Small-Cell Lung Cancer - Episode 4

Management of ES-SCLC: Second Line and Beyond

April 2, 2021
Jared Weiss, MD, University of North Carolina at Chapel Hill

,
Stephen V. Liu, MD, Georgetown University

Considerations for second-line treatment regimens, the role of immunotherapy in the relapsed/refractory setting, and using lurbinectedin for the management of ES-SCLC.

Stephen V. Liu, MD: When we look at the survival curves for the IMpower133 and for CASPIAN studies, the separation really occurs after the completion of induction chemoimmunotherapy. What we know from CheckMate 451 is that maintenance immunotherapy before progression and after chemotherapy did not improve survival. We conducted an exploratory analysis of IMpower133 looking at the benefit of atezolizumab versus placebo in patients who reach that maintenance phase. What we found in this analysis was that atezolizumab offered a significant survival advantage over placebo, with an overall survival hazard ratio from the start of maintenance of 0.59. The median survival from the start of maintenance was 12.5 months with atezolizumab versus only 8.4 months with placebo, and there were no new safety signals. Grade 3/4 adverse events from the start of maintenance were seen in 28% of patients receiving atezolizumab, but also seen in 23% of patients receiving placebo. To me, these data reinforce the use of atezolizumab with induction chemotherapy but also with maintenance, and continuing atezolizumab maintenance is a critical piece of optimizing outcomes.

Jared Weiss, MD: The good thing about first-line treatment of extensive-stage small cell lung cancer [ES-SCLC] is that it usually works, response rates are high. This is important because of how symptomatic patients with extensive-stage small cell are. Probably about one-third of my patients present with hospitalization due to extreme shortness of breath. And it’s very gratifying, when you give them their first cycle of treatment, they feel a lot better very quickly. The weakness is that it doesn’t last very long. Pretty much all patients relapse, and unfortunately relatively quickly. With appropriate monitoring and aggressive supportive care, most patients are eligible for second-line therapy. When you consider patients who are not physically eligible or the values-based choices of patients, I would say you’re left with about 75% or 80% of patients who get second-line therapy. This is very different by different practices in terms of patient values and physical characteristics. That’s roughly what I’m seeing in my practice.

We have multiple regimens that are either FDA approved or NCCN [National Comprehensive Cancer Network] guideline recommended for second-line use. The dominant ones in clinical practice are topotecan, lurbinectedin, and immunotherapy, meaning nivolumab, pembrolizumab, or IPI/NIVO [ipilimumab plus nivolumab]. I would note that while the results of immunotherapy are favorable, immunotherapy is now a part of first-line therapy. For example, in CheckMate-032, we had a randomized phase 2 study of nivolumab versus 2 studies of ipilimumab, nivolumab. The response rate went up with ipilimumab, nivolumab. It went from 12% to 22%, but survival didn’t. It was 5 or 6 months regardless. In KEYNOTE-028 and KEYNOTE-158, we saw pembrolizumab’s efficacy in this context. There were very similar data here, late-line pembrolizumab in second or third line here, a response rate of 19%, 2-month PFS [progression-free survival], 8-month survival. All of the immunotherapy regimens are roughly similar and active.

In the theoretical case of seeing a patient who hadn’t received immunotherapy in the front line, these remain great options. In reality, they’re not great clinical options because patients have almost always received it as a part of first line. The dominant place we see this in practice is the patient with de novo limited-stage disease who subsequently relapses. And nivolumab, ipilimumab, nivolumab, or pembrolizumab are fine choices of agents in that limited context.

Other options, topotecan is approved in this context. Topotecan may be the most hated drug in all of thoracic oncology. The response rate isn’t that high, toxicity is rather dramatic, mostly related to myelosuppression and its downstream sequalae. And it’s fallen out of favor, particularly now that lurbinectedin has approval in this single-agent context. This was based on a basket trial, where the response rate looked a little better than topotecan, the adverse effect profile a little better, and it’s been rapidly adopted because of being a little better than topotecan. And it is my answer in my practice, at least when a patient is not eligible for trials.

There are 2 other contexts that deserve mention, one that I already mentioned, which is that clinical trials should be strongly considered for patients with small cell lung cancer, particularly in later lines of therapy. Unfortunately, our existing therapeutics are limited in efficacy. And there’s a lot that’s promising on the horizon and in clinical trials. The other thing that can be considered is that if a patient remains platinum sensitive, it’s quite reasonable to repeat the regimen they got before, or to restart platinum with a different partner agent.

Stephen V. Liu, MD: Lurbinectedin is a transcription inhibitor. It received accelerated approval by the US FDA for small cell lung cancer that has progressed after platinum-based chemotherapy. This was based on a single-arm phase 2 study where lurbinectedin, given at a dose of 3.2 mg/m2 IV [intravenously] every 3 weeks, had a response rate of 35%. In patients with chemotherapy-sensitive relapse, the response rate was 45%, and those with chemotherapy-refractory disease, where we don’t have effective options, the response rate was a respectable 22%.

We now know that the confirmatory phase 3 ATLANTIS trial did not meet its survival end point. In that study, patients were randomized to lurbinectedin plus doxorubicin or standard chemotherapy with either topotecan or CAP [cyclophosphamide, doxorubicin, cisplatin]. That study we heard did not feature a survival benefit to lurbinectedin, but the dose used was lower, and it was in combination with doxorubicin. We need to see those data to understand the impact of lurbinectedin on survival in small cell lung cancer. I have used the agent myself many times. The main toxicity is myelosuppression, neutropenia more so than anemia, and thrombocytopenia. In my practice where I do use lurbinectedin, particularly in the chemotherapy-refractory set, it is my practice to use primary G-CSF [granulocyte colony-stimulating factor] prophylaxis with lurbinectedin.

Transcript Edited for Clarity

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