Innovations in Small Cell Lung Cancer: ADRIATIC Study

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program.

Today I'm happy to be joined by Dr. Luke Delasos, a medical oncologist here at Cleveland Clinic with a focus on thoracic oncology. He's here today to talk to us about the recent results from the ADRIATIC study, so welcome.

Lukas Delasos, DO: Thank you for having me here, Dr. Shepard. Pleasure to be here.

Dale Shepard, MD, PhD: Absolutely. So to start off, tell us a little bit about what you do here.

Lukas Delasos, DO: Yeah, so I just graduated fellowship in June. I've stayed here as thoracic oncology staff, but I'm also out in the region doing community oncology one day a week with a primary focus as a clinician scholar to become a clinical investigator.

Dale Shepard, MD, PhD: Excellent. Well, speaking of clinical investigator, we're going to talk about a trial today. We're specifically going to talk about a trial that involves small cell lung cancer. A lot of different people might be listening in. Give us an idea of small cell lung cancer. We've had a lot of episodes with non-small cell lung cancer. Give us a little bit of an idea of what this is.

Lukas Delasos, DO: Yeah, so whenever I explain it to my patients, I like to break it up into two broad categories, so either aggressive or non-aggressive types of lung cancer. Small cell lung cancer definitely fits into the more aggressive form of lung cancers. It's categorized within the group of neuroendocrine tumors. Something called large cell neuroendocrine carcinoma, as well as combined small cell lung cancer in addition to small cell lung cancer are the more aggressive forms of these neuroendocrine tumors. Something more of like a low-grade tumor would be carcinoid tumors, but we're not going to talk about that at all today.

Speaking of small cell lung cancer, I mean, in terms of its aggressive behavior, it has a rapid doubling time. Usually it presents as advanced disease with widespread metastasis, but we only see about 14% of cases of small cell lung cancer out of the majority of lung cancer cases that present in the United States.

Dale Shepard, MD, PhD: Okay, and then within small cell, that's further broken into a couple of categories. Is that right?

Lukas Delasos, DO: Yes. There's actually been some data coming out in terms of subgrouping small cell lung cancer based off of transcriptomic and proteomic features.

Dale Shepard, MD, PhD: Okay, so when we think about how small cell lung cancer is managed, how does that fundamentally vary? How does that differ from non-small cell?

Lukas Delasos, DO: Yeah. Well, actually, as I alluded to before, usually it presents as advanced disease with widespread metastases. So a lot of these patients fit into something called the extensive-stage of small cell lung cancer as compared to limited-stage. We do have TNM staging for small cell lung cancer, but its prognostic value isn't as important as compared to non-small cell lung cancer. Usually, we'll still classify patients using TNM staging primarily to indicate patients with early Stage 1 disease who may be amenable to surgery, but when we talk about small cell lung cancer and staging, as I mentioned, it's split basically between limited-stage and extensive-stage.

So, the way that we like to think about that is for limited-stage, usually the disease is confined to the ipsilateral hemithorax and nodal disease that can be targeted in one radiation field that's tolerable to the patient. Anything beyond that, so if there's pericardial or pleural involvement, obviously distant metastases or contralateral nodal involvement usually fits into the extensive-stage form of the disease.

Dale Shepard, MD, PhD: Okay. We're going to talk a little bit about how these are managed. We've had discussions in other podcasts about things like genomic testing and markers and things like that. What kind of role does that play in small cell?

Lukas Delasos, DO: It's still important to do genomic testing. Most of these small cell lung cancers harbor a TP53 mutation and RB1 mutation, but as I mentioned before, there's more subgrouping now based off of transcriptomic and proteomic features, which only plays a role in research at this point in time. Usually, there's not a target for small cell lung cancer as you would see in non-small cell lung cancer. Although I should have mentioned before actually, too, that some patients with EGFR-mutant non-small cell lung cancer, they can have transformation to small cell. Usually, that's only seen in about 14% of cases, but we need to really pay attention to their scans. If you see rapid progression in a certain area, biopsy is definitely warranted to rule that out.

Dale Shepard, MD, PhD: When we think about small cell lung cancer, there's the trial that we're going to talk about called the ADRIATIC study. So, give us an idea about how we currently treat that group of patients and then a little bit about what the study was about.

