Predictions on the Future of Lung Cancer and Immunotherapy

New clinical research unveiled at the recent American Society of Clinical Oncology (ASCO) annual meeting has the potential to significantly alter the treatment of lung cancer. But what will be the innovations being talking about in 10 years?

MedPage Today brought together three expert leaders in the field: Moderator Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, is joined by Julie Brahmer, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and Sarah Goldberg, MD, MPH, also of Yale Cancer Center, for a virtual roundtable discussion. This final of four exclusive episodes focuses on some predictions about the future landscape of treatment in lung cancer.

Following is a transcript of their remarks:

Herbst: Okay, we’re in the final question, the lightning round. So what we’re going to do is we’re going to do predictions about the future. As Yogi Berra said, it’s hard to make predictions, especially about the future. But we’re going to make some predictions. So, I’m going to throw out a topic, and I’m going to give you each 30, 40 seconds to give me your thoughts. First, and I’ll give you the topic. Lung cancer screening, it’s underutilized. Julie.

Brahmer: Oh, absolutely. I agree. And we have to, as oncologists, push our primary care physicians and our colleagues in the community that they have to push this. We know that these types of therapies when used in the adjuvant setting can cure people. So we need to diagnose these patients in very early stages, and that’s where screening comes in.

Herbst: Sarah?

Goldberg: I absolutely agree. Looking at the statistics is so sad. We know we can make such an impact on these patients, and we just … screening is in most places less than, I don’t know, 5, 10% of patients. One thing at ASCO that was really interesting, and other conferences now too, there’s a lot of medical oncologists that are getting involved in screening, right? I think a lot of us always thought it was like a pre-oncology thing. It was for primary care, it was for pulmonary, but I think people are realizing the benefit here and people are getting involved in looking at broader populations and other ways of screening and trying to up the patients that we’re screening. So really, really critical to point out.

Herbst: Okay, topic number two of the lightning round. We see commercials on TV for immunotherapy. People come in with great expectations, but as we know, even though this is historical, what we’re seeing, and I believe we cure patients even in the metastatic setting, we still have only 20% maybe who have the wonderful response. And many patients become refractory. So, Sarah, you first this time, what’s on the horizon for resistance? What do you predict we’re going to do to target resistance — for primary or acquired?

Goldberg: So I think that’s really, actually an important point, primary or acquired. I think there probably are differences in primary versus acquired resistance. So primary being patients who just never benefit and then acquired being they benefit and then the effect wears off over time.

I think we have to understand a lot more about why patients become resistant. These are things we’re starting to learn, where we’re understanding better that there are some tumors that just don’t have TILs [tumor infiltrating lymphocytes]. There are some tumors that aren’t presenting antigens, and a lot of other mechanisms. I think if we understand that better and we can kind of try to match therapies to the mechanism, I think that’s where we’re going to have more success.

There’s been now, unfortunately, a lot of negative trials in the refractory setting — primary or secondary resistance. And they’ve been negative. We really haven’t seen much activity. And I think probably in part it’s because we’re not selecting patients. We know in lung cancer, we should know of any group, we should know that we need to select patients to see the most benefit. And I think that that’s hopefully what we’ll see in the future.

Herbst: Okay, and that’s important. Julie, what do you think?

Brahmer: I think we’re heading towards precision IO [immuno-oncology], just like Sarah talked about. Definitely in both the acquired and the initial refractory setting. I think if we can tell upfront how patients will do and which therapies combined would be actually more efficacious for them, I think that will garner us results and go farther.

Obviously I think we’re getting closer and closer to use ct [circulating tumor] DNA clearance and see whether or not that may help guide us to add therapy or even potentially subtract therapy.

But hopefully with some of the studies now in the phase III setting, Pragmatica, comparing pembrolizumab [Keytruda] and ramucirumab [Cyramza] for those patients with acquired resistance, in those patients maybe that combination will do better than docetaxel [Taxotere] in the second-line setting, obviously. But we have a long way to go.

Herbst: I would predict we’re going to have to understand resistance better and use science to inform our therapy and try to find a way that we can understand why is the patient resistant? Is it the lack of T-cells in the tumor? Get the T-cells into the tumor. Is it some resistance pathway? Target that.

But we’re making progress. We just have to batten down. It’s not going to happen right away, but we have to look back at how much progress we’ve made.

Okay. Let’s do another question. What about biomarkers? We have PD-L1, but we don’t really have anything else. What’s the next biomarker on the horizon, Julie?

Brahmer: Oh, man, you asked me the hard questions first, but I do think, one, maybe we don’t need a biomarker, like I said before, maybe it’s ctDNA. Maybe we can tell the dynamics of ctDNA and be able to adjust therapies accordingly.

Obviously a lot of these gene expression profiles would be helpful, but we’re learning more and more about genomic profiles of tumors and which tumors may be less responsive to immunotherapy. Now we’re just starting to figure out why. So I think it’s coming, but beyond that we’re still stuck with PD-L1.

Herbst: Sarah?

Goldberg: Yeah, PD-L1 has been okay in lung cancer. I think it helps us, it helps guide us. It’s not ideal, it’s not optimal. I think one interesting thing about PD-L1 is we’ve seen the higher the level, the better the outcome in patients with metastatic disease. So the greater than 50% may not even be the best cutoff. Maybe it’s even higher, but I think maybe it will become a kind of a multifactor biomarker in the future.

Maybe partly PD-L1, TMB [tumor mutational burden] — we stopped talking about that as much lately. There is something there. Patients with higher TMB do tend to have better outcomes. It’s just not clear what the cutoff is and how we measure it, and then how we use it to select patients. And then the other assays that are being developed as well, I wonder if in the future it’ll be some sort of mix of these various assays that we use to identify patients and co-mutations as well. We’ve seen a lot on that as well.

Herbst: Okay. We’ve come to our final minutes, so I’m going to ask you just one more question each, and that’s give me a prediction. In 10 years, the biggest advance we’re going to see in lung cancer, the paradigm shift that we’re going to see? And I’m going to ask you first, Sarah, lest Julie think I’m picking on her.

Goldberg: I think you asked me this last year, and I hope I’m not going to say the same thing. I think right now we are getting really good at precision medicine. We find the biomarker, we match it to a patient. We’ve, I think, led oncology in that. We have so many patients that we are able to give targeted therapy. It’s not curing patients, and so I think that we need to figure out a way. These patients, a lot of them, tend to be younger and not have significant other health issues, and a couple of years is just still not enough.

So I think in the targeted therapy realm, I think we’re going to figure out a way to get longer-term benefit, and maybe even cure disease. The drugs work so well, but the resistance develops. So that’s my prediction, that we’re going to be better at precision medicine in the targeted therapy realm and be curing patients maybe in 10 years.

Herbst: Thanks, Sarah. Julie, final thoughts?

Brahmer: Well, I think IO, immunotherapy, will even extend into prevention in patients who are extremely high risk for developing cancers, particularly lung cancer. We may see immunotherapy, particularly checkpoint inhibitors, move into that space in order to prevent lung cancers from developing to begin with.

And I agree with Sarah, being able to find ways to harness the immune system almost for every patient in order to finally get rid of those persister cells so that we can cure even more patients. And I think over the next 10 years, I would love to see chemotherapy go away.

Herbst: Well, we’re at the end of our time. What a wonderful discussion. So many exciting things out of ASCO; more to come. Thank you, Julie. Thank you, Sarah. On behalf of all of us, thank you to the audience. It’s been great to be here, and we’ll sign off now.

Click here to watch the other videos from this ASCO roundtable series on immunotherapy.

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