Treatment Options for Relapsed Small Cell Lung Cancer

Jared Weiss, MD: Unfortunately, the majority of our patients progress. By 2 or 3 years, we’re a bit under 20% of patients who haven’t progressed, and by 5 years, quite a bit less. We have a typical duration of response to the front line of about 5 months. As we’re talking here, we’re querying our audience on where they’re typically seeing the first progression. In my practice, it’s imaging. How about you?

Carl M. Gay, MD, PhD: It’s still imaging. I image patients with small cell lung cancer more frequently than I do those with non–small cell lung cancer. With non–small cell lung cancer, I’m relatively quick to get on an every-3-month imaging interval for patients who are doing well and reach maintenance. For example, I almost never develop that level of comfort with my patients with small cell lung cancer. Maybe it’s because I’m imaging too frequently, but I do usually catch it on imaging. That said, it’s not all that unusual for a small cell lung cancer to have an image and come into clinic and say they have a new headache, pain in my thigh, or something like that. That gives me a sick feeling in the bottom of my stomach because I know what the imaging that I’m going to order is going to show. But I agree with you, Jared.

Jared Weiss, MD: Our questions aren’t entirely about right or wrong. They’re to stimulate discussion. If I could pick anything I would have said, B [imaging] and D [symptoms]. They’re often the same. We’re often seeing the same thing on imaging at the same time the patients are complaining about it. It’s perhaps more of a segue to what to do with folks when they do relapse. What are our standard answers?

Carl M. Gay, MD, PhD: If you’re following the US Food and Drug Administration, we have 2 options in the relapsed setting for patients who aren’t considered platinum-sensitive.

Jared Weiss, MD: My second attempt at a joke. If you don’t follow the FDA, they arrest you.

Carl M. Gay, MD, PhD: Fortunately, they give us a little latitude with small cell lung cancer. I’ve rarely gotten pushback. I sit on prior authorizations all week for patients with my non–small cell lung cancer, but for patients with small cell lung cancer, you can justify giving them almost anything because it’s a matter of life or death at almost every step of the way. I appreciate the NCCN [National Comprehensive Cancer Network] Guidelines giving us a list of options for these patients. The official answer to that question is either retreatment with platinum-based chemotherapy if they’ve made it 6 months since their last dose of platinum or topotecan and lurbinectedin. In practice I offer and have utilized lurbinectedin a fair amount since its approval. I don’t utilize topotecan a lot, partly as a convenience to the patient. These are patients who often value quality of life, and topotecan is a difficult drug to give practically and from a toxicity standpoint, so I’ll consider some of these other recommended regimens. I like temozolomide a lot because a lot of these patients also have brain metastases, and the response rates and blood-brain barrier penetration are very good. I’m curious to hear your recommendations. There are a lot of drugs on that list, and there’s no rhyme or reason to choose among them.

Jared Weiss, MD: There’s a lot of wisdom in what you said. I have a lot of equipoise. In the United States, there’s almost a religion in re-treating with platinum if they’ve hit at least 6 months. But the survival isn’t improved by doing that. The response rate is PFS [progression-free survival], not OS [overall survival]. I don’t think that’s mandatory, but I do it in my practice. If you use the 6-month cutoff and we’re in an era of triplet, it’s only 22% of patients. I pulled that off IMpower133 in prep for our conversation. Most are not going to get there. It’s not controversial for most.

Then I have equipoise. As a thought experiment, if you run a massive randomized trial for all these, you’d have nearly superimposable curves for survival. In my practice, lurbinectedin is used more than topotecan. Perhaps I should rephrase that: I hate lurbinectedin less than I hate topotecan for toxicity profile. It’s a little more patient-friendly. We have no comparative data between topotecan and lurbinectedin, but in the forbidden but omnipresent cross-trial comparisons, I find the data perhaps superior. It’s what I tend to do. But I agree. I have equipoise.

