Case 4: I-O Combination Regimens in Stage IV NSCLC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Benjamin P. Levy, MD:Systemic management for this has changed dramatically. Like every other case we’ve talked about, we’ve witnessed these incredible shifts in the past 12 to 24 months that have all popped up in theNew England Journal of Medicine. We have KEYNOTE-189, which was, again, a very clean study adding immunotherapy to carboplatin-pemetrexed versus carboplatin-pemetrexed alone. Patients were allowed to be on maintenance pemetrexed and pembrolizumab. It came out very early on, before this trial was presented, saying that maybe we’d see a PFS [progression-free survival] advantage but not an OS [overall survival] advantage.

We saw a PFS advantage and we saw an OS advantage with a hazard ratio 0.49, which is unheard of in a driver-negative patient population. I think that shocked a lot of us, and it has clearly cemented this therapy, whether you call it carboplatin-pemetrexed-pembrolizumab, or triplet therapy, or PCP. This is the regimen that has been standard for most of, our patients. Do you want to talk briefly about the regimen? What is your experience with it? Have you had good results or toxicity concerns with giving these 3 drugs together?

Isabel Preeshagul, DO, MBS:I think this has sort of become bread and butter for my practice with patients, especially like the gentleman in this case we’re discussing here. What I explain to my patients is that initially, when you’re getting the 3 drugs up front, you may have more symptoms, like nausea, vomiting, fatigue, cytopenias. But then when you’re on the maintenance portion, it may seem a little bit lighter. Treatments are much shorter. Most of the toxicity that I’ve experienced has been in the outside setting, and maintenance has been easier.

Benjamin P. Levy, MD:One of the things, and I think it’s important in this trial, and I get a lot of questions from community oncologists: The PD-L1 [programmed death-ligand 1]—and this goes back to PD-L1 testing and whether it matters—a third of the patients in this trial had a PD-L1 less than 1%, and that subgroup derived a meaningful benefit. Do you have to coach your patients? Your patients say, “Well, I’m PD-L1 0. Why are you giving me this regimen?” Is that a conversation that comes up at all?

Isabel Preeshagul, DO, MBS:Some of my patients, especially the ones who are very well versed, do question me about that. I do end up exploring the data and the subset analysis that has transpired. Shared decision making needs to occur. But they did gain a benefit, and I think it is something to explore with them.

Benjamin P. Levy, MD:Yeah. And so, there has been 1 more trial that maybe just got FDA approval. Again, we saw it in theNew England Journal of Medicinepaper. This is a new regimen that has made it to the forefront—IMpower150. You and I were asking, or we were talking about this before, the discussion about whether we should use this regimen or not. Patients, again, who were stage IV were randomized into 3 arms. The focus of the trial again is on 2 arms, with the same theme of adding immunotherapy to a platinum-doublet backbone and comparing it with a platinum-doublet backbone alone. This platinum doublet happens to be in combination with bevacizumab, the old ECOG [Eastern Cooperative Oncology Group study] 4599 standard. And again, we saw by adding atezolizumab to carboplatin-paclitaxel-bevacizumab, as a quadruplet regimen, there was an improvement in survival compared with carboplatin-paclitaxel-bevacizumab. Again, this was only for a bevacizumab-eligible patient population. There was an improvement in progression-free survival, and there was an improvement in overall survival.

There were some interesting hints from this trial that run counter to everything else I’ve said about immunotherapy andEGFR-mutant lung cancer. We know that single-agent immunotherapy inEGFR-mutant lung cancer is a lousy drug. Yet this trial allowedEGFR-positive patients. If we were to apply everything we knew before, we would think there’s no way that adding atezolizumab would do anything to these patients. But this was the 1 study where we saw a benefit in theEGFR-mutant subset, in combination. This was not single-agent immunotherapy. This is 4 drugs, so there is a lot of back-and-forth and a tremendous amount of Twitter arguments on whether the regimen should be used. But it is now FDA approved. Interestingly, the FDA excludedEGFR-mutant patients from the approval. It’s not ready to be used forEGFR-mutant patients. Certainly, I think it’s a consideration without the FDA approval, given the data we saw.

And then I just want to mention 1 more trial, which is CheckMate 227. Not to get too complex, but does dual-checkpoint blockade outperform chemotherapy in patients with a high TMB [tumor mutation burden]? Tumor mutation burden may be a biomarker that is predictive of outcome for patients with immunotherapy. This was a trial looking, again, at nivolumab and ipilimumab—a wonderful combination, I hear, in melanoma—and comparing that with chemotherapy, specifically in patients with high TMB who are stage IV. We saw an improvement in progression-free survival, but we did not see an improvement in overall survival. We would have loved to see an improvement in overall survival, given this is a neat little biomarker that has a lot of science behind it.

Transcript edited for clarity.