Narjust Florez, MD, and David R. Spigel, MD, on Limited-Stage Small Cell Lung Cancer: Results From the ADRIATIC Study

Narjust: Thank you David for being here with us today. We're delighted to have the plenary speaker with us in this intervention. David: Well, it's an honor for me to be here with you. Narjust: All right, so let's start with the basics. What is the ADRIATIC Trial? David: So this was really designed to see if you could improve the care of patients with limited stage small cell lung cancer. These patients currently get chemoradiation therapy. It's just that the outcomes are poor. Most patients have cancer come back within two years, and as you know, very few patients will live beyond five years. And so can you improve how patients do? That's really the impetus for designing this study. Narjust: Now that we have the basics, let's break it down the design. We know this is a Phase III trial. Can you walk us through the design? David: Yeah, that's correct. So the way to try to improve outcomes for patients in this study was to use immunotherapy. And so this study employed durvalumab, a PD-L1 antibody, and as I'll show you in a moment, there was an arm that had a CTLA-4 antibody, tremelimumab. So as you say, it was a randomized Phase III trial. This was a global study, it was placebo controlled, and it was looking at patients with limited stage small cell lung cancer. Had to have good performance status. But here's the key to this trial. Every patient had to receive chemoradiation therapy before they got randomized. And that was typical therapy you're familiar with. It's platinum etoposide. And then radiation could be given either once daily or twice daily. After all patients got standard chemoradiation therapy they were then randomized if they didn't have progressive disease or exceptional toxicities to either durvalumab, placebo or a third arm of the combination with tremelimumab. Narjust: So now you're talking about those three arms. That was the initial design, but later patients were randomized only one to one to placebo durvalumab. Can you talk to us about that change? David: Yeah, no, it's a great question. So the study was designed to look at the primary endpoints for a comparison of durvalumab versus placebo for overall survival and progression-free survival. But as you point out, there was a third arm with tremelimumab that is a secondary endpoint. The study originally had 200 patients randomized to each arm, but was later amended for this focus on the durvalumab versus placebo arm. And the way the statistical plan works is you first look at the analysis for durva versus placebo for OS and then PFS, and then if those are met, you look at the analysis, the secondary endpoints for the combination with tremi versus placebo. So this is the first planned interim analysis for durva versus placebo. The comparison of durva-tremi versus placebo remains blinded for a next feature analysis. Narjust: Oh, that's very exciting. This is just the beginning. David: Just the beginning, yeah. Narjust: Looking forward to it. So you mentioned primary endpoints. So what are the primary endpoints of that ADRIATIC Trial? David: Yeah, what's great about this study, and you're familiar with this debate about should you go for overall survival, progression-free survival. So this study was designed to look at both. And so overall survival was a key primary endpoint. But as was true for that progression-free survival by blinded independent central review was a co-primary endpoint. Narjust: So now that we're getting to the endpoints, let's talk about the results. Let's talk about overall survival. What were the results of the study? David: Yeah, so durvalumab demonstrated a statistically significant improvement in overall survival. The hazard ratio was 0.73 and sometimes the better way to look at that is that means there's a 27% reduction in the risk of death if you received durvalumab versus placebo. So that was quite outstanding. There's about three years of follow-up. And if you look at the median survival for durvalumab, it's approaching 55 months. And for placebo it's 33 months. So that's about a 22-month improvement in overall survival. Narjust: And I think patients have to take into account, there's not a little benefit. It's 20 months. David: Yeah, it's almost two years. Narjust: So progression-free survival, what are the numbers there? David: So it was a co-primary endpoint as we discussed. And so durvalumab also hit that endpoint. The hazard ratio for that benefit was 0.76 or said another way, a 24% reduction in the risk of dying or having cancer returned. That was statistically significant. So another major finding, the median progression-free survivals were about 16 and a half months versus about nine and a half months. So about a seven-month improvement in progression-free survival. Narjust: Which is actually very impressive for small cell. David: It is. You and I are used to seeing improvements sometimes of a few weeks, maybe even one or two months. And then for overall survival, maybe a little bit longer. So this is pretty substantial. Narjust: Especially when we were als so excited about IMpower133. This is nearly three times that. David: I agree. I think it's been a while since we've seen any kind of major kind of impact in small cell lung cancer. Narjust: So my last question is toxicity. We are concerned about the rates of pneumonitis in chemoradiation followed by immunotherapy. What were the rates of pneumonitis in these patients? David: Yeah, so it's a great question. If you look at radiation pneumonitis in both arms, because remember, every patient received radiation. The rates were 23% in both arms. But as you know, doctors sometimes score things differently. So there's a separate term called pneumonitis. When you combine pneumonitis and radiation pneumonitis terms, the rates overall are about 38% with durvalumab and about 30% with the placebo arm. So not really too surprising in terms of that difference. There's some other expected toxicities with durvalumab like skin toxicity, thyroid abnormalities, but really nothing surprising NJ that we haven't seen with durvalumab say in the treatment of non-small cell lung cancer for stage three disease. So no surprises. Narjust: And we have to remember that this comparison is to placebo. David: To placebo, that's correct. Narjust: That's very important. So my last question to you is how would you summarize the results of the trial to our patients and their families? David: Yeah, I think it's great news. I think now we're trying to cure patients with limited stage small cell lung cancer. And so what these results mean is that we have a new therapy, durvalumab, to add after standard chemotherapy and radiation that we think, well, we know can improve overall survival as well as how long they live without cancer returning. Narjust: Well, thank you for your time and thank you for everything you do every day to improve the care of all patients with thoracic malignancies. David: Oh, that's very kind. Thank you. As well.