The Role of Immunotherapy in Early-Stage NSCLC

At the American Society of Clinical Oncology (ASCO) annual meeting, several positive trials were presented on the benefits of adding immune therapy in the early treatment of patients with early-stage non-small cell lung cancer (NSCLC).

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 first of four exclusive episodes focuses on the role of immunotherapy in early-stage NSCLC treatment.

Following is a transcript of their remarks:

Herbst: Welcome to MedPage Today, post-ASCO. I’m Dr. Roy Herbst, deputy director of the Yale Cancer Center and assistant dean for translational research here at the Yale School of Medicine. I’m very excited about the conversation we’re about to have with two distinguished panelists. The first is Dr. Julie Brahmer, from Johns Hopkins Medical School. Julie, would you please introduce yourself?

Brahmer: Hi, I’m Dr. Julie Brahmer. I’m the co-director of the Upper Aerodigestive Cancers Program, as well as the co-leader of the Cancer Immunology Program at the Johns Hopkins Kimmel Cancer Center.

Herbst: Thanks, Julie. And then my colleague from Yale, Dr. Sarah Goldberg. Sarah, can you say a few words please?

Goldberg: Hi, I’m Dr. Sarah Goldberg. I’m an associate professor of medicine in medical oncology at the Yale School of Medicine, and the chief of thoracic oncology at the Yale Cancer Center.

Herbst: Thanks, Sarah. Thanks, Julie. Great to have you here. Let’s discuss a couple of topics from ASCO. The first topic I want to put on the table is the perioperative space. Certainly, I know, a major presentation on KEYNOTE-671. We heard about AEGEAN at AACR [American Association for Cancer Research], there are other studies. Julie, can you just give us a little background about the perioperative space and your thoughts on that; how it compares to CheckMate-816?

Brahmer: Well, I think just starting off with neoadjuvant therapy. Doing neoadjuvant chemotherapy and immunotherapy does increase the chance of pathologic complete response in patients compared to chemotherapy. Now the question is what post-op therapy should be given, if any? And obviously the CheckMate-816 study did not give any post-op immunotherapy, and did show an improvement in EFS [event-free survival] … [and] the 2-year EFS rate was significantly improved as well, despite not giving any adjuvant therapy.

Now for perioperative, so giving both neoadjuvant immunotherapy and chemotherapy, following surgery with adjuvant immunotherapy, both AEGEAN as well as the KEYNOTE-671 study did that. So the AEGEAN added durvalumab [Imfinzi] to chemotherapy. Following surgery, patients received durvalumab. And then in KEYNOTE-671 patients received pembrolizumab [Keytruda] plus chemotherapy. And then after surgery, patients received adjuvant pembrolizumab.

Both studies did show an improved pathologic response and then the event-free survival at 2 years was also significantly improved in both studies. So the question now is, what do we do? Do we err on the side of giving adjuvant immunotherapy in patients? Maybe we should base that on pathologic complete response. But Sarah, what are your thoughts?

Goldberg: So we’ve now seen several positive trials with adding immune therapy in the early-stage setting, so for patients with stage II and III disease. And so, we know that there’s benefit with neoadjuvant therapy when we add it to chemotherapy, and also benefit when you have immune therapy in the neoadjuvant space, as well as adjuvant. So the question now, as Julie said, is how do we put this into practice?

I think it’s really hard to know whether we should give neoadjuvant alone, which is tempting because it’s only three or four cycles, or if the additional year of adjuvant therapy adds to the benefit. And I think in the future, it probably will be about patient selection. And that the nice thing about neoadjuvant therapy is you have the pathologic results, if someone had a pathologic complete response or a major pathologic response.

And I hope that one day we’ll be able to use that information to know if adjuvant therapy is useful or necessary, but I think at this point we’re not quite there yet. And so we just are left with several positive studies, and not entirely clear how to select which patients receive neoadjuvant alone or perioperative therapy.

