Second-Line Treatment of SCLC

Vamsidhar Velcheti, MD, leads the discussion on the current standard of care and approaching the treatment of second-line SCLC.

John V. Heymach, MD, PhD: A space that’s a little more challenging, with a lot more players but a lot less clarity, is the second-line small cell lung cancer space: what to do after CASPIAN or IMpower133. Vamsi, let me go to you first. There are a lot of different ways to go. What do you use in this setting?

Vamsidhar Velcheti, MD: It’s a very challenging population, John. Almost all our patients who go on both regimens have already progressed. Often, they have a lot of other comorbidities and a lot of disease burden. This is a difficult patient population to treat to begin with. The standard options are lurbinectedin, which got accelerated FDA approval recently based on a small study. It’s not much better in terms of tolerability or efficacy compared with topotecan. I’ve still been using topotecan in my patients in that setting. Sometimes I use a taxane but mostly topotecan. I haven’t used irinotecan in that space.

There’s a lot of excitement for newer drugs being developed. As I said, lurbinectedin was FDA approved, but safely at 3.2 mg/m2 dosing. A recent study at the World Conference on Lung Cancer was done with lurbinectedin in combination with doxorubicin. It was a large phase 3 trial in the second-line space. The comparator arm was like topotecan or CAV [cyclophosphamide, doxorubicin, vincristine].... The study was a 1:1 randomization with a primary end point of OS [overall survival]. It’s a negative study. It’s very disappointing to see this. This drug, lurbinectedin, is already FDA approved as a single agent but at a higher dose. There are some toxicity concerns. It’s not significantly better than topotecan in my eyes to switch to doing that.

John V. Heymach, MD, PhD: You mentioned that the ATLANTIS study with lurbinectedin and doxorubicin combination was negative. That wasn’t lurbinectedin by itself, but it’s interesting because it’s never beaten another drug head to head in any combination. Ani, do you have a preference in second-line small cell lung cancer, especially because the labels for nivolumab and pembrolizumab have been taken away in that space, given the first-line immunotherapy approval? What do you like?

Ani Balmanoukian, MD: I have to echo what was just said. For me, it’s been topotecan. I acknowledge that there aren’t any great second-line options, which is disappointing. But going with what we have now, I usually go with topotecan in the second-line setting.

John V. Heymach, MD, PhD: Stephen, we talked about how we don’t have any randomized data for lurbinectedin. But they’re at least planning that, aren’t they?

Stephen Liu, MD: Right. ATLANTIS wasn’t the perfect trial. It was a lower dose of lurbinectedin. It was a combination, not monotherapy. There’s a phase 3 trial that’s been agreed to in principle from the sponsors and the FDA that will look at lurbinectedin monotherapy at the dose we know, 3.2 mg/m2 vs lurbinectedin at 2 mg/m2 with irinotecan based on some phase 2 data out of Dr Luis Paz-Ares’s group in Madrid, Spain, vs a control of irinotecan or topotecan and physician choice. We’ll see if this demonstrates a benefit to mono or combination.

For me, lurbinectedin is an active drug. It’s easier to schedule than topotecan. It’s 1 day. You don’t have that 5-day regimen. Topotecan is a tough drug to tolerate, and it has clear activity. The space where it shows unique activity is in the platinum-refractory space, where topotecan isn’t effective. We do see responses there, and using lurbinectedin, but it has its own toxicities. You especially have to watch cytopenias. We’ll see how it fares in this randomized study.

John V. Heymach, MD, PhD: Does anybody have any other regimens they’d like to talk about? Does anybody like to use CAV [cyclophosphamide, doxorubicin, vincristine]. I know it’s an older regimen.

Stephen Liu, MD: Be careful of dating yourself there, John.

John V. Heymach, MD, PhD: It’s still a standard. I’ll admit, both CAV [cyclophosphamide, doxorubicin, vincristine] and etoposide or… were considered old regimens when I started treating lung cancer in 1998, 1999. Thus, they haven’t gotten any younger since then or better or less toxic.

Stephen Liu, MD: I use temozolomide. If there’s a lot of CNS [central nervous system] involvement, sometimes I’ll lean on temozolomide.

John V. Heymach, MD, PhD: We use that pretty commonly here as well, and we’ve used it as a partner for things like PARP inhibitors. Mechanistically they make a lot of sense. Heather, what’s your favorite in this space?

Heather Wakelee, MD: I’ll use irinotecan. That’s 1 thing I’m comfortable with, though you do have to be a little cautious.

John V. Heymach, MD, PhD: Sandip, you get the last vote for second-line small cell lung cancer.

Sandip P. Patel, MD: I use Temodar more for CNS tropic disease and irinotecan for visceral disease.

John V. Heymach, MD, PhD: I want to thank everybody. It’s been a fantastic discussion. We covered a lot of ground, and it fills me with enthusiasm to see how much is happening in this space. Thank you all for the wonderful insights into the data. Let me take the last minute for rapid-fire questions. Talk about 1 thing you’re very excited about that’s emerged from these studies. Heather, let’s start with you.

Heather Wakelee, MD: That’s obvious: adjuvant immune therapy.

John V. Heymach, MD, PhD: OK. Going to change the standard of care. Ani?

Ani Balmanoukian, MD: I’m also very excited about data in immunotherapy—adjuvant, but there are some neoadjuvant data coming. All of that is very exciting.

John V. Heymach, MD, PhD: Yes, it’s coming to early stages, so stay tuned. Vamsi?

Vamsidhar Velcheti, MD: I want to say the same thing, but I don’t want to be repetitive. But in the post–TKI [tyrosine kinase inhibitors] EGFR space, with ADCs [antibody-drug conjugates] there’s a lot of excitement. We’ll see some approvals.

John V. Heymach, MD, PhD: Yes, you’re right. We’ve got a couple of regimens or drugs with more than 30% response rate in osimertinib resistance. I’ll plug in. I’m excited to see atypical EGFR mutations getting attention. We have exon 20 drugs, and we’ll have other drugs coming to the atypical EGFR-mutation space that’s been ignored for a long time. Stephen?

Stephen Liu, MD: With all these refinements, the key message is that first step and the importance of broad-panel NGS [next-generation sequencing] before we use completely different paths.

John V. Heymach, MD, PhD: Yes, with all these targetable alterations, you’ve got to capture all of them. Sandip, last word?

Sandip P. Patel, MD: To echo Stephen, this could be done in liquid biopsy, right? Even if you run a tissue, the ability to get a quick answer, to get a whole exon coverage of EGFR and liquid biopsy, is liberating. We used to be satisfied just with the street name: EGFR mutation, KRAS mutation. That’s not enough; you need the address. Do you have KRAS G12C? Do you have an EGFR exon 20? L858R? It’s important to get broad-based molecular testing. If you don’t have the tissue, you could do it as a liquid biopsy and get that answer within a week.

John V. Heymach, MD, PhD: That’s a very important point. I want to thank you all again for the great discussion. And for our viewing audience, thanks for joining us. We hope you found this OncLive® Peer Exchange® to be useful and valuable for treatment of patients with lung cancer.

Transcript Edited for Clarity

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