Dual IO Therapy in Advanced NSCLC: Long-Term Followup From CheckMate 227


Expert perspectives on the CheckMate 227 clinical trial, which combined ipilimumab and nivolumab IO therapy in patients with advanced NSCLC.


Stephen V. Liu, MD: Let’s talk about some of the CheckMate studies. We talked about monotherapy with the PD-1 or PD-L1 inhibitor. We talked about chemotherapy combinations. We have a lot of different options depending on histology, [with] more to come presumably. The other category we have is dual checkpoint blockade. That’s looking at 2 different checkpoint inhibitors; one targeting PD-1 and the other targeting CTLA-4, both playing an important role in priming immune cells. That combination of nivolumab and ipilimumab in this setting, PD-1 and CTLA-4, has proven to be very effective in melanoma. We then saw it being explored in lung cancer. There was some early success in lung cancer, including in small cell lung cancer. I know, Neal, [that] you led a lot of those studies but here in non–small cell lung cancer, the trial we’re really talking about is CheckMate 227, and this was a bit more of a complicated study. It was for patients with advanced non–small cell lung cancer who had no prior therapy, also excluding EGFR [mutations] and ALK [rearrangements]. It allowed both histologies but stratified by squamous or nonsquamous and split it up into 2 different studies almost.

It was 1 trial, but if you had PD-L1 expression of 1% or greater, you randomized to nivolumab and ipilimumab, so dual checkpoint; standard chemotherapy; or nivolumab alone. Whereas if you were PD-L1 negative, it was also 3 arms: nivolumab and ipilimumab, chemotherapy alone, but that third arm was different, and that was nivolumab with chemotherapy. The thought here was that giving nivolumab alone to PD-L1 negative patients wasn’t well advised. The primary end point here was in the PD-L1–positive subgroup, and that’s going to have important implications in how we interpret this, and maybe more importantly, how the regimen was approved. Neal, I know you were involved in a lot of those early studies. Do you want to talk a little about that decision to focus on that PD-L1–positive group?

Neal Ready, MD, PhD: In the phase 1 trial, where we established that nivolumab at full dose and ipilimumab 1 mg/kg was specifically safe in patients with lung cancer, because it was a phase 1 trial, we included patients with actionable alterations. In the 77 patients who had a biomarker analysis for PD-L1 and we looked at activity, there were 12 patients with EGFR mutations.

Stephen V. Liu, MD: Big number.

Neal Ready, MD, PhD: A big number, and usually those tumors are low for PD-L1. Thus, I think we wrongly interpreted that it was the PD-L1–positive patients who were benefiting. That, I think misled the plan of the trial around primary end point, and in retrospect, I’m not surprised at all that it looks like the PD-L1–negative subgroup is the one that might benefit the most.

Stephen V. Liu, MD: That’s an interesting point, thrown by that PD-L1 negative when really, we should just be excluding the driver-positive lung cancers. But as you alluded to, CheckMate 227 was a positive study, and this is an FDA-approved regimen. We have long term follow-up. These were presented last week or 2 weeks ago at ASCO [American Society of Clinical Oncology annual meeting] 2022 led by Dr Julie Brahmer, [MD]. These are the 5-year results from CheckMate 227, so 5 years flies by pretty quickly. What we saw here as the clear winner was dual checkpoint blockade, outperforming nivolumab alone, outperforming chemotherapy alone. Those weren’t directly compared, but nivolumab and ipilimumab were superior to chemotherapy; the hazard ratio for survival was 0.77. I think the impressive piece here is that long-term survival. We see it at 3 years, the rate of 3-year survival is 33% versus 22% with chemotherapy; 4-year survival is 28% versus 18%; 5-year survival is 24% versus 14%. The difference between the 3-year and 5-year survival, there’s not a whole lot of difference there. We do see that flattening out, and remember there’s no chemotherapy involved in this. This was nivolumab and ipilimumab alone. We have 1 out of 4 patients alive still at 5 years; now this was in the PD-L1–positive group.

In the PD-L1–negative group, which was not the primary end point, we see significant benefit. In fact, the hazard ratios here, even better. What’s interesting about CheckMate 227 is that the numbers here are better in the PD-L1–negative group, with a hazard ratio of 0.65 for nivolumab and ipilimumab versus chemotherapy, but the nivolumab and ipilimumab arms almost overlap. It really is the fact that chemotherapy does worse in the PD-L1–negative group, with nivolumab and ipilimumab performing very well with about 1 in 5 patients alive at 5 years PD-L1 negative. However, the FDA approval does not include the PD-L1–negative part of the label, but I agree that is perhaps where we see a bigger need, and maybe even more benefit with this.

Neal Ready, MD, PhD: I’m sorry to interrupt, but I think one important part of the PD-L1–negative design in 227 is that unlike a lot of the current trials, if chemotherapy is the comparator, that’s not a standard of care anymore. Here in the PD-L1–negative group, we have a comparator arm of nivolumab plus chemotherapy, so that we actually have in 1 trial a direct comparison of nivolumab and ipilimumab versus chemotherapy and nivolumab, and we see about a 10% difference in survival at 3 years, 4 years and 5 years, in a direct comparison. I think those are significant data that we really don’t get in any of the other trials.

Stephen V. Liu, MD: That’s a great point. It’s helpful to see all of these curves, [and] how they perform concurrently. When we look at those 5-year survivors, I think the important point here is that among patients who get to 5 years still alive, the patients on nivolumab and ipilimumab, the median PFS [progression-free survival] was 5 years. I would interpret this as saying the patients who are alive at 5 years on the nivolumab and ipilimumab arm never progressed. The people in the chemotherapy arm who are alive at 5 years actually progressed within 9 months in that PD-L1–֪positive group, and then [they] went on to something else, some other type of immunotherapy, showing that it is the immunotherapy that’s driving things. What we’re seeing now in our long-term survivors are steadily increasing numbers of treatment-free intervals, where patients are alive and off therapy for a year, 2 years, 3 years and climbing, and that’s what we want. We want people who are alive from their lung cancer and no longer needing any therapy, and at some point, we’re going to call that a cure, and that’s really what we’re going for with lung cancer. Not everyone gets there. Most people don’t get there, but that’s our goal, and a larger and larger number are going.

Transcript edited for clarity.

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