Experts Discuss Unanswered Questions in NSCLC

A roundtable discussion, moderated by Millie Das, MD, covered challenges, advances, and future directions for the diagnosis, treatment, and management of non-small cell lung cancer (NSCLC), as well as critical clinical trial data and updates from the 2024 American Society of Clinical Oncology Annual Meeting. Dr. Das was joined by Ticiana Leal, MD, Martin Dietrich, MD, PhD, and Kent Shih, MD.

In the sixth segment of the roundtable series, the panel discusses critical unanswered questions about treatment strategies for NSCLC and the research that could potentially address these questions.

In the next segment of this series, the panel discusses management considerations for patients undergoing NSCLC treatment.

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Dr. Das: I do think it would be really interesting to see a trial in the PD-L1-negative subgroup of patients, in the STK11, KEAP1-mutated patients, randomizing them to getting a chemo-[immune-oncology] regimen versus chemo plus dual checkpoint inhibitors. And to really help answer that question, there are some prospective trials underway to try to look at this, I think in more detail. Specifically, again, [for] PD-L1-negative, STK11, KEAP1, does adding that CTLA-4 inhibitor really add something to the usual chemo plus the PD-1, PD-L1 regimen?

Dr. Leal: Yeah, we have the TRITON study.

Dr. Das: That’s one of the trials I was referring to.

Dr. Leal: Exactly, so that trial is going to try to answer that question prospectively, that signal that we saw in CheckMate 227, 9LA, and in POSEIDON for that benefit of adding the CTLA-4 inhibitor for this patient population with STK11 and KEAP1. This is a randomized phase 3 study comparing the KEYNOTE-189 regimen to the POSEIDON regimen in this specific population of [patients with] KEAP1 and STK11. That is a really, I think, interesting trial. We’re going to be having that at Emory. I’m looking forward to seeing if that will really answer that question and perhaps establish a new standard for those patients.

Dr. Das: Yeah, I’m very much looking forward to that trial as well.

I wanted to talk a little bit more about what we talked about earlier, which was: Do we continue the CTLA-4 inhibitor forever? And we were talking about different trials sort of having a different duration of the CTLA-4 inhibitor. In POSEIDON, we talked about how tremelimumab is discontinued after 5 cycles. Do you all have concerns about the increased autoimmune toxicities with the dual inhibition? Do you want to stop at that fifth dose? Do you want to continue? And Ticiana, I think you were saying you tend to want to continue as maintenance as long as patients are tolerating. But I think it’s one of those unanswered questions: What is the optimal number of cycles of the CTLA-4 inhibitor?

Dr. Dietrich: Oh, we don’t know. It’s a simple answer, but I agree with Ticiana that the CTLA-4 probably has its most usefulness up front. I think that’s how most regimens are written in T-cell mobilization. But the real prognostic impact of CTLA-4 discontinuation comes in the context of an autoimmune adverse event. So I would agree that in a protocol that was written to accommodate for the increase in CTLA-4 toxicity in CheckMate 12 that established the Q6 weekly dosing of low-dose ipilimumab with 1 milligram per kilogram body weight really made CTLA-4 tolerable, much better than what we’ve seen in CheckMate 067 for a first-line melanoma, or even obviously in the adjuvant setting of melanoma, where the doses were even higher. I think I would continue this until an adverse event prohibits further usage.

But oftentimes, and I think the data is pretty clear in the trials that CTLA-4 is a self-limiting drug. It’s very rare that we can give this on a continuous basis. And partly because we preferentially discontinue CTLA-4 if an autoimmune side effect happens, we sort of ascribe this more preferentially towards the CTLA-4. And I’m not sure if that’s the bad reputation from the initial experiences with CTLA-4, sometimes it’s very hard to discern, is it PD-1 or CTLA-4 driving this autoimmune side effect? But I continue until an autoimmune adverse event. However, I do think that if I look at the data, and again this is a cross-trial comparison, I think the majority of effect is harvested by giving it in the first couple of months of treatment. I think that’s where the largest amount of immune priming happens.

Dr. Shih: I’ll just share a personal anecdote. In 24 years of practice now, I’ve had 2 grade 5 toxicities because of cytotoxic chemotherapy: febrile neutropenia, [intensive care unit], they didn’t want to be coded. I’ve had 4 grade 5 toxicities from immunotherapy, and they’ve all been pneumonitis, they’ve all been in lung cancer patients, and I treat all cancers. I also lead our brain tumor program, but they’ve all been in just folks that don’t have a lot of pulmonary reserve. Grade 1, grade 2, what should be pneumonitis probably turns into a grade 3, grade 4, and then [acute respiratory distress syndrome] and whatnot. I have a very healthy respect—and I’m not picking on CTLA-4 in these particular cases, I think it’s just checkpoint inhibitor [toxicity] —but I have a very, very healthy respect for toxicity. Because of that, even though I said I am certainly comfortable with delivering CTLA-4 inhibitors, when in doubt, I will stop.

Dr. Das: On that topic of how are our patients experiencing these toxicities, how are we managing them? I think when I do see, in my own clinical practice, I’ve seen a higher incidence of immune-related adverse events when I do the dual inhibition of PD-1 and CTLA-4, I do tend to blame the CTLA-4 inhibitor and I drop it, and it usually does get better.

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View the first segment of this roundtable series here.

View the second segment of this roundtable series here.

View the third segment of this roundtable series here.

View the fourth segment of this roundtable series here.

View the fifth segment of this roundtable series here.