Herbst: Well, Sarah, you’re the leader of the lung group at Yale, and we have a tumor board every week. What are we doing now? Post-ASCO, pre-ASCO? What’s the sentiment you see from the surgeons?

Goldberg: Yeah, so everybody has their own unique takes on things. I think we have absolutely bought into the idea of the benefit of immune therapy in the early-stage setting. I think for some patients with stage IIa disease, where it’s a resectable tumor, I think the surgeons like to take those patients to surgery upfront and then we give adjuvant therapy afterwards. That was before ASCO. We did give some neoadjuvant therapy, especially with lymph node-positive disease, especially the stage III patients.

But ASCO this year, I think, really showed us several studies, and other conferences and papers throughout the year have shown us several studies now where neoadjuvant therapy looks incredibly promising. And I think more and more now we’re going to be considering neoadjuvant therapy for our patients, knowing we still could take these upfront for surgery and then do adjuvant therapy afterwards.

But I think the benefit of neoadjuvant therapy has been clearly defined now. And I think more and more we’re going to be considering this for our patients. But it’s a change, it’s a change in how we practice and how we think about seeing our patients and deciding on therapies.

Herbst: Well Julie, Hopkins is one of the places that sort of pioneered this, and the CheckMate-816 [study] came out of there. So how do you compare this to that and do you use this for all patients or just for stage IIIs, and any selection factors? I sometimes worry you take the tumors and they’re too big and what about not getting patients to surgery?

Brahmer: Yes, I think we saw in updates in the CheckMate-816 study, of those patients who don’t go to surgery, they don’t do as well. But it’s a minority of patients that don’t end up going to surgery, and there’s various different reasons. But … most of those reasons are not due to progression of their disease or toxicities. It’s mainly either patient choice or those patients just were not resectable to begin with. So I don’t think we can look to say that these neoadjuvant therapies can make someone resectable or their disease resectable where the disease was not resectable or safe to resect to begin with.

I do think some of the pushback against doing a neoadjuvant therapy is that we prefer to have some mutation testing back before patients start on chemotherapy and immunotherapy. And so there is a push in some patients to get them to surgery because it just seems like it takes a long time to get those results. And so people are resorting to doing IHC [immunohistochemistry] or FISH [fluorescence in situ hybridization] to try to get some of those EGFR or ALK results before starting chemotherapy and immunotherapy.

But like in the KEYNOTE study, they did include patients with EGFR mutations, so I’m still not comfortable giving immunotherapy to those patients. So I’d prefer to have those results. But sometimes patients and other physicians want to get those patients to surgery and so they go directly to surgery.

Herbst: Absolutely. We’re going to wrap up in a second, but my last question, maybe for you, Sarah, are all the drugs the same or is one better than the other? We’re seeing all these trials are comparing to a chemotherapy control. They’re all going to come out with different EFS, is the new endpoint there, an event-free survival. Of course we’re waiting for overall survival. How do you pick which drug, or what do we do?

Goldberg: You saved the hardest question for last there. There’s never been a trial comparing these drugs head-to-head. I’m not sure there ever will be. So we don’t really know. We only can compare across trials and there’s a lot of other differences between the different trials.

I think we’ve seen several trials that are positive with a variety of different drugs. Is one better than another? I’m not sure. I think we have a lot of comfort using pembrolizumab because there are a lot of positive studies with pembrolizumab, and so that becomes a common one we reach to. But I think it’s also, what did we have first? We had atezolizumab [Tecentriq] in the adjuvant space. We had chemo plus nivolumab [Opdivo] in the neoadjuvant space. So I actually, personally, I feel comfortable using any of those. How do you select formulary? I’m not sure. I think it would be nice if we really knew which one was best, but I think the regimens are all a bit different and so that might feed into it as well.

Herbst: Okay. Good. Well, we’ll move on, but hold that thought and we’ll bring it up in our next topic.