SUO 2017: Renal Cell Carcinoma: Predicting Response and Overcoming Resistance

Washington, DC ( The future of combination targeted therapy and immunotherapy in renal cell carcinoma (RCC) is very promising. Over the last few years, we have identified synergies between VEGF TKIs, PD1/PDL1, CTLA4, IL 2, and IL 10. Identifying the most appropriate sequences and combinations both for primary and mRCC treatment and to overcome TKI resistance will be key to obtaining better responses with these therapies.

Dr. Hammers spoke in detail about a trial he is spearheading: Checkmate 214, which randomized nivoluab (PD1 inhibitor) + ipilimumab (anti-CTLA4) vs. sunitinib in previously untreated metastatic RCC. A notable feature to this study was the accrual of many intermediate- and high-risk patients (based on IMDC criteria), which is obviously an important group to target. There were 800 intermediate/high-risk patients and 200 low-risk patients that were included in the intention-to-treat analysis.

25% of patients expressed PDL1 (at a cutoff of >1% expression). In the intermediate-high risk group, the overall response rate (ORR) for nivolumab+ipilimumab was 42% vs. 27% for sunitinib. Nivolumab+ipilimumab impressively had a 9% complete response rate, vs. 1% for sunitinib. The duration of response was also noteworthy, with 18mo for sunitinib and not reached for nivolumab+ipilimumab. Although the progression-free survival was not significant, it did favor nivolumab+ipilimumab, and the OS HR was 0.63 for nivolumab+ipilimumab vs. sunitinib. The mOS for nivolumab+ipilimumab was not reached.

Importantly, these responses appeared to remain present after including low-risk patients in the intention-to-treat group. However, when isolating just IMDC favorable risk patients, the nivolumab+ipilimumab ORR was 29% vs. 52% for sunitinib, indicating that this cohort may be more responsive to anti-VEGF therapy based on their biology. Intriguingly, the ORR was 37% for PDL1 NEGATIVE patients, meaning the survival benefit of nivolumab+ipilimumab appears to be somewhat independent of PDL1 status. Lastly, the toxicity profile of this combination was in line with other studies of checkpoint inhibitors. 60% of patients on the combination required steroids for Grade >3 adverse events, but the adverse events were otherwise acceptable/manageable.

Cytokines appear to be making a resurgence on the immunotherapy landscape. Studies of IL 10 + PD1 inhibitors are underway and have so far been well tolerated. Biologically, these sorts of combinations make sense, since they may both increase and/or augment immune responses that have proven benefits in RCC.

As more trials begin and as we follow patients from completed trials out for more years, we need to better define what we consider successful outcomes. The quality of the immune response is clearly important, as is the durability of response, the treatment-free interval, and the overall survival (the primary endpoint of most trials is progression-free survival). Also, when is it okay to stop immunotherapy? For example, some patients who were on nivolumab from Checkmate 025 had long-term progression-free survival. So far, there is no clear answer as to when cessation of immunotherapies is appropriate. Appreciating the “tails” of survival curves will give us a better understanding of the long-term outcomes from these treatments.

As immunotherapy use increases in both the first-line and post-TKI spaces, it will be important to logically study sequences and combinations of treatments that have the highest likelihood of success. We already see trials that are biomarker-directed, and some studies are stratifying patients by risk-group, such as in Checkmate 214. It is also important to remember that all of these treatments have toxicities, and treatment-related deaths are not uncommon. Nonetheless it is an exciting time as the options for treatment of advanced RCC continues to explode.

Presented by: Hans Hammers, MD, PhD, UT Southwestern Medical Center

Written by: Shreyas Joshi, M.D., @ssjoshimd, Fox Chase Cancer Center, at the 18th Annual Meeting of the Society of Urologic Oncology, November 29-December 1, 2017 – Washington, DC