PACIFIC Trial: Durvalumab Following Chemotherapy for Stage III NSCLC

Mark Socinski, MD: Let’s transition to one of the more influential trials. It’s been so wonderful to be a lung cancer doctor in the last decade and certainly recently. Someone pointed out we had 6 or 7 approvals in lung cancer over the last couple of months. It’s been a land of plenty and probably more to come as we’ll talk about. One of the more influential trials, and I want to ask Dr Liu his perspective on this, is the PACIFIC trial. We had reached a plateau in terms of what we could achieve for cure rates and survival in the concurrent chemoradiotherapy world. We saw PACIFIC come along and change the standard of care. Give us your perspective on that, and then do you think it’s been adopted at the community level? Are most people doing it and that sort of thing?

Stephen Liu, MD: I think it’s been widely adopted because this is what we’ve been waiting for, for so long. As a reminder, the PACIFIC trial was a randomized phase 3 trial for patients with unresectable stage III non–small cell lung cancer. Patients received definitive chemoradiation with platinum-based chemotherapy delivered concurrently, and after completing treatment, in the absence of progression, they were randomized to receive durvalumab or placebo for 1 year. What we saw initially was a pretty profound improvement in PFS [progression-free survival], and at the [World Conference on Lung Cancer] in 2018 we saw that did translate to an OS [overall survival] benefit. The hazard ratio at that point was 0.52 for PFS, 0.68 for survival.

What we saw in the past year was more maturity, and with more follow-up we saw that survival benefit persist. We don’t see a dropping of that tail, that hazard ratio 0.69, a consistent benefit with delivery of durvalumab. We saw a median survival of 29 months with placebo, not reached with durvalumab, but the 3-year survival rate was 57%, and I think it’s been embraced by all of us. This is a space where we deliver a fairly toxic treatment. Chemoradiation is one of the tougher treatments that I have to coach patients through. The hope with that treatment is to deliver a cure. We know that for the majority of patients we don’t achieve that. The addition of immunotherapy [I/O] consolidation gives patients the potential for long-term benefit, long-term survival, and I think at first there was some concern about safety. I think that’s largely been quelled. It’s a safe drug to give; we don’t see very high rates of pneumonitis. There were some who were reluctant to get rid of consolidation chemotherapy. Maybe some on this call right now, and who instead are maybe giving that as induction therapy. Now, we’re very comfortable using durvalumab, and it’s become a clear standard.

Mark Socinski, MD: In the trial design of PACIFIC, we had 26 doses or a year of treatment. At least some recent market figures suggest that the average patient doesn’t get nearly a year of treatment. How important is that to you to think you’ve got to push them through and get the full year in?

Stephen Liu, MD: It’s 1 year, which is a nice, round number. That means it’s pretty arbitrary. At that 2018 update, if we look at the 473 patients who received durvalumab, only about 232 completed all 12 months. Some of the patients will drop off for progression, notably less than the placebo arm, and some patients will stop due to toxicity. Those patients may still derive benefit from durvalumab, but just may not need to continue therapy. My general approach is to go for a year, but certainly in the face of toxicity, if I coach patients through, the toxicity resolves, I’m unlikely to rechallenge someone because it may not be critical to finish that year.

Mark Socinski, MD: Roy, any reason to check PD-L1 status in the consideration in this setting?

Roy S. Herbst, MD, PhD: We do, but normally that will be the PD-L1 at the diagnosis and not after the chemoradiation, so all bets are off to what's going on in the tumor microenvironment. We tend to use it on patients regardless of PD-L1 status. There were some data I think early on that suggested lesser effects in low PD-L1. We’re pretty much using it in all groups.

Mark Socinski, MD: We’ll eventually get to the ADAURA trial in this discussion, but that’s certainly going to push more frequent molecular testing in early stage disease. Right now, we don’t have a defined reason to do molecular testing in stage III, but it’s often done so you know that people may have a driver. Does that influence your use of immunotherapy after chemoradiotherapy, given the questionable data we have for instance in a patient with an EGFR mutation?

Roy S. Herbst, MD, PhD: Yes, it might, although if you look at the PACIFIC trial, there were a reasonable number of patients, under 10% or so….

Mark Socinski, MD: Six percent, I think.

Roy S. Herbst, MD, PhD: That had EGFR mutations, and that subgroup, albeit small, did well. I wouldn’t avoid it, but I think we’re moving toward a new trial where we’ll probably molecularly profile stage III patients. And then based on the results of ADAURA, there’s a trial called LAURA, and LAURA is going to be using osimertinib in that stage III chemoradiation post setting. I think that might be a very nice thing to do as well. Same concerns, the worry about ILD [interstitial lung disease] and other issues, and the effect of an EGFR inhibitor plus an I-O agent. Working out some of those timings, I think that would be a very nice thing to study in the future.

Mark Socinski, MD: It changed practice, and I agree with you Dr Liu, I think people are enthusiastic about it. Everyone loves immunotherapy nowadays.

Transcript Edited for Clarity