DR. RAMALINGAM: Hello. Welcome to The ASCO Post Roundtable Series on the Appropriate Management of Challenging Cases in Lung Cancer. I'm Dr. Suresh Ramalingam, Deputy Director of the Winship Cancer Institute of Emory University. Today I'm joined by two of my esteemed colleagues in thoracic oncology, Drs. Julie Brahmer and Heather Wakelee.
DR. BRAHMER: Hi, I'm Dr. Julie Brahmer. I’m a professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.
DR. WAKELEE: Hi, I'm Dr. Heather Wakelee. I'm a professor of medicine and the interim chief of the Division of Oncology at Stanford University in California.
DR. RAMALINGAM: Thank you for joining us. Today we will be discussing the latest in emerging data on the treatment of small cell lung cancer.
So small cell lung cancer is a disease where we've not seen much progress in systemic therapy for a very long time. In fact, the standard regimen of platinum and etoposide chemotherapy has remained as frontline treatment for patients with extensive-stage disease for a very long time. Heather, that has finally changed. We have two new approved drugs. Can you summarize those data and what you do for your patients today in your clinic?
DR. WAKELEE: Sure. I think the biggest change that we've seen is the data with adding immune checkpoint inhibitors to first-line chemotherapy. So we first saw the data with atezolizumab being added to platinum-etoposide with a small but significant survival benefit. And then we saw the data with durvalumab as a single-agent added to chemotherapy in the CASPIAN study, which also showed a very similar overall survival benefit compared to the atezolizumab data. And at this year's ASCO, we had a small phase II trial that Ticiana Leal presented with nivolumab, an ECOG-ACRIN study, which also showed a survival benefit with a hazard ratio there of 0.67, which was pretty impressive for a phase II. Again, phase II, we don't have approval for that, but it was intriguing that the data looked so good.
And then there was data with pembrolizumab, which had very similar PFS and OS curves compared to the other trials but, for statistical reasons, didn't meet its overall survival endpoint. But again, if you look at the curves across all four trials, they're strikingly similar.
So we have approvals for atezolizumab and durvalumab, but I think in the United States, most patients with small cell starting on first-line chemotherapy are going to be getting platinum-etoposide and either atezolizumab or durvalumab unless they have a reason where an immune checkpoint inhibitor would be too toxic for them.
And then this year, actually just in the last month, we had an approval for a second-line option in the chemotherapy drug lurbinectedin. And it had been a long time since we'd had anything other than topotecan or irinotecan to think about in second line, so that's also pretty exciting.
DR. RAMALINGAM: Thank you. Julie, unlike as in non–small cell lung cancer, where we use PD-L1 expression levels to make treatment decisions, in small cell, that is not the case. Can you talk to us a little bit about the biomarkers for treatment selection in the front line? Do you use PD-L1 expression?
DR. BRAHMER: Yes, so PD-L1 certainly has not borne out for small cell lung cancer compared to non–small cell lung cancer, and it's really not completely clear why. I think that for right now, I'm treating all patients with extensive disease for small cell with the IO-chemo combination. And certainly in the future, we hope to be able to tease out who best would require immunotherapy in combination with chemotherapy.
DR. RAMALINGAM: Thank you. Heather, can you comment on a safety profile of this chemo-immunotherapy approach? Is there any specific toxicities that people need to be aware of?
DR. WAKELEE: That’s a great question, Ram. When we look at the data, it really isn't any different than what we've been seeing in non–small cell. There had been concerns given that we do see higher rates of paraneoplastic syndromes with small cell, that perhaps we'd be seeing significant rates of those when we added it. And there are of course anecdotal reports, but it's not a big issue. So I feel comfortable using the combination. It is important for the audience to know, as we've talked about in non–small cell, chemo plus IO plus IO with nivolumab/ipilimumab was looked at and looked pretty good. But in the setting of small cell, the only data we have of combination was durvalumab with tremelimumab plus chemo, and adding the tremelimumab didn't really seem to add any positive outcomes, only toxicity. So at this point, with small cell, it's chemotherapy plus a single PD-1/PD-L1 checkpoint inhibitor—PD-L1 in this case for both of those drugs—and without adding in a fourth agent.
