Insights From: Dan J. George, MD, Duke Cancer Institute
Daniel James George, MD: CheckMate-214 was really based on the preliminary data of the combination of ipilimumab and nivolumab in patients previously treated with VEGF-targeted therapies and other therapies in renal cell carcinoma. And in a phase I study, that combination demonstrated some pretty significant toxicity but also some pretty significant responses, even in that heavily pretreated population. At the time that that study was designed for a frontline comparison to sunitinib, nivolumab as a single agent had been tested in that same refractory population. I’ve been awaiting the results that ultimately led to its approval, demonstrating an overall survival benefit over everolimus. And so, using the combination really leapfrogs the single-agent data and puts this into the frontline setting.
The population chosen for CheckMate-214 was interesting. It was all-comers at first, but then the population was limited to intermediate- and poor-risk, which makes up the majority of the population, and was really the primary endpoint for the study. As I mentioned earlier, the initial results that were reported earlier this year as a press release demonstrated a significant difference in the overall response rate in favor of ipilimumab and nivolumab versus sunitinib, about 41% versus about 22%. And that was statistically significant and one of the co-primary endpoints. Another co-primary endpoint was the progression-free survival.
The secondary endpoints included evaluation of outcomes based on PD-L1 status. And it’s interesting because there was an enrichment for all of these outcomes—response rate and overall survival and progression-free survival—in favor of ipilimumab/nivolumab for the PD-L1–positive tumors. What’s interesting about that is as we might expect, because PD-L1–positive tumors are a poor prognostic indicator, it tracks with the intermediate- and poor-risk patients. The favorable-risk patients only had about a 15% incidence of positive PD-L1 status.
So, not surprisingly, even though these are favorable-risk patients, we didn’t see the same kinds of benefits with that subgroup of patients with the nivolumab/ipilimumab combination compared to sunitinib. It suggests that for practice applications of these data, we’re going to probably focus our attention first on treating the intermediate- and poor-risk patients with ipilimumab. And nivolumab—perhaps for the good-risk patients, particularly the PD-L1–negative good-risk patients—either deferred therapy or single-agent TKI therapy like sunitinib is still a very reasonable choice.