IPI/NIVO in Metastatic NSCLC



Mark A. Socinski, MD: Karen, let’s move on to another interesting trial that was presented at AACR—CheckMate-227. This was a complicated study.

Karen Kelly, MD: Right, complicated indeed. You’ll remember that CheckMate-227 is really 2 cohorts—those who don’t have, or have less than 1%, expression; and those with greater than 1% expression. Each of those cohorts were randomized: for >1%, to nivolumab alone, nivolumab plus ipilimumab, or chemotherapy; and for <1%, to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. And so, this trial was going along. We saw the results of CheckMate-012, which was a negative trial. [Note: CheckMate-012 is a multi-arm Phase 1b trial; positive results have been reported for frontline nivolumab plus ipilimumab (Hellmann, Lancet Oncol, 2017) and for nivolumab plus chemotherapy (Laurie, WCLC 2017)]. And then we saw the TMB results come in, showing efficacy in those patients with high TMB. TMB has now emerged as a potential biomarker for efficacy for immune therapy. Certainly, we do need more biomarkers. We all criticize PD-L1, but it is really the best biomarker that we have, to date. We’re looking for better biomarkers.

What happened was that this trial was amended to include this co-primary endpoint of progression-free survival in the high TMB patients. They looked at nivolumab/ipilimumab versus chemotherapy. This was a subset of this very large 1200-patient [Note: N = 1739] trial. The other thing to point out is that you have to remember that not all patients could get TMB done. Only about 58% of the patients had TMB. We can talk about the issues with TMB in a minute. But in this group of patients, about 300 patients, we saw that the progression-free survival favored nivolumab/ipilimumab in the high TMB group, which was defined as greater than 10 mutations per megabase, versus the chemotherapy, with a hazard ratio of about 0.59. Here, again, we saw that objective response rates were doubled as well. That’s a consistent theme that we’re seeing with immunotherapy.

However, we don’t have overall survival data here. Until we see some overall survival data, I think the data is provocative. [Note: Early descriptive analysis showed encouraging overall survival for nivolumab plus ipilimumab versus chemotherapy in patients with high TMB ≥10 mut/Mb (HR 0.79; 95% CI: 0.56 to 1.10)] We can talk about what we think of TMB as a marker. I also want to point out that even though they didn’t put this in the primary manuscript—it was in the appendix&mdash;we did see the toxicity profile for this particular group of patients. The grade 3/4 toxicity for nivolumab/ipilimumab versus chemotherapy was about the same&mdash;at 37% and 36%.

Transcript Edited for Clarity

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