For the overwhelming majority of my referral practice, when I’m looking at what others have done—even if it’s not what I would’ve done—I say yes because there’s very little that’s incorrect. I’m in the minority of small cell doctors in not being a particular lover of temozolomide. I’m in the minority in the thoracic community for the reasons you stated. I found it to be a bit of a stem cell toxic substance, and I found it hard to give anything else after it. But the penetration of the blood-brain barrier is a clear advantage.

Carl M. Gay, MD, PhD: In my clinic, we often say that before we prescribe someone temozolomide, we should make sure we’ve reestablished goals of care. Because after you get past lurbinectedin and topotecan, you’re circling things that have response rates bordering on 10% with a fair amount of toxicity. You want to make sure patients understand that they may be just as well doing nothing at that point and enjoying their life. It’s sad to have so few [treatments]. Not that there are a lot of diseases that have great treatments for refractory disease, but small cell lung cancer seems like a major outlier.

You mentioned the lurbinectedin vs topotecan head-to-head option. There was a press release from Jazz Pharmaceuticals and PharmaMar [in December 2021] announcing the LAGOON study, which is going to be a variation of that: 1 arm is lurbinectedin, another is lurbinectedin plus irinotecan, and the third is dealer’s choice between topotecan and irinotecan. So we’re going to get some of those head-to-head data to finally settle that score. Obviously, that will be important for knowing how to prioritize these agents and where lurbinectedin stands. That’s a drug that was approved on the basis mostly of response rate, and that’s something we don’t know. It gives you insight into just how bad things are in small cell lung cancer when you can get a drug approved based on the response rate and a little single-arm outcome data.

Jared Weiss, MD: We’ll dive into lurbinectedin in a moment. First, let’s have a polling question. The question is rechallenging with a platinum-based regimen: are we Europeans when it’s a first-line response of fewer than 3 months? Are we Americans with 6 months, or are we sticklers and looking for chemotherapy-sensitive and 9 months? What do you think? Is there regression discontinuity in 1 of these numbers?

Carl M. Gay, MD, PhD: I have to admit that I like to hold myself to the 6-month cutoff. But on occasion I’ve talked myself into it at 4½ or 5 months for patients who’ve had an excellent response early on. It’s not something I’m proud of doing, but is awfully tempting to try to recapture the magic of the first PET [positron emission tomography] scan these patients had. Especially before lurbinectedin, when our options were so limited. I wouldn’t fault anyone for offering it in less than 6 months, but it’s fair to hold everyone to that standard.

Jared Weiss, MD: I’m going to move us on a little in the interest of time. Can we talk about the data that led to lurbinectedin’s approval?

Carl M. Gay, MD, PhD: I mentioned this a little. It comes from the phase 2 basket study illustrated here. The data looked very promising. To me, lurbinectedin came out of nowhere from somebody who’s in the weeds in small cell lung cancer trial development. We had this study open in our phase 1 program at [The University of Texas] MD Anderson [Cancer Center], and I knew about it. I referred patients to it, but I didn’t necessarily expect it to go from, “We’re enrolling patients,” to “This is an FDA-approved agent in the second-line setting,” as rapidly as it did. But the OS data, particularly in platinum-sensitive patients, were fairly promising. With all the caveats of the size of the study and the single-arm design in small cell lung cancer, you’re getting 9 months of overall survival in the relapse setting. These are patients who are living only 12 months give or take, according to frontline trials. That’s incredible to get 9 extra months of survival. I embraced it relatively rapidly based on this. Further confirmation is certainly necessary. It sounds like you’re using it with some confidence as well, Jared.

Jared Weiss, MD: In true second line, I’m using it. I’d love to see more data, of course. We all would. In a world where I have to make a specific recommendation to a patient when they’re not interested or not a candidate for a clinical trial, that’s clearly my answer if we’re in that platinum-refractory setting. Where I have a lot of equipoise…in trying to figure out what to do is in the platinum-sensitive population. Because if you look at the data for lurbinectedin in that population, for survival, it looks to be as good as re-treatment.