Lukas Delasos, DO: Yeah, so for conventionally, we treated patients with a combination of chemotherapy and radiation therapy. This has been the case for decades now, before I even went to medical school, so it's really good to see some novel research in this area and the incorporation of immunotherapy for limited-stage disease. As you and a lot of our colleagues already know, immunotherapy has made its way into the small cell space, but that has been for extensive-stage disease, and we did see a benefit in survival for those patients. Obviously, not going to talk about them today, but the EMPOWER-1 through 3 study and the CASPIAN study, which incorporated the checkpoint inhibitors, atezolizumab and durvalumab, it showed a benefit for patients in combination with chemotherapy.

Dale Shepard, MD, PhD: So the ADRIATIC study, what was the question we were trying to answer?

Lukas Delasos, DO: Yeah, so the ADRIATIC study was a Phase 3 trial evaluating the efficacy and safety of durvalumab, which is an anti-programmed death-ligand 1 inhibitor, after patients had completed a combined chemoradiation therapy. So, it was, as we were talking about before, just limited to patients with limited-stage small cell lung cancer.

Dale Shepard, MD, PhD: So this was looking to see if addition of immunotherapy after primary therapy, so everybody got the standard therapy, and then does the immunotherapy help or not?

Lukas Delasos, DO: Yeah, so consolidation therapy is what we call that. I like to consider this study the cousin to the PACIFIC trial, which once again was using durvalumab for patients that had locally advanced unresectable non-small cell lung cancer and got a combination of chemoradiation followed by consolidative durvalumab for one year.

Dale Shepard, MD, PhD: I guess when we think about small cell lung cancer, it's one of those diseases that usually patients will respond pretty well.

Lukas Delasos, DO: Yeah, it's an aggressive tumor. It's very sensitive to chemotherapy, and it already showed from the extensive-stage studies that immunotherapy showed potential, so it's really good to see this in the limited-stage space.

Dale Shepard, MD, PhD: This study certainly generated a fair amount of attention, so what were the results, and what led to that enthusiasm?

Lukas Delasos, DO: Yeah, so this study, it was an interim analysis. The investigators had a pre-specified cutoff of OS and PFS benefit, and at that point, they unblinded the results. I should mention that this study, patients were randomized 1:1:1 to receive either durvalumab or placebo. The third cohort is a group of patients that received a combination of durvalumab and tremelimumab, but that wasn't included with this interim analysis.

So, what they saw was that there was a substantial OS and PFS benefit. The OS benefit had a hazard ratio of 0.73 with a median overall survival benefit of 55.9 versus 33.4 months. So, pretty close to two years of overall survival benefit in the patients that received consolidation therapy. We see that also translated in a PFS benefit with a hazard ratio of 0.76, 16.6 months versus 9.2 months. So again, seven months of PFS benefit for those receiving consolidation therapy.

Dale Shepard, MD, PhD: Is there any indication so far if some particular kinds of patients ... You mentioned further characterization of patients and things. Too early to know at this point if there's some patients more likely to benefit than others?

Lukas Delasos, DO: Yeah, it's too early to know. I don't recall off the top of my head if that was actually a subgroup analysis included. This was an interim analysis, and we're still waiting for the final results to come out from the entire study.

Dale Shepard, MD, PhD: So, is there a downside? How about toxicity? Was there anything that came about from the study that would suggest this is a bad idea?

Lukas Delasos, DO: Yeah, that's a great question, one that the investigators paid attention to as a secondary endpoint. They didn't see any new safety signals, and the rates of Grade 3 or 4 toxicities were similar between the two groups. The one thing that I applaud the investigators for looking for specifically and bringing to our attention at the ASCO plenary session was rates of pneumonitis. So, we did see a slightly higher rate of pneumonitis in the patients that received durvalumab as compared to placebo. It was 38% versus 30%. I believe most of us are already looking for that in patients receiving immunotherapy, especially after receiving chemoradiation because radiation therapy can also cause pneumonitis. So, it's something that both the radiation oncologists and medical oncologists look out for during follow-up appointments.

Dale Shepard, MD, PhD: Did the pneumonitis end up preventing patients from continuing with therapy, or was it controllable with steroid? I mean, was it significant pneumonitis? There's a whole range of impact of pneumonitis.

Lukas Delasos, DO: Yeah. I don't believe they shared the grade of pneumonitis in their interim analysis, but they did show that it led to treatment discontinuation of one patient, I believe. So, it seems to be well-tolerated and well-managed with steroids, but they didn't go into too much detail about that specifically.

