Insights From: Stephen Liu, MD, Georgetown University; Benjamin P. Levy, MD, John Hopkins Sidney Kimmel Cancer Center
Benjamin P. Levy, MD: We have some new agents that are currently being looked at in refractory extensive-stage small-cell lung cancer. One of those options is lurbinectedin, which is an interesting molecule. It’s actually a murine-based synthetic quinolone, which is an anti-tumor agent. It actually inhibits active transcription. And we know that small-cell lung cancer is quite addicted to transcriptional activation. This makes this agent the right fit or a good fit for small-cell lung cancer. And what we’ve learned about lurbinectedin has just been recently presented in a single-arm phase II trial of roughly 100 patients with extensive-stage small-cell lung cancer. It was tested as a single agent.
Interestingly, what we saw was outcomes that we really haven’t seen in the refractory setting, outcomes we haven’t seen for patients receiving a drug as a second-line drug. We saw a response rate of roughly 35% in all patients, a PFS [progression-free survival] of 4 months, and a median OS [overall survival] of 9 months, which is quite incredible because they’re measuring the time of start—the time of receiving the second-line drug—to death. So this has really pushed the envelope.
Interestingly, while this is a single-arm study, they did sort out patients who were either platinum sensitive or platinum refractory. And we saw very different outcomes based on whether patients who initially received platinum-etoposide were sensitive or refractory. In the platinum-sensitive group, we saw a response rate of 45%. We saw PFS roughly around 4 to 5 months and a median overall survival of 12 months. That’s quite different from the platinum-refractory group, where the response rate was around 20%, the PFS was around 2 months, and the median overall survival was 5 months.
These are still favorable outcomes, but when you look at a median overall survival time of 12 months as a second-line drug, that’s pretty interesting. That’s certainly moving the needle significantly. I think there’s a lot of excitement around lurbinectedin. I’m really eager to get my hands on this drug and use it for our patients. We have to think about what we have currently. We have topotecan with a response rate of around 15%. This is really doubling or coming close to doubling that, at least in the platinum-sensitive patients.
We will have a study, a phase III study, called ATLANTIS that is essentially comparing lurbinectedin in combination with chemotherapy—I believe doxorubicin—versus topotecan. We’ll have a definitive phase III trial that is looking at this agent compared with topotecan, which I hope will show an improvement in outcome in all 3 measures: response rate, PFS, and OS. I’d be surprised if it didn’t. The drug is reasonably well tolerated. There are some cytopenias and GI [gastrointestinal] adverse effects that we need to be mindful of. But overall, this is a very exciting drug and a welcome change. On the heels of immunotherapy coming first line, this agent coming potentially second line will really push the envelope in improving outcomes for patients with extensive-stage small-cell lung cancer.
Stephen Liu, MD: Lurbinectedin was a relatively tolerated drug. If we review its tolerability and safety profile, the primary toxicity is hematologic in nature. Mostly grade 3 or higher adverse events were related to myelosuppression, about 40% of patients receiving high-grade neutropenia. This is primarily reversible. Often these are paper toxicities, which patients are often unaware of and may be able to manage using prophylaxis. In the randomized phase III ATLANTIS trial, when we see those results, we’ll have to remember that the toxicity profile from that trial will be from a combination of lurbinectedin and doxorubicin. So many of those toxicities may be attributed to the anthracycline. However, in practice, lurbinectedin monotherapy generally is a very well-tolerated drug.