Frontline Treatment of Stage IV NSCLC: What’s Next?

Future projections regarding the role of novel I-O therapies as frontline treatment for patients with metastatic non–small cell lung cancer.

Mark A. Socinski, MD: I want to transition to stage III here in a few minutes, but I wanted to go back and ask Roy. In our careers, we haven’t seen a step up like we’ve seen with the PD-1/PD-L1 inhibitors and to a certain extent the CTLA-4 data that we’ve just been talking about. It’s been such a change in the standard of care and the potential outlook, even being able to talk about 5-year survivors, which we never did historically. What’s your prediction for what’s next, Roy? Do you have a favorite target or a strategy that’s coming up, or what are your thoughts with regard to the next big breakthrough, if you will?

Roy S. Herbst, MD, PhD: As a great philosopher said, Mark, it’s hard to make predictions, especially about the future. But with that said, it is amazing, when at least 3 of us started this, 1 year of survival was something with a 20%, 30% [chance], and if we had 2 years, “wow.” It is nice to see what we’re having. We have proof of concept that immunotherapy works, and I would even dare say we can cure people with immunotherapy. The problem is clearly it’s only 15%, 20%. Every 5-year study that’s coming out, there’s a bimodal curve and there’s a tail, but it’s 15%, 20%, at least in the second line. In the front line it may be 30%, 35%, or more. So the question is, can we do better? I think there are 2 things to think about: primary resistance and acquired resistance. There are clearly some tumor cells that are not hot, they’re not inflamed, in fact I would say that’s more than half of them. If they’re not in that environment, no matter how much you block PD-1 or PD-L1, it’s not going to matter because you don’t have any T cells there.

I would predict we’re going to see therapies in the next few years to try to increase that, whether it be TIL [tumor-inflitrating lymphocytes], take the cells out, ex-vivo, and put them back, or agents that might alter the microenvironment, whether it be a molecule that has a CD3 on the other end, a T-cell CD3, or some sort of interleukin, IL-10, IL-15 has been looked at, IL-18. I think we’re going to see more and more of that. Then I think we also have to realize that some of these tumors might not have PD-1/PD-L1. It might not be a universal mechanism, or there might be other checkpoints, TIGIT. There’s another drug we’re studying here at Yale [Cancer Center], Siglec-15. That has to be looked at as well. But then of course it’s the whole resistance. I think we’ve all been happy to see patients who do well, and then they are resistant to immunotherapy. What you do then? I’m going to give you a thought for the future. We’ve spent 20-plus years, it was 1997 when we did the first EGFR studies, and we’re still figuring out resistance. We have to do that now with immunotherapy, and we have to personalize it, and that’s not what we’re doing, Mark. We’re just putting combinations together. So I would predict 10 years from now, or maybe even 5, we’re getting a biopsy of the tumor and the microenvironment, and we’re understanding what are the inhibitory factors, what are the inhibitory T cells, what’s missing. Then we’re putting a cocktail together in a personalized way. But the proof of concept is there, and it’s amazing to me. I would have never thought 20 years ago that we would have seen this much progress.

Mark A. Socinski, MD: I would completely agree with you. It has been amazing, and I agree with you, I think we are curing some patients. You and I stared at a time when our counsel would be, “You have a treatable disease but not a curable disease.” I remember when everyone thought it was a big deal when Alan Sandler, [MD,] got up at ASCO [American Society of Clinical Oncology annual meeting], and there was a 1-year survival rate from the ECOG 4599 trial that exceeded 50%. We thought that was a milestone at that time, and that was just 15, 16 years ago, so we have come a long way. But also, to your point, we have a long way to go in understanding all of this and what do we do next.


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