Dale Shepard, MD, PhD: When we think about small cell lung cancers, a two year improvement in survival is impressive.

Lukas Delasos, DO: Very impressive.

Dale Shepard, MD, PhD: I mean, most solid tumor studies, you can maybe get the laser pointer between the two lines.

Lukas Delasos, DO: Yeah.

Dale Shepard, MD, PhD: So, I guess what's next? I mean, what's the unanswered question? Either in extensive or limited-stage small cell, how does this data help contribute to where we go from here?

Lukas Delasos, DO: Yeah. Well, strictly speaking about limited-stage, something that I didn't mention before is in terms of our old way or historical way of treating this disease was with chemoradiation. Even though there's been controversial data about PCI or prophylactic cranial irradiation, it does seem to have an overall survival benefit as well as decreasing the risk of symptomatic CNS metastases, which is pretty obvious, but mainly large meta-analyses have shown an overall survival benefit, and it's become a standard of care.

Now with this new data from ADRIATIC, that becomes an important question. Do patients really benefit with PCI when they're getting consolidation immunotherapy, or is the consolidation in IO enough? So, I think that is a question that remains after these study results were shared with us. The study did include patients that were stratified by PCI. I believe 50, 54% of patients total received PCI. So, I think it's important to piece that aspect out from the study as well, and possibly to have further studies breaking up patients by PCI, yes or no, and everybody gets consolidation durvalumab.

Dale Shepard, MD, PhD: Then I guess since this was an interim analysis, any expectations about how long it might take for the final analysis? I mean, how long did it take to get to this interim point?

Lukas Delasos, DO: Yeah. The interim point, the median follow-up time was about 37 months. I'm not sure when they expect the final analysis. I mean, small cell, like I said, is a more aggressive form, so I would expect us to have the final results within the next couple of years.

Dale Shepard, MD, PhD: Remind me. The duration of the immunotherapy was for two years?

Lukas Delasos, DO: For two years as opposed to PACIFIC, which was one year.

Dale Shepard, MD, PhD: Yeah, so I mean, I guess the question comes up. One thing historically has always been a problem with small cell is it comes back, and then that second therapy just never works quite as well as the first. Is there some thought that maybe adding immunotherapy to those second-line therapies might be beneficial?

Lukas Delasos, DO: I believe that there is a subset of patients that would benefit from IO re-challenge. This is something that I have personally explored in the non-small cell lung cancer space and definitely an important clinical question that for the research needs to be conducted for.

Dale Shepard, MD, PhD: Outside of this study. I mean, just thinking small cell in general, is there anything else on the research side in small cell that looks particularly interesting at this point?

Lukas Delasos, DO: Well, you might've heard of the recent approval of tarlatamab for extensive-stage disease as subsequent therapy from standard of care chemo/IO. So, it'd be interesting to see additional studies possibly incorporating tarlatamab or other bispecifics, other forms of immunotherapy into the frontline setting for not just extensive-stage but also for limited-stage and possibly if that could be of any benefit. I'm looking forward to see what the results from that last cohort show with Durva and Treme from the CASPIAN study for extensive-stage disease. Oddly enough, the Durva/Treme arm, even though there was a numerical benefit in terms of overall survival with the combination of Durva/Treme, it didn't meet statistical significance, so I'd like to see what that looks like in the limited space.

Dale Shepard, MD, PhD: I guess it does beg the question. They had the three groups, and the interim analysis was just the two groups.

Lukas Delasos, DO: Just the two.

Dale Shepard, MD, PhD: What was the reason for not including the third group? Was it the number of events, or was there another reason for it?

Lukas Delasos, DO: I think it was the number of events. It was a pre-specified interim analysis from the investigators just to determine if they met a certain hazard ratio within a certain amount of time between the two groups, that they would unblind the study for those two groups, for Durva and placebo.

Dale Shepard, MD, PhD: The trial itself did complete that third group, and they didn't decide to drop that group along the way?

Lukas Delasos, DO: Yeah.

Dale Shepard, MD, PhD: Okay, makes sense. Well, it sounds like some exciting things going on in what has historically been a pretty difficult disease. Appreciate you coming on today and telling us about it.

Lukas Delasos, DO: Yeah. No, thank you so much for having me here. It's a pleasure.

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