Immunotherapy for Management of Stage 3B NSCLC

Panelists: Everett Vokes, MD, University of Chicago Medicine and Biological Sciences; Roy Herbst, MD, PhD, Yale Cancer Center; Fred Hirsch, MD, PhD, University of Colorado School of Medicine; Suresh Ramalingam, MD, Winship Cancer Institute Emory University; Naiyer Rizvi, MD, Columbia University Medical Center


Everett Vokes, MD: At this point, we should move on and talk a little bit about earlier stage disease and how therapies are developing. This year, at The European Society for Medical Oncology (ESMO) 2017 Congress, in particular, we’ve received new information regarding stage 3B non–small cell lung cancer. Looking at that history a little bit, we go from what is largely palliative care and palliative intent therapy to curative intent stages. Stage 3B is that marginal stage, just at the tip—the most advanced of the previously untreated patients with, still, regionally confined disease.

The therapy of choice is concurrent chemoradiation, and we have a long history that many of us have participated in of trying to improve outcomes—adding more chemotherapy up front. Adding consolidation chemotherapy was tried; adding targeted therapies was tried. A dose escalation of radiation (all the way up to the high 70-Gy range) was not successful. And other approaches, such as adding cetuximab, were also not successful. In a way, we’ve had some stagnation where we do cure people, but that cure rate is, at 3 years, about 25% to 30%.

What was presented this year at The European Society for Medical Oncology 2017 Congress, and is now published, is the so-called PACIFIC trial, where patients with previously untreated stage 3B disease, after completion of chemoradiation, were randomized to placebo versus durvalumab. And the data that were presented showed a marked increase in progression-free survival of about 5.5 to 16.5 months—so stretching by 11 months the progression-free survival. We don’t know about survival, but as progression-free survival goes, this is really a novel and impressive finding that is unmatched in the literature by anything else like it in the last 15 years or so, if not longer.

So, we should talk a little bit about this trial and maybe all of us should comment? How do we view these data? The toxicity spectrum, which was mild or typical for durvalumab, but certainly was not suggestive of a major interaction with just recently completed chemo-RT, does this define this as a new standard at this point? Or do we need to wait longer? Do we need more data?

Suresh Ramalingam, MD: I was very impressed with the results of the PACIFIC study overall. And it goes back to an issue you had brought up earlier, during this conversation, about the so-called abscopal effect. When you give radiation, does it make the immune system more likely to respond to a checkpoint inhibitor? Does radiation increase the inflammation in the tumor? We don’t know the exact mechanisms, but all, or some, of these could be in play here—where giving a checkpoint inhibitor right after chemoradiotherapy results in a significant improvement in progression-free survival.

I was also happy to see that the toxicity was not increased by the addition of an immune checkpoint inhibitor in the setting. Another point that came out from the trial was that the PD-L1 expression didn’t seem to matter. Both patients with low and high PD-L1 expression benefited from getting the durvalumab maintenance or consolidation therapy (however you refer to it). So, I think that these results come as a very refreshing step forward in a disease where we have been stuck with stagnation. And I think it will be incorporated into clinical practice.

Naiyer Rizvi, MD: I think it’s important to appreciate how many patients this actually would impact, right? If you think that of all non–small cell lung cancer, 50% are metastatic, 25% are locally advanced, and 25% have early stage disease, that locally advanced group represents actually a bigger population than those eligible for first-line pembrolizumab (about 30% of 50%), right? So, it’s a lot of patients that this is going to impact. I think the decision around surgery versus chemotherapy and radiation therapy is often a tough one. But I think that most patients are unresectable. They’re unresectable because they have 3A disease and they have pulmonary function tests that preclude resection. Or they have comorbidities that preclude resection. Or they have too extensive nodal involvement. Or they’re stage 3B with contralateral disease.

And for those patients, after chemotherapy and radiation therapy, consolidation chemotherapy hasn’t worked. The adjuvant vaccine therapy, L-BLP25, didn’t work. Nothing has moved the bar for this patient population, where most of them have micrometastatic disease, clearly. To see a trial with an 11-month progression-free survival difference is massive. I think it’s going to be the new standard of care. And although the data is not mature enough to have overall survival data, it’s almost impossible, in my mind, to think that there isn’t going to be an overall survival benefit. If you hit progression-free survival with an immunotherapy agent, you’re going to hit overall survival.

Everett Vokes, MD: Does the timing of the randomization influence your interpretation of this trial—that it happened after people had completed chemotherapy-RT? They had not progressed. They at least had stable disease. Does that make it a real-world trial?

Naiyer Rizvi, MD: I think so. I think for the majority of patients, you end up staging them and testing to make sure they have stage 3 unresectable disease. They largely respond to chemotherapy and radiation therapy. So, I think it’s real work. What was interesting from the data, though, was that in those patients that were randomized within 2 weeks of finishing radiation therapy, it looks like their hazard ratio was actually a little bit better than in those patients who were randomized more than 2 weeks after (suggesting there really is some synergy going on between whether it’s the radiation or the chemotherapy, or both). And so, trying to move your treatment with durvalumab, adjuvantly, and as soon as possible, is important.

Everett Vokes, MD: Fred?

Fred Hirsch, MD, PhD: I do agree with what has been said. There are certainly very encouraging results for a disease group where we haven’t seen any progress for many, many, many years. But we are talking about a disease group where a subgroup is potentially cured. I’m still missing, of course, 2 important parameters. One, as we have talked about, is overall survival. I would like to see the overall survival data. Two, I would like to see the quality of life data. Does the improvement of progression-free survival also lead to a better performance for the patients? We don’t know that. There hasn’t been data presented yet.

So, I think those 2 data sets would be very important. I’m a believer that these data will lead to game changing results for this group of patients. But I think there are a lot of people who want to see survival data and quality-of-life data first.

Everett Vokes, MD: They will, of course, comment. Formal quality-of-life data, I don’t know. But the comparison of toxicities between the 2 arms were not, as far as I saw, suggestive that quality of life would be negatively impacted by the treatment (although I think the cough rate was a little bit higher and maybe there was a higher pneumonitis rate). Until the survival data are there, and the progression-free survival data are what they are, and you now see a patient, what are you going to tell the patient?

Fred Hirsch, MD, PhD: No, I think you cannot ignore those results, and I think, as has been said by Ram [Suresh] and Naiyer, that certainly many places, tomorrow, would certainly consider changing their treatment plan to this regimen. If I saw a patient tomorrow, I certainly would consider it. But, again, there are 2 data sets, which are crucial.

Everett Vokes, MD: That we’ll need to eventually get. Roy, what are your thoughts?

Roy Herbst, MD, PhD: Well, I don’t have much to add, although I will say you’re right—this is a selected group of patients. They took the patients after what’s quite a good fit test (getting through chemoradiation), because many of those patients will have toxicities and other issues. Also, some patients do progress through that. I’ve seen my share. That said, the 2 groups were equal and they’re randomized, and we’ll treat based on the trial eligibility. So, in that group of patients, I thought the result was historic. The difference was quite large. Certainly, we do want to see survival, eventually, and at least make sure that it’s trending in the right direction. Remember, in the real world, hopefully, these patients are getting immunotherapy at some point in their life. But, I think that I would, certainly as soon as there’s an approval and a reimbursement available, recommend this to those patients and use it.

Transcript Edited for Clarity 
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