So we'll see. That story might continue to evolve. Perhaps the nivolumab will be explored further, maybe with ipilimumab. We don't know yet. But that's where I'd be more worried about the toxicity. With single checkpoint inhibitors in combination with chemo, it's okay. And nivolumab/ipilimumab is of course sometimes used in small cell and seems to be reasonably well tolerated.
I think that what Heather said is – you know, most of us were concerned about the potential increase in side effects in this patient population, and that really hasn't been seen, and so, this combination has allowed us to sort of open the hood to immunotherapy for small cell lung cancer patients and really across the board.
DR. RAMALINGAM: Absolutely. One of the things I was struck by is now we have at least four different trials using PD-1 or PD-L1 inhibitors in combination with chemo for the frontline treatment setting that we just talked about, and the results are very consistent across these four trials – be it atezo, durva, pembro, and nivo, you look at the hazard ratio for survival, very comparable. You look at the one-year survival rate, you look at the PFS. So this shows as a class, these drugs are effective, but the reality is, the efficacy is relatively modest. It is still not – we're not where we would like to be for our small cell lung cancer patients that we have.
Julie, what are some of the next steps as the field evolves based on these advances?
DR. BRAHMER: I think clearly trying to develop new combinations for immunotherapy, perhaps a different checkpoint, or in addition to the PD-L1 antibodies, or potentially new chemotherapies or different therapies that are targeted. You know, clearly the older Rova-T directed towards DLL3 did not bear out. Potentially, there are other tantalizing data with different targeted therapies that do have an immunotherapy bent to it.
DR. RAMALINGAM: Yup, absolutely. Now that we have finally made some progress, hopefully this will form the basis for some bigger advances to come for our patients.
Heather, you touched on lurbinectedin approved as a second-line therapy. It's an accelerated approval from the FDA. There were 105 patients that received lurbinectedin in the second-line setting. Response rates were about 35%, and in sensitive patients it was 45%. In chemo-assisted small cell, it was 25%. But even at a 35% response rate, that's not trivial in the second-line setting.
DR. WAKELEE: Right. So it's exciting to have another option. I mean, we do have many chemotherapy agents that have some activity in small cell, but that is a higher rate than we've seen in many other studies. And so I think that is something that has a role and a place to be used. But as Julie said, there's still so much potential with immune therapy that we haven't realized. Small cell just by the nature of it has neoantigens that we should be able to exploit. And I think that's really going to be where we're moving forward, is trying to focus on whether it's with antibody-drug conjugates, which, as Julie mentioned, haven't been as exciting as we would have liked based on earlier data. So it didn't really pan out with round one, but I think there are other drugs in development that are antibody-drug conjugates. And also as we think about the next level of immune therapy, the CAR-Ts and what not, I think small cell is ripe for exploration there, because we still have a long way to go.
DR. RAMALINGAM: Absolutely.
DR. BRAHMER: Ram, I think that one thing I didn't cover was the TMB. You know, now that pembrolizumab has a label for high TMB, you know, small cell lung cancer patients could fall into that. Clearly, that trial did not have very many small cell lung cancer patients in it for the basis of the pembrolizumab FDA approval for TMB. Clearly, Matt Hellmann on the nivolumab and ipilimumab story, you know, higher TMB, more likely of response, you know, maybe that's something that we could explore even further for the small cell lung cancer patient, but it hasn't been consistent. Heather, Ram, do you guys have – know any other data?
DR. RAMALINGAM: We are not routinely checking TMB, and that's another challenge – what is the appropriate threshold and so forth. But the pembro data are definitely of relevance to small cell lung cancer. Considering that in present day, every patient is now getting chemo plus immunotherapy in the frontline setting, I'm not so sure you're gonna repeat the immunotherapy after they progress. But nevertheless, it's important for us to share that with our audience.
So a very interesting time for small cell lung cancer. Our takehome messages: chemotherapy plus either atezo or durva is now standard therapy for extensive-stage disease in the frontline setting. We have a new approval for salvage therapy in lurbinectedin, which is an accelerated approval with confirmatory phase III trial to be reported out very soon. So this is good news for our patients and for the research community.
I want to thank both Drs. Brahmer and Wakelee for joining us today. I also want to thank you, our audience, for joining us. Please don't forget to watch the other videos in this ASCO Post Roundtable Series. Thank you.
