Immunotherapy in Unresectable Locally Advanced NSCLC - Episode 4

Locally Advanced NSCLC: Durvalumab and the PACIFIC Trial

March 20, 2018

D. Ross Camidge, MD, PhD:The PACIFIC trial was a very user-friendly trial. Essentially, somebody who had stage 3 disease, it had to be histologically or cytologically confirmed stage 3 disease to then go through induction chemotherapy and then chemoradiotherapy, sequential chemoradiotherapy or just chemoradiotherapy. And then, the entry in the study came after they had not progressed on the chemoradiotherapy and then they were randomized either to placebo or durvalumab every 2 weeks for up to a year. The primary outcome was either PFS or overall survival.

So, it was incredibly easy to put patients on. It was a real-world kind of clinical trial. And what it showed, what we’ve seen, is the PFS in the control arm was just over 5 months, 5.6 months, and in the experimental arm, it was 16.8 months; something like an 11-month difference in median progression-free survival.

I think the other thing that’s really exciting about the study is, if you look at a different endpoint, if you look at the time for either death or distant metastatic disease—so are you doing something other than just changing where the radiotherapy was aimed at—there was a significant improvement in that, too, suggesting you’re actually changing, in the natural history of the disease, potentially—even though we don’t have overall survival yet—the cure rate.

Because immunotherapy clearly works in some people, it’s important to try and ask, “Well, who is benefiting and from what?” And within the PACIFIC trial, we could see that most major subgroups still showed benefit from the addition of the durvalumab to the standard chemoradiotherapy or given after chemoradiotherapy.

The one group that stands out and perhaps not clearly deriving benefit was theEGFR-mutant group. And there, the confidence intervals actually spanned 1, meaning that you can’t actually prove that it didn’t worsen outcomes. The point estimate may still have been in favor of durvalumab, but we know from multiple trials that theEGFR-mutant group maybe is a group that we need to look at in a little bit more detail. But if you don’t have a driver oncogene, this looks like a treatment that you could probably plug into lots of other people.

Within days of the PACIFIC study being presented, the NCCN had already updated their guidelines to say that adding in immunotherapy, specifically durvalumab, post-chemoradiotherapy should now become the new standard of care. The FDA very recently approved it, too. So, I think it is going to be the new standard of care. The obvious question to ask is, is this an effect that’s specific to durvalumab? And we don’t know. There’s no particular reason why it should be. We haven’t seen a lot of differences between pembrolizumab, nivolumab, durvalumab, but, nevertheless, it’s the one that has generated data so far.

Any company with a PD-1 or PD-L1 antagonist is doing a huge suite of trials and durvalumab is no different. In non—small cell lung cancer, it’s being looked at in the adjuvant setting—so after resected disease. It’s being looked at in combination with a CTLA-4 antagonist in MYSTIC, although we’ve seen a press release suggesting that that was unable to beat combination chemotherapy in a first-line study. And it’s being looked at as a monotherapy after 2 lines of prior chemotherapy.

Transcript edited for clarity.