When I look back to the old topotecan data, in that same arena I wonder if the term platinum-sensitive is a misnomer and if it ought to be chemotherapy-sensitive. For patients who are less fit or didn’t tolerate that initial platinum doublet well, I don’t consider it a religion to have to re-treat with a platinum doublet at all. There are historical data that survival is not improved. There are lurbinectedin data for patients doing well there. For the patient who’s anything other than super motivated, super fit, with a super good response to front line, I’m thinking about lurbinectedin as my second-line option because I can always go back to a platinum doublet later. I know you’re not going to tell me that’s crazy—although feel free if I’m wrong—but how often are you thinking about that in your practice?

Carl M. Gay, MD, PhD: I’ve given lurbinectedin straight up to patients who would have otherwise met all the criteria for re-treatment with platinum. If you do that enough times, you see that it doesn’t move the needle in a major way. This was a new drug that we hadn’t gotten the opportunity to use a lot, so you think the outcomes will be different. I agree that head-to-head, they may stack up similarly. And I agree 100% about chemotherapy sensitivity, not platinum sensitivity—every biomarker we’ve found in the lab that predicts benefit from platinum seems to predict benefit from every other thing that you can use in small cell lung cancer. It’s probably just a matter of whether these tumors have undergone EMT [epithelial-mesenchymal transition] or whatever their resistance mechanism is going to prevent them from responding to cytotoxic therapy. It’s not about the platinum at all.

Jared Weiss, MD: Of course, we’ve both carefully avoided the copout for educational purposes, but in our practice we’re looking toward clinical trials, right? That’s often why people travel to 1 of our centers, so it’s worth taking a moment and talking about some of the completed and ongoing trials that are important to our decision-making. We know that ipilimumab-nivolumab in pre-frontline immunotherapy stratus had some data for efficacy. Are you still using it ever?

Carl M. Gay, MD, PhD: We’ve kept it on our formulary at our institution and are still occasionally using ipilimumab-nivolumab. Sometimes we have patients who, for whatever reason, didn’t get immunotherapy in the frontline setting. You think, “If I’m going to give it to them, maybe I’ll give them doublet.” Or for patients who seem to have had a good response, a durable response to immunotherapy for a while, and then start to progress—you think you can recapture some of that benefit there. I still use it, probably less than 5 times a year, but I do still use it. How about you?

Jared Weiss, MD: Less than that: once or less than once a year.

Carl M. Gay, MD, PhD: Less than 0?

Jared Weiss, MD: But what I do see a little bit more of is the patient. You and I may or may not have excluded them from immunotherapy in the front line, but they’re excluded for a soft exclusion. The classic is rheumatoid arthritis, which hasn’t required treatment for a few years, but it’s still on the chart. I see a handful of those a year, specifically that 1. Then I’ll certainly come back to immunotherapy in the next line. Ipilimumab-nivolumab, nivolumab alone, or pembrolizumab—I consider all of these perfectly reasonable options that have relative equipoise among them.

Carl M. Gay, MD, PhD: One scenario I can think of is that occasionally patients will progress rapidly after chemotherapy–RT [radiation therapy] in the limited-stage setting. And I think, “This is not a patient who’s clearly going to do well with platinum, so why don’t we try something else?” But I have 1 patient who did really well with this. I keep reverting back to that and making this decision. At some point, that 1 patient is going to be diluted by a lot of failures, unfortunately.

Jared Weiss, MD: This slide shows us some of the future directions with ipilimumab-nivolumab and lurbinectedin being studied together. It’s an interesting combination because lurbinectedin, in addition to acting as an alkylating agent, seems to be a good agent for depriving myeloid drive suppressor. There may be some synergy there. That’s probably the rationale for lurbinectedin-atezolizumab.

Carl M. Gay, MD, PhD: That and issuing some replication stress that might enhance the response to immunotherapy, similar to what’s been shown with PARP inhibitors and ATR inhibitors. But you’re trying to hit them with as many things as you can in the earlier stages.

Transcript edited for clarity.