Combination Immunotherapy in Newly Diagnosed mRCC

Toni Choueiri, MD:Nivolumab was approved in 2015 for the treatment of patients with metastatic kidney cancer progressing after traditional antiangiogenic therapy. It actually showed an overall survival benefit over everolimus, with a very good quality of life in all scores and benefit. And we know from the melanoma literature that combining both nivolumab and ipilimumab—in other tumors that, to some extent, responded to cytokines like renal cell or, in the past, melanoma—the combination of a CLTA4 like ipilimumab and a PD-1 inhibitor like nivolumab results in a higher response rate.

So, this was investigated initially as part of a phase I study of 3 cohorts that have 3 different doses: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1 + I3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3 + I1), or nivolumab 3 mg/kg. The higher dose in both the drugs, the cohort, was aborted for toxicity. And then when N3 + I1 was compared with N1 + I3, the response rate was high, between 40% and 45%—higher than historical responses with nivolumab, though, which is around 20% to 25%. It’s not head-to-head, but it was higher. The toxicities with higher doses of ipilimumab were higher. So, finally, the regimen of nivolumab 3 mg/kg with a lower dose of ipilimumab was taken to the next stage toward a large phase III trial, called CheckMate-014, that compared the nivolumab/ipilimumab combination to sunitinib, which is, again, the standard—the most widely used drug in metastatic kidney cancer.

Interesting design, because the study focused on intermediate and poor risk, and that’s justifiable. These are the patients who need the most treatment. And the study had 3 endpoints: response rate, PFS, and OS—so, 3 coprimary endpoints. And the study actually met 2 out of the 3. Response rates were higher with nivolumab and ipilimumab—42% compared with 27% with sunitinib—so it was the same response rate, actually, as the phase I. And the overall survival was higher with that combination—a hazard ratio of 0.6 compared to sunitinib. Now, the progression-free survival, numerically, was higher, but it didn’t meet the prespecifiedPvalue for at least statistical significance.

So, this regimen is expected to be FDA approved soon. There were more toxicities on the nivolumab plus ipilimumab leading to more treatment discontinuation than sunitinib. And the toxicities usually are immune-related adverse events, to a degree that 60% of patients needed use of a steroid. But certainly, this is the first time we witness that a combination immunotherapy in kidney cancer could be better than sunitinib, a VEGF tyrosine kinase inhibitor, and an antiangiogenic agent.

Transcript edited for clarity.