Overall Survival Results of I/O Combinations Differ Across Risk Groups of Metastatic RCC

The overall survival (OS) benefit of immunotherapy combinations compared with sunitinib (Sutent) for the treatment of patients with metastatic renal cell carcinoma (mRCC) who have favorable risk may differ from those who have intermediate or poor risk, according to a pooled analysis of frontline combination therapy conducted by the US Food and Drug Administration (FDA).

“We know the possible differential benefit is larger for the combined intermediate/poor-risk group, compared to the favorable risk group. The caveat is that follow up is ongoing in each study, therefore the results and conclusion from this analysis are exploratory, noted Daniel Lee, MD, PhD of the FDA, during his presentation.

Across all mRCC risk groups, clinical trial data have shown that the outcomes are consistent for anti-VEGF therapy. For immunotherapy combinations, however, the low number of patients with favorable risk who are included in the analyses makes the outcomes observed less reliable. Although investigators are uncertain about the benefit of combination immunotherapy in this patient population, they did hypothesize that outcomes may differ and therefore studied the matter further.

Data from 3447 patients were pooled from 4 randomized phase 3 clinical trials. One of the trials combined 2 immunotherapy agents, and the 3 others studied combinations of immunotherapy and anti-VGF therapy. Utilizing an International Metastatic RCC Database Consortium (IMDC) risk model, each patient assessed was classified as either intermediate/poor risk or favorable risk. Then, Kaplan-Meier and Cox Proportional Hazards methods were used to compare the OS between the immunotherapy combination to the sunitinib control arm.

In total, 422 patients were treated with an immunotherapy combination in the favorable risk group and 404 were treated with sunitinib. The death rate in the arms was 22.0% versus 23.0%, respectively. The median OS was not reached (NR) in either arm (95% CI, NR, NR). The hazard ratio (HR) was 0.953 (95% CI, 0.72-1.27).

In the intermediate/poor risk population, 1,308 patients received an immunotherapy combination compared 1,313 who received sunitinib. There were deaths rates in the study arms of 40.8% versus 50.9%, respectively. The median OS observed in the combination arm was 46.8 months (95% CI, 39.9 to not reached). In comparison, the median OS was 29.3 months with sunitinib (95% CI, 26.0-32.9), showing an HR of 0.696 (95% CI, 0.62-0.78).

Providing an explanation of these data, Lee stated during his presentation, “In looking at the hazard ratios, there was an absence of benefit for the favorable risk group, whereas there was a benefit in the combined intermediate poor-risk group. And looking at the survival curves, for the favorable risk there was no difference in survival, whether the patients received the combination therapy or sunitinib. In comparison, for the combined intermediate poor-risk group, there was a difference in survival, which favored the combination therapy.”

_Reference:

_{Lee D, Gittleman H, Weinstock C, et al. J Clin Oncol. 2021;39(suppl 15):4559. doi: 10.1200/JCO.2021.39.15_suppl.4559}