Second Line Treatment Options in SCLC and Selecting the Appropriate Therapy

Vivek Subbiah, MD: Let's discuss on how one would manage this patient.

Charu Aggarwal, MD, MPH: The treatment options for second-line or third-line setting for extensive state small cell lung cancer are quite numerous. If we were to open the guidelines, many different drugs are listed. There's taxanes, there's lurbinectedin, of course, there’s topotecan, there's also PD-1and PDL-1 inhibitors are listed, maybe not in combination, but alone. And then, re-initiation of platinum-based chemotherapy is a very viable option. And I just wanted to ask you, Vivek, did you think about reinitiating carboplatin and etoposide in a patient like this before coming in with lurbinectedin? And do you think about that?

Vivek Subbiah, MD: Absolutely. That's a great question. This is a great academic question as well, because when fellows rotate with us, we got to teach them, and it's easy for small cell lung compared to many other cancers because we have a few in our therapeutic armamentarium, right? It's simple. Less than 6 months if they have a relapse within 6 months, or if they have a relapse after 6 months, within 6 months, again, major academic centers, we will consider the clinical trial if the patient has stable disease, if the patient clinically has a good performance status. In the community setting, if the patient doesn't have access to a clinical trial specifically for second-line small cell lung cancer, then active agents here in this setting are, of course, topotecan. And the new agent, new kid on the block, lurbinectedin. And beyond 6 months, right? That's when we have a lot more options that you all mentioned. The NCCN [National Comprehensive Cancer Network] Guidelines list checkpoint therapy, right? With CASPIAN and IMpower reading out, it'd be hard for me to challenge a patient who's progressed on frontline platinum-based plus immunotherapy with immunotherapy again. In this patient, possibility is we could reach out in the patient with immunotherapy. We could try immunotherapy. But right now, since PD-1 is a standard of care in the frontline setting, I would say lurbinectedin is an option, topotecan is an option. Again, the conventional agents like paclitaxel is an option, rechallenge of platinum. Again, if it is greater than 6 months, there's so much data about rechallenge of platinum. Why did I choose lurbinectedin for this patient? We see that lurbinectedin is an active agent in small round blue cell tumor cancer. And again, I wanted to try something different for this patient because I did not want to try the same thing for the patient and have the platinum-based therapy as a back pocket option in case the patient progresses on lurbinectedin.

Charu Aggarwal, MD, MPH: Yes, we often find that the toxicity profile may define the choice between platinum re-initiation or re-sensitizing somebody with a platinum doublet versus using lurbinectedin. And I often find that if a patient had a lot of myelosuppression in the first-line setting and if it's been a short interval, I'm more likely to reach out for a single-agent therapy then I go back in and go to platinum doublet. Taofeek, what do you usually do? Do you have a preference? Let's say, let's talk about chemosensitive disease. Let's not talk about chemo-resistant disease. We're trying to make it harder and challenging to treat patients. Let's talk about the chemosensitive disease. And we know that lurbinectedin has data. In the chemosensitive setting, we obviously know there is at least one clinical trial that looked at re-initiation of platinum etoposide combination. What is your preferred approach?

Taofeek Owonikoko, MD, PhD: The old concept of platinum-sensitive and platinum-refractory resistant is probably no longer as a simplistic option available to us now because the initial data that was driving that decision came from patients who were just with chemotherapy. Now, with chemotherapy and immunotherapy. Having said that, there were 2 big trials that were done. One in Europe and the other one in Japan. We added 2 patients with chemo-sensitive disease, and we exposed them to the same doublet chemotherapy, the European trial, and randomized that against topotecan. We knew that from that study, it took longer for patient to progress when they were on the platinum doublet chemotherapy compared to those who enter topotecan. But at the end of the day, the survival was the same. The toxicity was more with topotecan as we all know. The Japanese study is different, a little bit different than the European trial where they try to intensify the platinum doublet. So instead of just giving the same platinum doublet that was given in the frontline, they added irinotecan to their regimen. And that to date, at least in terms of data for rechallenge is the strongest data. The problem there is almost, if I remember correctly, almost 60% of patients had hematologic toxicity. It's something that is not doable in majority of our patients.

