the adjuvant setting, but IO therapies may prove to be even more impactful if the results from mRCC hold true for high-risk localized disease. What we do know, however, is that VEGF inhibition doesn’t cure kidney cancer -- but we still have hope that maybe IO therapy can!
Presented by: Naomi Haas, MD; Abramson Cancer Center
Written by: Shreyas Joshi, MD, Fox Chase Cancer Center, Philadelphia, PA at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA