Chemo + I-O in Frontline mNSCLC: PD-L1 TPS >50%



H. Jack West, MD: Let’s turn to the patients, approximately 28% or 30%, who have a high PD-L1 where we have competing standards of a few trials. We have the KEYNOTE-024 trial, which is very positive across the endpoints for pembro [pembrolizumab] monotherapy with a response rate of about 45%. So it’s not quite the majority but a lot of patients do very well for a long time. And we have a higher response rate with the concurrent chemo/I-O [immuno-oncology] trials with pembrolizumab for both nonsquamous and squamous patients. Either would be reasonable. So how do you decide whether to favor chemo/I-O or single-agent therapy for your patient with a PD-L1 of 80%, Charu?

Charu Aggarwal, MD, MPH: So I think they’re both good options. I think the data behind both studies are very strong. You look at KEYNOTE-024, which looked at pembrolizumab versus chemotherapy for the PD-L1 greater than 50% population. That looked very positive, both for survival as well as response rate and PFS [progression-free survival]. And then you look at KEYNOTE-189, where even for the subset with a PD-L1 greater than 50%, chemo/I-O versus chemotherapy was superior. What we don’t have is a study obviously for the PD-L1 greater than 50% group, where we can safely say pembro is better than chemo/pembro or vice versa because that study doesn’t exist. So I think both answers or both options are reasonable. I tend to favor using pembrolizumab monotherapy alone, just because that gives me other options to go to when and if that progression happens. Patients certainly like the idea of using a chemotherapy-free approach. It’s a little less toxic. I know we all are very comfortable with managing the toxicities of chemotherapy and immunotherapy, but it’s an easier discussion to have. It’s an easier regimen, so it’s a winner all around.

H. Jack West, MD: Yeah. And Hoss, can I ask, first, do you agree with that approach? And, second, if you do and your general trend or overwhelming favorite is monotherapy, are there some patients for whom you would make an exception and be more inclined to favor chemo/I-O?

Hossein Borghaei, DO: So the only way that I’ve decided to work this into my practice is to look at patients’ symptoms and disease burden. Clearly for a symptomatic patient with a lot of disease burden, somebody who has lost 30 pounds and they’re losing weight while sitting in front of you as you’re talking to them, and they have night sweats, and they have a lot of disease, it’s kind of hard to say no to a 60% response rate with chemo/I-O. So I think with that patient population, I’m more than happy to do it. On the other hand, if I have a patient, as you said, who is maybe a little bit more frail, not as much of a disease burden but clearly metastatic, and I don’t think I’m going to lose the opportunity to save the patient, then I think I’m OK with using single-agent I-O, in terms of pembrolizumab, in that patient population. So what I have decided to do in my clinic is to look at these clinical parameters and decide whether I want to use chemo/I-O versus just pembro alone.

H. Jack West, MD: Yeah, I agree with your thought that I tend to favor monotherapy as a chemotherapy-free approach, one that preserves more options. And 1 other thing is if patients are responding, you know what they’re responding to and you’re not giving them maintenance pemetrexed/pembro without knowing which is doing the heavy lifting and which is coming along for the ride and adding cost. These are both expensive agents. So fine if you need both, but if one of them is really the active one and the other is just riding on its coattails, I’d prefer to know what’s the active agent and not have someone on 2 years of maintenance pemetrexed with the potential for toxicities there. We don’t have a lot of experience with years of pemetrexed, and I would not say it’s exactly the same as the first 4 months, or 6 or 8 months, and then moving on.

But for patients who have a very significant disease burden, just riddled with it or active symptoms, or the ones who have doubling of their disease between their initial CT [computed tomography] in the ED [emergency department] and the PET [positron emission tomography] scan you get 3 or 4 weeks later at the end of their staging—those are patients for whom you may have only 1 opportunity. Basically, if I can’t look at them and be completely confident that I think they’re going to be a candidate for the subsequent treatment if they progress on that pace over the next 6 or 9 weeks, those are the ones whom I would do concurrent for.

Hossein Borghaei, DO: Right. The only thing I’d like to raise is that there is a subanalysis of patients on KEYNOTE-024 who got chemotherapy followed by pembro, and it doesn’t look like they’ve benefited quite as much. So, I mean, that concept is sort of there, so we do have to be careful how we use the drug. But I think as long as we all agree that a patient who is otherwise eligible should, at the minimum, get pembrolizumab alone in this patient population, I think they should.

Transcript Edited for Clarity

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