Charu Aggarwal, MD, MPH: We know that Japanese patients may metabolize.

Taofeek Owonikoko, MD, PhD: Irinotecan differently. Correct. What do I do currently is when I have a patient who would maybe fall into the category of more than 6 months before they would need treatment-free interval from the end of platinum being more than 6 months, we actually don't know at this point whether they are failing because of the platinum chemotherapy they had before or the immunotherapy maintenance that they've been. The question is what do you use to salvage at that point? The one thing I don't do is to do PDL-1 plus CTLA-4 as a strategy to reverse immunotherapy resistance. I look at how the patient tolerated the chemotherapy in the frontline as you indicated. If a patient struggled to go through that and growth factor support, have residual adverse side effect, and patient preference. The patient will also tell you whether they want to go through that experience again, then I may or may not go with a rechallenge with platinum-based doublet but lurbinectedin is always there for us to use. Because at the current time, it has approval in that setting. And even in patient with platinum-resistant disease, it also has conditional approval to be used. I have that conversation with the patient, look at how they tolerated the platinum doublet to start with. And then, what I don't know now, and I don't think anyone of us has any real data to guide us is, do you stop the immunotherapy when you introduce the salvage chemotherapy? Or do you keep it and add the chemotherapy to it? If I decide along with the patient to rechallenge the platinum doublet chemotherapy, my inclination and there's no data, OK? But my inclination would be to just keep the immunotherapy there and add the chemotherapy. If I'm going to switch to a completely different regimen like lurbinectedin or taxane, or any other agent, then I stopped the immunotherapy as well and just go with a clean salvage option.

Charles Rudin, MD, PhD: I differ from both guys.

Jared Weiss, MD: That makes it more fun.

Taofeek Owonikoko, MD, PhD: Small cell has got my interest.

Charles Rudin, MD, PhD: Repeating platinum etoposide is such a desperation move. It just reflects the fact that we don't have very active therapy here. And I feel like you rarely get any kind of durable benefit out of going back. The tumors have already been exposed to these drugs. The acquisition of acquired resistance happens quickly. And I rarely would go back unless I didn't have other good options. I wouldn't have treated this patient next with l lurbinectedin, although it's a perfectly reasonable choice. I would have preferred to give immune checkpoint inhibitor because even though the majority of patients don't benefit from immunotherapy, again, when it works, it can be quite dramatic. And I feel like small cell lung cancer patients should have the opportunity to be within that 10 or 15% that are durable responders. In a patient that was treated first-line with chemotherapy and has recurrence, I'm reaching out for the immunotherapy first.

Charu Aggarwal, MD, MPH: You're tending to use immunotherapy single agent in a patient like this?

Charles Rudin, MD, PhD: Yes.

Charu Aggarwal, MD, MPH: I would argue that you could come in with this patient had a response for more than 6 months, clearly, chemo-sensitive. If you had to come in with a PD-1 or PDL-1 inhibitor, I would argue that you should come in with chemo immunotherapy because you know there's data.

Charles Rudin, MD, PhD: That would be perfectly reasonable. There isn't data in the recurrence.

Charu Aggarwal, MD, MPH: But there’s a combination.

Charles Rudin, MD, PhD: But there’s certainly tolerability data, and you could certainly support doing that.

Charu Aggarwal, MD, MPH: Jared, any thoughts about how you would have altered the management here?

Jared Weiss, MD: I had a totally divergent opinion until Charlie started talking. I agree. If I have to add some commentary, I will comment that platinum-sensitivity, I'm glad no one's using those words, and instead using chemotherapy sensitivity because the phenomenon is the same if you're retreating with platinum, if you were coming in with lurbinectedin, if you're coming in with topotecan. We have decades-old data is more likely if there's been a long chemotherapy treatment-free interval. I would further reflect that there's been intercontinental divide on how we define platinum sensitivity, which thankfully, we're not using those words. And there's no evidence for clear regression discontinuity at 90 days or at 6 months. But yeah, I would have either come in with triplet or a slight variant, I guess. I would have thought about it for this patient.

Charles Rudin, MD, PhD: Totally reasonable.

Transcript lightly edited for clarity.