Updates in Immunotherapy for Advanced Thoracic Malignancies - Episode 9
Suresh Ramalingam, MD: When patients get the chemotherapy–I/O [immuno-oncology] approach—and they benefit for some time, and down the road, maybe 6 or 8 months later, the patient progresses—in the past, we would rechallenge them with a chemotherapy doublet again, right? This was when there was no maintenance. If you give chemotherapy for 4 to 6 cycles, and 6 months later the cancer progresses, we look at how did the patient do the first time around. If they did well, we rechallenge them. Is that approach going to change based on what these trials tell us, or will we continue to rechallenge them with platinum?
Stephen Liu, MD: I’m smiling because it has happened to me, and I did rechallenge with mine. But my cutoff is 6 months; that’s my minimum cutoff. If they’re closer to a year, I feel more comfortable with it and I have rechallenged with platinum. Do I continue the immunotherapy in that portion? Do I think it’s doing anything? I don’t know if it’s doing anything. I do continue it. That’s not based on any evidence, but just more admitting that the outcomes are quite poor overall. In those settings, I rechallenge and I continue the maintenance, although it’s certainly an area in which we need more trials.
Suresh Ramalingam, MD: Christine, what’s your approach in that situation?
Christine Bestvina, MD: I have also rechallenged if they recur more than 6 months. If less than 6 months, we’re oftentimes looking for a clinical trial option for that patient.
Suresh Ramalingam, MD: Certainly. Is the approach in Florida any different, Martin?
Martin Dietrich, MD, PhD: Obviously 6 months is a time frame in which I feel that platinum sensitivity can be rechallenged. I do what Stephen does without evidence; I continue the backbone of immunotherapy. I just basically readd it. These are data that are probably 30 years old, or 20 years old. The rechallenges are based on a certain time cutoff, but we have new options. We have a long-term survival population now, we have a strong interest in clinical trials with antibody-drug conjugates, and lurbinectedin is another option that has entered the arena for both platinum-refractory disease and platinum-resistant disease on almost an equal basis. There seems to be a different angle of resistance that is independent of the responsiveness to platinum. That would be, in my opinion, a strong second-line candidate.
It depends on the clinical context. If they’re doing well, you have a better option with the rechallenge of platinum, but acknowledging that the response rates significantly drop the closer you’re near the last cycle of treatment, lurbinectedin becomes more attractive. The response rates were around 40%. Responses were not very durable. The toxicity profile wasn’t easy, but it was one that overall, in the greater context, was clearly a new addition and certainly has replaced topotecan in the second-line setting as my standard go-to agent.
Suresh Ramalingam, MD: That’s great. It’s good to have a new drug approved in the second-line space after a very long time. Admittedly, lurbinectedin is based on a single-arm trial that you mentioned. I was impressed by the fact that the response rate in the chemotherapy-refractory patient population was 25%, and the chemotherapy-sensitive group was 45%, myelosuppression being the main toxicity. We’re beginning to give this in our clinic. I don’t have a lot of personal experience yet. Steve, have you given it? What are your thoughts on the lurbinectedin study?
Stephen Liu, MD: One of the big pluses of giving lurbinectedin is that it’s not topotecan. I mean, this was a drug that was the standard for decades, approved in the 1990s, and it’s not a drug that we like giving. There’s a lot of toxicity. It’s a really tough schedule: It ties up a chair for 5 consecutive days, and patients don’t feel well when they’re receiving it. Lurbinectedin has a more favorable schedule and more activity, and there is toxicity; it’s a cytotoxic drug. It’s much better tolerated than topotecan, and there’s a lot of value in that. As you mentioned, I was most impressed by that chemotherapy-refractory response rate. With topotecan, our response rate in that setting was close to 0. To have a drug that’s going to get responses there, where patients are often symptomatic, is a real welcome addition to our arsenal.
Suresh Ramalingam, MD: Christine, anything you want to add to what Steve mentioned?
Christine Bestvina, MD: No. It’s just nice to have something else to present to the patients. It felt like historically with topotecan, you’re saying this drug is going to make you feel terrible. It’s going to take away all your blood counts, and your chance of having success is 5%. It’s just nice to be able to present a much more enticing option to the patients.
Suresh Ramalingam, MD: This is also the setting where we’ve seen a lot of promising drugs fall away. Amrubicin, about 15 years ago, was a very promising drug, but it did not play out in phase 3 trials. Rova-T [rovalpituzumab tesirine] was another promising monoclonal antibody with the antibody-drug conjugate platform, and that did not, unfortunately, play out. It’s good to have a drug that helps patients. We’ll wait to see the phase 3 trials with lurbinectedin, and hopefully they will confirm the efficacy data that we’ve seen in the phase 2 setting. We also have pembrolizumab approved in this space, for patients who progress on prior chemotherapy. Admittedly, the trial that led to the approval was done in the pre–chemotherapy-I/O days. Where does that fit in in the landscape now? Let’s assume a patient got chemo-I/O in the front line, has seen lurbinectedin in the second line, and has progressed on the third line. Would someone feel that pembrolizumab would be appropriate and reasonable to try in this setting?
Martin Dietrich, MD, PhD:If we go back to the experience from non–small cell lung cancer, even with crossover sequence matters, and if you didn’t derive a benefit in the first-line setting, where you’re probably in the best physical condition, I believe that PD-1 or PD-L1 followed by PD-1 is probably not a reasonable concept. This may be an option to palliate your mind, but this is not very evidence based. You have to acknowledge that in the third-line setting, with the current algorithm that Stephen established, we don’t have anything to offer outside a clinical trial.
Transcript Edited for Clarity