The New Frontier in NSCLC: Immuno-Oncology Combinations - Episode 11
Corey J. Langer, MD, FACP: Just a year ago, we saw the presentation of the PACIFIC trial—the evaluation of durvalumab as consolidation in this setting versus placebo. Again, there was 2:1 randomization, which seemed to be popular among many of these trials. To get on this trial, patients had to complete chemoradiation. They had to have no evidence of progression. So, they could have been stable or responding. The randomization was fairly quick—within 2 to 6 weeks of the completion of chemoradiation. There was no mandate or handcuff regarding the chemotherapy regimen, so there was a fair use of paclitaxel/carboplatin, etoposide and platinum, and other combinations.
The original presentation, which is now published in the New England Journal of Medicine, showed a remarkable improvement in progression-free survival—16.8 months versus 5.6 months—and a delay or reduction in the incidence of metastasis at every potential organ site, whether it was the brain, liver, lung, bone, adrenal, local, or regional recurrence. There was a marginal increase in toxicity. The big fear, of course, was of the enhanced pneumonitis. It was slightly higher, but certainly not in the range that we would typically see.
Mark A. Socinski, MD: It was mostly grade 1 or 2 and not grade 3 or 4.
Corey J. Langer, MD, FACP: Frankly, the numbers that were generated in that trial were amazing, but I was still a skeptic.
Karen Kelly, MD: And we don’t know why.
Mark A. Socinski, MD: And then, Karen, we recently learned in a press release about overall survival.
Karen Kelly, MD: If you were a betting person, you would have bet that the overall survival was going to be superior based upon, again, widely separated curves.
Corey J. Langer, MD, FACP: And standard hazard ratio.
Karen Kelly, MD: Yes. We could have predicted that it was going to be positive. One might have thought it wasn’t going to be positive. When people crossed over and got immunotherapy, when they did progress, that could have made those curves come together enough that there wouldn’t have been a difference. And, of course, we don’t know what the numbers show, but it is now positive.
Corey J. Langer, MD, FACP: Survival is now positive.
Karen Kelly, MD: This is great for our patients with stage 3 disease. It’s the first trial…
Mark A. Socinski, MD: That we’ve done something in, in over a decade.
Benjamin P. Levy, MD: In over 2 decades.
Karen Kelly, MD: Over 2 decades.
Benjamin P. Levy, MD: How hard is it for us, as clinicians, to tell patients, “You know, you’re getting chemoradiation.” They say, “What’s after that?” “Nothing, and you know there’s a strong chance that you may recur.” Obviously, these conversations don’t go down immediately. But this is a welcome change.
Karen Kelly, MD: And 42% of the patients actually completed the 12 months. I thought it would be a little bit lower than that. I was surprised.
Corey J. Langer, MD, FACP: I thought it was going to be a little bit higher.
Karen Kelly, MD: I thought that 12 months was a long time for this group of patients.
Mark A. Socinski, MD: Especially every 2 weeks.
Karen Kelly, MD: On that every-2-week schedule. The other thing was that there was no difference in PD-L1 expression. So, this is a phenomenal result.
Corey J. Langer, MD, FACP: Higher PD-L1 patients did have a relatively greater benefit, but the benefits we’re seen across…
Mark A. Socinski, MD: And it was cut by 25% greater or less, or…
Karen Kelly, MD: They do it a little bit different but…
Corey J. Langer, MD, FACP: I still have some concerns about the trials. The control arms did abnormally poorly.
Karen Kelly, MD: Right.
Corey J. Langer, MD, FACP: Granted, the clock started ticking at the completion of chemoradiation, not at the beginning. But even if we spot them an additional 2, 2.5 months, it’s lower than we’ve typically seen in other trials. And then, standard practice in North America, and parts of Europe and East Asia, is to do a PET simulation. That was not mandated in this trial. I realize it’s a minority of patients, but all of us have had individuals who we thought had locally advanced disease. We did a PET as part of their workup and, lo and behold, they had asymptomatic, otherwise occult metastasis that had not been detected by CAT scan. Needless to say, durvalumab is going to do better than placebo in that population. So, that was 1 of the reasons why I was still skeptical of overall survival. It’s still a concern. Nevertheless, overall survival trumps everything else. We have never seen any other agent in this setting show a survival advantage. For the last 7 or 8 months now, I have been standardly giving durvalumab after chemoradiation.
