David Spigel, MD: I’m David Spigel. I’m the chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee. I’m also a medical oncologist at Tennessee Oncology. And I lead our lung cancer research program. It’s my honor to be here to talk about stage III non–small cell lung cancer management and focus on the recent update of pivotal data on the use of immunotherapy in the treatment stage III disease.
A little about stage III lung cancer in terms of how we manage it. This used to be a medical school and fellowship, a topic folks stayed away from because it was so controversial. Basically, we’re trying to define whether someone has resectable cancer or is unresectable. In non–small cell lung cancer, that usually starts with CT and PET [positron emission tomography] imaging and an assessment of mediastinal disease. If we’ve ruled out distant disease, you’re trying to assess if somebody has mediastinal disease. Using the help of our navigational bronchoscopy tools with our pulmonologist, interventional pulmonologist, or interventional radiologist—or even our surgeons getting sample of the mediastinal nodes—is critical in confirming disease or not.
Once we know a patient has stage III disease, the question comes down to if they are resectable or not. Obviously that depends on your institution. But in general, we’re looking for minimal station or mediastinal disease. So low volume, single-stage disease. It’s very rare these days to take somebody with stage III cancer beyond 1 station or 1 lymph node to surgery, just because the outcomes have been poor in that group in patients with stage III disease. As I’ll show you, our patients do much better with chemoradiation followed by immunotherapy than they used to with just simply chemotherapy and radiation.
One last thing about stage III cancer. We try to get chemotherapy and radiation therapy for unresectable patients together. It’s not the end of the world if it’s sequential, but we try to get concurrent because that’s been proven to be better than sequential. I’ll come back to molecular testing, but right now, for unresectable stage III disease, molecular testing, PD-L1 testing—at least in the United States—really doesn’t have a bearing on your choice of therapy in terms of unresectable stage III disease, but maybe we can get into some of that in a little bit.
Everything changed really when PACIFIC was finished and results were made public. This is the pivotal randomized phase 3 trial looking at the role of immunotherapy, specifically the PD-L1 inhibitor durvalumab after standard chemoradiation. Remember the design of this study. This was looking at patients with unresectable stage III cancer. All patients were allowed to receive chemoradiation therapy according to institutional standards. And the randomization was after that, so up to 42 days after chemoradiation therapy ended, patients were randomized to durvalumab given at every-other-week schedule, so 10 mg/kg every other week for 1 year or placebo.
This was a placebo-controlled trial, and the study was designed to look at both overall survival and progression-free survival and then a variety of secondary end points we’ll get into. This study was already presented by Dr Scott Antonia and colleagues. We were fortunate to be a part of this trial at Sarah Cannon, and we’ve seen these results. They’ve been published in the New England Journal of Medicine twice, first for progression-free and then for overall survival.
But most recently at ESMO [European Society for Medical Oncology Congress], we saw an update, specifically a 4-year overall survival update. That’s what’s been exciting. We had known obviously that durvalumab is superior to placebo following chemoradiation therapy and leads to a survival and progression-free survival advantage, but at ESMO we saw the 4-year update. The hazard ratio remains quite low, 0.71, so a 29% reduction of risk of dying for those patients on durvalumab vs placebo. What was most impressive, though, was the kind of landmark assessment. At 2 years, the overall survival was about 2 of 3 patients were alive on durvalumab compared with about 55%. At 3 years, it was about 57% vs about 44%.
As I mentioned, the purpose of this update was the 4-year overall survival analysis. What we know is that about 50% of patients were alive compared with about 36% of patients on just standard chemoradiation followed by a placebo—a substantial advantage. That alone was groundbreaking. This updated analysis gives us confidence that the initial results are holding true, that there’s a group of patients who continue to benefit and appear to be long-term survivors. More to come as the years pass. The numbers are still quite large. There are about 270 patients involved in the 4-year analysis, which isreally quite fantastic.
We also learned that progression-free survival was in favor still for durvalumab at 4 years. About 35% of patients were progression-free vs about 20%. That 20% number really hasn’t changed for 2 decades or so. We see that 35% of progression-free is really fantastic.
Transcript edited for clarity.