NSCLC: Practical Considerations With Quadruplet Regimen

Paul K. Paik, MD:Of course, the results were positive. We’ll have to see whether or not the FDA ends up approving this quadruplet regimen, whether or not the regimen gets incorporated into the NCCN guidelines. And assuming it does, let’s say it does, then we’re going to have to think about how we end up prescribing this and in whom we end up prescribing this. And here there are lots of challenges. There are lots of challenges both I think from practical standpoints as well as psychological standpoints. The practical standpoints are perhaps clearest. The strongest biomarker in that study and the one that I think will emerge as the thing we need to rely on remains the TC/IC score, particularly the TC3/IC3 score, which predicted patients who would respond very well and then, conversely, a group of patients who were TC0/IC0 who really did not derive a lot of benefit at all from adding atezolizumab to the backbone regimen.

The problem is that scoring system is unique to SP142, and at this point, laboratories in the United States use that antibody if for no other reason than the antibody that was validated in the KEYNOTE studies is 22C8, which is what most people are using. We don’t have a lot of experience as a result, a lot of laboratories calculating TC scores and IC scores; it’s a composite score. We do know from existing work done by David Rimm at Yale, for example, and by the Blueprint group for IASLC, that the IC scoring has a lot of variability to it. It is not straightforward. There’s a fair amount of interpathology variances to this score. So, its reliability is something that we have to be concerned about. And it is entirely unclear to me as to whether or not laboratories, and your particular laboratory, for example, will make the investment to purchase the requisite equipment that is very expensive to use for this single indication. So, the practical rollout of this is a big question mark.

The second issue has to do with, again, existing standard-of-care arms. We do know that the standard of care for PD-L1 ≥50% patients is pembrolizumab. How does that translate to a TC/IC score? We don’t know. We’ve never done that before. But it’s an important question we’re going to have to answer if we’re going to figure out, do we give people basically 2 opposite sides of the treatment spectrum, everything at once, quadruplet therapy, or just a single drug at the beginning? There are all of these practical things that we’re going to need to address that we can’t address right now. We’re going to have to see exactly how this ends up getting incorporated in terms of approval status and then how we’re going to pivot to try to figure these things out.

It is very difficult, as a result, at this point to give recommendations about in whom to give this regimen versus the other standard first-line regimens, chemotherapy for example. The other sort-of elephant in the room right now is that the chemotherapy backbone of carboplatin/Taxol is different from the chemotherapy backbone of carboplatin/pemetrexed that’s in the other trials, for the KEYNOTE trials in particular, and a standard regimen that we give. How do we pick? Do we give one versus the other? We do know from data that were published by Jyoti Patel that the triplets for pemetrexed and Taxol, when you give it with carboplatin and bevacizumab, the outcomes are identical. But it does look like carboplatin/pemetrexed is a little bit better tolerated. So, from a tolerability standpoint, is there going to be a favor for pemetrexed? Again, we don’t know when you add immunotherapy to these things. All of this is to say that the data are interesting, but in practice, we’re really going to have to think carefully about how we roll these things out. As of right now, I have very little in the way of recommendations because we’re going to have to see exactly what the approval indications are at this point.

Transcript edited for clarity.