Mark A. Socinski, MD: Yes, it does bring up some issues. For instance, I’ve had several physicians say that they’re not willing to give up those 2 cycles of consolidation chemotherapy, right?
Benjamin P. Levy, MD: That’s what I was going to mention. Tucked away in the appendix of this trial are data that reveal that the hazard ratio was even better within 14 days in patients who got durvalumab. I think there was some reluctance not to give it too close to radiation because of potential side effects. But to see that significant of a benefit in those patients who got it within 14 days—we’ve had a conversation, especially for our squamous cell patients who may not be that fit, who were getting weekly paclitaxel/carboplatin. Remember, this trial did not allow consolidation. It allowed induction. But they’re now in consolidation.
Mark A. Socinski, MD: And 26% of the patients got it.
Benjamin P. Levy, MD: Got induction. If you’re giving a patient weekly paclitaxel/carboplatin…I still felt uncomfortable not doing the consolidation, until I saw this data.
Mark A. Socinski, MD: I completely agree with you, but I give it as induction. We changed our paradigm.
Benjamin P. Levy, MD: We don’t do that.
Corey J. Langer, MD, FACP: Most of us don’t do that.
Mark A. Socinski, MD: Let’s face it, it’s the old CALGB study.
Benjamin P. Levy, MD: Yes.
Mark A. Socinski, MD: Which, in my opinion, is a very biased and poorly designed trial. It is misleading. That’s my opinion.
Karen Kelly, MD: And now you’re going on record.
Mark A. Socinski, MD: I am. I still think that if you’re using weekly paclitaxel/carboplatin, I do feel uncomfortable with that being the only chemotherapy. I think if you use full doses…
Corey J. Langer, MD, FACP: I’ve seen the same discomfort, but durvalumab is a systemic therapy that’s effectively replacing chemotherapy in this setting.
Mark A. Socinski, MD: I will tell you another reason why we use induction therapy. It takes all of the pressure off of our radiation oncologists. They have 6 weeks to get the plan together, rather than have us saying, “Let’s get started.”
Corey J. Langer, MD, FACP: Granted, the CALGB trial did not show a reduction…
Mark A. Socinski, MD: It actually showed a benefit of 2 months in favor of reduction. It was not statistically significant, but it really underpowered. The overall survival in both arms of that trial was horrible as compared with other cooperative groups, and I think there was a selection bias because they didn’t want to randomize to 6 weeks on paclitaxel/carboplatin.
Corey J. Langer, MD, FACP: A bigger issue that comes up is that to get on the study, you had to have a CT that showed no evidence of progression. It’s a bit of a game changer. We typically don’t get CTs within 2 weeks of continuous chemoradiation.
Karen Kelly, MD: Right.
Benjamin P. Levy, MD: So, that’s another question.
Corey J. Langer, MD, FACP: As a standard, we would do that at a month or 6 weeks or 8 weeks later. To alter how we actually assess folks and how we do imaging, I think, is going to require some recalibration on the part of both medical and radiation oncologists.
Benjamin P. Levy, MD: Yes, we’re doing that. I agree, Corey. I usually wait until we get that first set of images. But I try to get a CAT scan to assess how the patient’s doing, for post and recurrent chemoradiation, maybe 1 week after. And I start them on durvalumab within 2 weeks.
Mark A. Socinski, MD: The risk of doing that is that there are a lot of radiation changes going on.
Benjamin P. Levy, MD: That’s right.
Karen Kelly, MD: Remember, that was a subset analysis. I don’t think we should be basing a lot of change on a subset. It’s provocative. I’m personally an advocate for radiation/immuno-oncology combinations, which really do need to be explored. But this is a subset analysis, and we have to be careful.
Corey J. Langer, MD, FACP: Those combinations are occurring.
Karen Kelly, MD: Right, that’s what I’m saying.
Corey J. Langer, MD, FACP: Emerging data for pembrolizumab and other agents concurrent with chemoradiation…Frankly, I’m hoping that will further improve the playing field.
Transcript Edited for Clarity