Updates in Immunotherapy for Advanced Thoracic Malignancies - Episode 10

Trials in Limited-Stage Small-Cell Lung Cancer

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Suresh Ramalingam, MD: You mentioned pembrolizumab. One of the other regimens that’s been studied in small-cell lung cancer is ipilimumab-nivolumab. Steve, you were following the ESMO 2020 [European Society for Medical Oncology Congress] conference closely. There was an ETOP [European Thoracic Oncology Platform] study that looked at ipilimumab-nivolumab. Talk to us about that trial.

Stephen Liu, MD: This was an interesting study, but get ready for a little more disappointment. This was the STIMULI trial presented by Professor Solange Peters, an ETOP study looking at patients with limited-stage small cell. Our focus has been on extensive stage. Limited stage is about a third of our patients, and while we can deliver curative chemoradiation, we’re not very good at getting those cures, and most patients, unfortunately, do relapse and still die from their disease. This was looking at patients with limited stage who had completed therapy, looking at consolidation treatment—a maintenance or consolidation immunotherapy approach. You’re randomized to receive nivolumab-ipilimumab, 4 cycles at the higher dosage of ipilimumab at 3 mg/kg every 3 weeks, with nivolumab at 1 mg/kg every 3 weeks, and 4 cycles of nivolumab-ipilimumab followed by nivolumab maintenance. The control arm was just observation, looking at immunotherapy after treatment for chemoradiation vs observation.

This was a negative trial. We did not see an improvement in survival. The hazard ratio was 1.06. Giving nivolumab-ipilimumab in that setting did not improve outcomes. Firas Badin had mentioned earlier the CheckMate 451 study, with nivolumab-ipilimumab failing to improve outcomes after induction chemotherapy in the extensive-stage setting, and we see the same thing here. Whether that’s building on patient selection; it’s the use of CTLA4 in small cell, which has been a little disappointing to date; or there are just flaws of the trial, the trial did take a long time to accrue. In fact, it stopped early for slow accrual; we don’t know. We just know that this approach isn’t 1 we need to pursue further.

Suresh Ramalingam, MD: Yes, that is certainly disappointing. Let’s hope that it’s a different story with the use of PD-1 or PD-L1 in the patient alone in that space. There is an ongoing NRG-LU005 trial with atezolizumab in the consolidation setting for limited-stage small-cell lung cancer, and my understanding is that trial is accruing fast, reflecting the large amount of interest we’ve got in this space.

Stephen Liu, MD: I think that’s the important study, and limited stage needs to have better outcomes. There are 2 big studies now. You mentioned NRG-LU005; that’s looking at atezolizumab with chemoradiation followed by atezolizumab maintenance. It combines the benefit we saw in PACIFIC from using of I/O [immuno-oncology] after radiation with the benefit we saw in IMpower133 by adding PD-L1 to chemotherapy. We also have the ADRIATIC study, which is in the same family as PACIFIC, and that’s looking at durvalumab alone or durvalumab with tremelimumab as consolidation after chemoradiation. I don’t think the ETOP study nullifies the validity of these studies. These are important questions; there’s a lot of rationale. These are big, well-powered studies that will hopefully give us an answer as we look to improve outcomes in that subset.

Suresh Ramalingam, MD: Absolutely. We’ve had very limited progress in the limited-stage small-cell lung cancer space as well. For a long time we were looking at the dose of radiation twice a day vs every day. Unfortunately, we haven’t seen any major differences there. Twice-a-day radiation continues to be of interest and potentially applicable for some patients. There was a trial reported at ESMO that looked at patient-reported outcomes with twice-a-day vs every-day radiation. Steve, what did you learn from that study?

Stephen Liu, MD: You’re referring to the Bjørn Henning Grønberg study. This was an interesting study that never sat right with me. This was looking at high-dose twice-a-day radiation vs standard dose, 60 Gy vs 45 Gy, and we saw earlier this year the delivery of high-dose improved outcomes and survival. One-year survival was comparable, but a 2-year survival difference was quite significant, which was under the radar for me. But delivering more radiation in the limited-stage setting in a twice-a-day approach is improving survival. One would expect that the improvement in survival would come at the cost of much more toxicity, going up to 60 Gy in a twice-a-day fashion. But that initial presentation did not show a lot of difference in toxicity, which didn’t sit right.

At ESMO this year, we saw some patient-reported outcomes from that study. Sure enough, while the twice-a-day high-dose radiation did improve survival, we saw that the health-related quality of life was good in both arms, supporting that this can be delivered safety. There was more toxicity, specifically more radiation-induced dysphasia with that higher dose, but it does seem feasible. We want to see these replicated in a larger study, maybe in a more international or a US study. But these are compelling data that altering the dose of radiation and delivery fashion could improve outcomes.

Suresh Ramalingam, MD: Great, thank you. This has been a great discussion on small-cell lung cancer. We now have chemotherapy plus I/O as the standard frontline approach with atezolizumab and durvalumab being approved agents in this setting. In the second line, we have a new drug in lurbinectedin, which is FDA approved. Hopefully, these advances will catch on in the limited-stage setting, where survival rates have remained flat for a couple of decades now.

Transcript Edited for Clarity