New Paradigms for Treatment of Locally Advanced NSCLC - Episode 5
Mark Kris, MD: Let’s move on to the disrupting force in this whole area—the PACIFIC trial. Walter, can you say a few words on the PACIFIC trial?
Walter J. Curran Jr., MD: Sure. PACIFIC is the term which refers to a 2-arm, phase III blinded trial for patients with stage 3 disease. The first part of the results published last year in the New England Journal of Medicine. Over 700 patients were enrolled in this study, which randomized patients with stage 3 disease after chemoradiation to durvalumab or placebo. The trial had 2 co-primary endpoints. One was progression-free survival and the other was survival. There was a 2:1 randomization ratio favoring the durvalumab arm. The results, which came out last year, favored the durvalumab arm. Here, we saw a very statistically significant advantage in progression-free survival. Survival data has not been reported yet. We are expecting this information later on in 2018. If you look at every subgroup that we normally divide stage 3 patients into, there is a benefit favoring durvalumab over placebo in the consolidation phase.
Mark Kris, MD: I have a question about the rationale for using an immune checkpoint blocker with other therapies. Is there a particular reason why it would be a good agent to combine with radiation or concurrent chemotherapy/radiation?
Walter J. Curran Jr., MD: There’s a lot of laboratory data, and what I would describe as growing clinical data, demonstrating that the activity of checkpoint inhibition is actually strengthened and accelerated by radiation. In this particular setting, it’s not the classic experimental design where you give a full course of radiation, have a several-week break, and then give a checkpoint inhibitor. Most of the trials have looked at a closer temporal relationship and, then, responsive disease outside of the radiation field as evidence that checkpoint inhibition has actually been helped by radiation. This is not the classic experimental design of the so-called abscopal effect. But, I think that everyone who’s looked at the data still views this trial as an extraordinary, landmark trial.
Mark Kris, MD: Are there any trial design issues that you think need some further clarification, or unique aspects of this trial, in terms of the radiation, first?
Walter J. Curran Jr., MD: Sure. It was different from almost every other phase III trial. The registration and randomization happened after the chemoradiation, and it really was available for those patients who were basically nonprogressors on chemoradiation. All of the guidelines regarding radiation quality, and all of the steps regarding the dosing and schedule of chemotherapy that really have become kind of part of the quality assurance of trials in Europe, Japan, or the United States were absent, here. When you have such a dramatic result, you wonder whether there was perhaps an uneven balance between the arms of risk factors for progression. The arms broke very early. This was surprising. I don’t have an answer as to why that was the case, but we will see other studies interrogate this issue. I think we’ll get more guidance on it, but there’s nothing that’s been available to the medical public to explain why or if there’s any maldistribution between the 2 arms.
Mark Kris, MD: Also, I’m wondering whether there is something different about the early stage of lung cancer and the responses to checkpoint inhibitors. I’m involved in a number of neoadjuvant trials, and I think people are very surprised at the profound benefit that we see—not the radiographic benefit but the pathologic benefit in those resection specimens. In the nivolumab experience, which was presented at ASCO last year, about a 40% pathologic complete response rate was demonstrated with 2 doses of single-agent nivolumab. Again, with chemotherapy, in that setting, we’d expect about a 15% or 20% rate. Now, we’re seeing the same thing with atezolizumab. So, it may be that there’s something about having an intact tumor lymph node system that makes it more amenable to the checkpoint blockade.
Transcript Edited for Clarity