Evolving Approaches in Small Cell Lung Cancer - Episode 12

Emerging Treatments in SCLC: Triplets + Limited-Stage Disease

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Anne Chiang, MD, PhD, reviews the study design of 2 clinical trials, adding a third agent to the standard-of-care regimen of chemotherapy plus I/O; Stephen Liu, MD, discusses clinical trials in limited-stage disease.

Hossein Borghaei, DO, MS: Anne, we have a couple of studies. There was a study targeting PP2A with a drug, LB-100. There are some data regarding the combination of immunotherapy and lurbinectedin. Could you comment on those studies?

Anne Chiang, MD, PhD: Sure. There aren’t any results, but I can talk a little about the study designs. When we’re starting out with our standard of care, which is chemotherapy plus I/O [immuno-oncology], what can we do to better that? One idea is to add something to it. That’s the case for the LB-100 study, where the premise is the addition of a protein phosphatase 2A inhibitor to our standard of care up front. It’s basically a phase 1b open-label study. The patients receive LB-100 IV [intravenously] over 15 minutes on days 1 and 3, and atezolizumab and carboplatin-etoposide, which we normally give.

The rationale behind this is that because the PP2A inhibitors work in combination, there are good preclinical data that show they’re effective chemotherapy and radiation sensitizers, either with cisplatin or doxorubicin. Ultimately, what happens is that the use of this in combination with chemotherapy lowers the cell cycle arrest and ends up in mitotic catastrophe and more cell death. There’s also possibly an increased vascular permeability aspect of it. But the idea behind that trial is to ask, is it safe? Are we adding additional toxicity? Hopefully not. And can we improve upon the efficacy of that regimen?

The other trial is basically ipilimumab-nivolumab and lurbinectedin. This is a single-arm phase 1/2 trial to determine the MTD [maximum tolerated dose], the recommended phase 2 dose, and safety and efficacy. The outcomes are response rate, progression-free survival [PFS], and overall survival [OS] in the phase 2 portion. This is for relapsed recurrent small cell lung cancer. This helps us provide an option for our patients that is combination chemotherapy-I/O.

From the non–small cell realm, if you have combination chemotherapy-I/O up front, then what do you do? You’re using chemotherapy alone. There are some trials asking whether you can add chemotherapy postprogression, but this would be a trial where you could look at the combination chemotherapy plus I/O after you use that up front. We talked at length about lurbinectedin and the combination anti-CTLA4 and PD-1 approach that might allow our patients to get an effect, although you’d have to look carefully at the toxicity of that regimen.

Hossein Borghaei, DO, MS: Great. Thank you, Anne. Stephen, since we’re talking about emerging therapies, there’s also a lot of movement in limited-stage disease. There are at least 3 trials with very similar approaches, perhaps checkpoint inhibitor plus chemotherapy–RT [radiotherapy]. Please update us on those.

Stephen Liu, MD: This will be potentially transformative for this subset. These all look great. Limited-stage makes up about a third, maybe a little less, of small cell lung cancer. We know that chemotherapy-radiation given concurrently is potentially curative. As we’ll all attest to, while cure is our goal, it’s not necessarily our expectation, because we achieve that in only maybe 20% to 30% of people. The promising strategy is to combine immunotherapy in this setting. It’s building on the rationale that supports the PACIFIC trial, our standard of care in unresectable stage III non–small cell lung cancer. We know I/O adds benefit to small cell lung cancer, based on the studies we’ve talked about. We know that it can improve outcomes after chemotherapy-radiation, based on PACIFIC. So this really was low-hanging fruit.

ADRIATIC is a randomized phase 3 trial. It’s looking at consolidation immunotherapy, structured in a similar way to PACIFIC. You finish chemotherapy-radiation and then randomize to standard observation, or durvalumab, or durvalumab plus tremelimumab. We’ll see if this context can find tremelimumab a home. We know tremelimumab is not beneficial in extensive-stage disease, but maybe this is a different therapeutic index. This is a big study, with over 700 patients, with PFS and OS end points. It’s a very important study.

Another similar trial is an NCI [National Cancer Institute]–sponsored study, NRG-LU005. That’s looking at concurrent chemotherapy-radiation with atezolizumab delivered during the chemotherapy-radiation vs chemotherapy-radiation alone, then atezolizumab vs placebo maintenance therapy. We know from data out of [The University of Texas] MD Anderson [Cancer Center] from Steven Lin that giving atezolizumab with thoracic radiation appears to be safe. Is there synergy by introducing that earlier? If we think back to the PACIFIC subsets, where patients who got durvalumab a little closer to radiation maybe did a little better, would there be more rationale to give atezolizumab with radiation? We’ll see. This is a study of over 500 patients. The phase 2 is looking at PFS as the end point, but it’s the phase 2/3 that will look at OS.

KEYLYNK-013 is a little more complex. This is looking at standard chemotherapy-radiation vs delivering pembrolizumab with chemotherapy-radiation and continuing pembrolizumab maintenance vs delivering pembrolizumab with chemotherapy-radiation, pembrolizumab maintenance, and olaparib maintenance. It’s looking at that PARP/PD-1 synergy, largely work from doctors Triparna Sen and Lauren Byers at MD Anderson. It’s intriguing to see if there’s some relationship between these 2. The biomarker data that are going to emerge from all these studies will hopefully inform our decisions a little more. At least 1, or maybe all 3, of these studies will end up being positive. It’s almost a race to see which will be positive first. There are very exciting things to come for limited-stage small cell lung cancer.

Hossein Borghaei, DO, MS: KEYLYNK-013 is not selecting patients based on any biomarker for olaparib. It’s just all-comers at this point, correct?

Stephen Liu, MD: That’s correct. None of them is selecting patients by biomarkers. We’re still very much in the infancy of biomarkers. It’s still discovery right now. We’ll see if that leads to subsequent studies that need to be validated as integral. But to start with, it’s just discovery.