There are a number of other regimens that are being tested. I'll plug a couple of these rather than go through them exhaustively. In the DNA damage arena, PARP inhibitors have not borne out quite as well as they looked preclinically, but there is some enthusiasm based around biomarkers there, especially with SLFN11. If any of you have Schwab 1929 trial open at your institution; you may be familiar with that. The targeting TIGIT [T cell immunoreceptor with immunoglobulin and ITIM domain] has gained a little steam because of how effective it's been in non-small cell lung cancer. The phase 2 CITYSCAPE trial data, which got an update last week, shows just this extraordinary benefit of anti-TIGIT plus atezolizumab in patients with PD-L1–high non–small cell lung cancer. I think it leaves people hoping to see some of that. Unfortunately, PD-L1–high small cell lung cancer [SCLC] is an extraordinarily rare entity, so hopefully, there's another biomarker for that population. DLL3 targeting left a bad taste in everybody's mouth after the failure of Rova-T [rovalpituzumab-tesirine], but now it has gotten a second life with Amgen's DLL3 strategies. I don't know if there are other drugs or strategies in development, Jared, that you're especially high on.

 I think there are some things. Small cell has a few preserved neoantigens, and I'm kind of excited about that as a therapeutic area. I spent a lot of time on personalized vaccination approaches, and I look to tumors that have preserved neoantigens with a little jealousy. In small cell, I agree, DLL3 is a really promising target. The updated data that Taofeek Owonikoko, MD, PhD, [Winship Cancer Institute of Emory University, Atlanta, Georgia] recently reported a response rate of 20%, but when I counted the patients at a higher dose, it looked like it was creeping toward 30%. I think a lot of people in the thoracic field sort of freaked out about the CRS [cytokine release syndrome] in that trial. But I kind of grilled them a little bit about that and it sounds like all events were treated in the infusion center, not in the MICU [medical intensive care unit] or even inpatient, so maybe it's a little less scary. I think that's going to be a winner of an agent. I reserve the right to be disappointed, as small cell research has disappointed all of us before. I don't have that 1 open, but I'm referring people for it. The other preserved neoantigen I'm excited about in small cell is GD2, and I think that that could be a very good cellular therapeutic target.

: I think in general, a shift towards cellular therapeutic agents or antibody-drug conjugate agents, and doing something different other than just trying different cytotoxic therapies in small cell lung cancer is right now a very justifiable way to go. We'll see how those trials pan out over the next few years. We have a few questions and probably need to make sure we've covered those for everybody in our audience.

We have a question about sequencing once a patient has progressed and can't receive platinum etoposide, preference of topotecan, lurbi [lurbinectedin], or other agents. I think you were very wise earlier when you said that when the standard therapies aren't very good, you look to something else. So if I have a patient that can't get a platinum doublet, I'm talking about hospice. I'm not pushing it, but I want to at least bring it up as an option and sort of assess a patient’s values. I'd favor 1 of the trials we've talked about, and if I don't have a spot for the patient, I encourage them to consider travel, which is possible for some patients and not possible because of values or resources and other reasons. Between topo [topotecan] or lurbi, again, we don't have comparative data yet, but in my practice, it's near 100% lurbi, with which I'm less scared of hurting people than I am with topotecan.

: That's my practice as well, and obviously there's no right or wrong answer there. Some of it might be recency bias where lurbinectedin is favored and topotecan is something that has failed us for a number of years, whereas lurbinectedin hasn't had the opportunity to break our hearts yet in quite the same way. But it also seems like a more valuable agent to build off of because designing trials where you add things to topotecan—5-day regimens or something like that, it's just so difficult to enroll and design things. I think the enthusiasm about where lurbinectedin might take us in the future is also really valuable, whether it's the combination with immune checkpoint blockade or something that's not obvious already. I think that that's nice. I want to reiterate your plug for getting these patients onto clinical trials. I think there could be a tendency with patients with small cell lung cancer to look at the failed clinical trials that have plagued us for decades and the general patient population, which is not necessarily a robust one, and think perhaps that's an excuse not to push them towards clinical trials. But really, if there was ever a subgroup of thoracic patients that really has nothing to lose by going on a clinical trial—and I mean that in the best possible way. I find it to be a very easy sell to these patients when you give them the data, as it stands for the standards of care; they see it that way as well: 

Best-case scenario I'm going to live a year. Why not try something different?

 And I think that's the only way that we're going to move the needle on this.

Yeah, I'm with you. My comfort level in recommending trials is higher than for other disease states. Stated much more simply, if tomorrow I got lung cancer, I would go on a trial because the standard of care just is not what we'd like it to be. But talking about that last question of toxicity, the next one is about performance status for systemic therapy.

: I think the idea behind a poor PS [performance status] in a patient with small cell lung cancer and how to manage them is something that I often focus a lot of time on in my lecturing to fellows who are learning to treat small cell lung cancer. And it's a little bit almost paradoxical. These are patients that in general are not going to do well overall, so if it's a patient with poor performance status who is heavily pretreated, I think the answer is fairly obvious to not push them towards more therapy. But if it's a patient with poor performance status who is treatment-naive, to me, that goes all the way in some cases to include patients who are either in the ICU [intensive care unit] or on the brink of going to the ICU. I think as long as you have a frank discussion with them about what the long-term looks like, there's very clear data supporting that there is a symptomatic benefit to treating these patients, even when they have very poor PS. To me, I don't think a PS of 3 is a disqualifier for systemic therapy in a patient with small cell lung cancer. But maybe that's me being too much of a Pollyanna or too optimistic about where we stand.

If you're wrong, I'm wrong with you. If the patient's precancer performance status was good and it's been trashed by the cancer, my experience is that if you blast with chemo—and I'm choosing my words intentionally—full-dose treatment, you very often improve that performance status. You get a Lazarus effect, including patients going from a ventilator to walking out of the hospital days after you're done. So my practice is very much the same. As long as it's not lots of comorbidities, as long as it's the cancer trashing the PS, I'll treat any PS with frontline. And my experience, we never really came back to trilaciclib too much, but my experience with retreatment has been a bit more friendly in the trila [trilaciclib] era. I recently had a patient that sort of hit me over the head a little bit, because it was the extreme of something I've observed in milder-case situations. It was a much older patient who in his front line went on one of the trilaciclib trials. Got his platinum etoposide and really had very little adverse effects, very little myelosuppression, very little fatigue. And then got second-line without it. It was in the interim before approval, and everything went downhill. And then I just more recently had the reverse of that. A patient who had a really tough time in front line with radiation then came back to get platinum-etoposide-atezo [atezolizumab] with trila, and the counts stayed really nicely preserved. So the superior supportive care [may vary], whether you're talking about 5-HT3 antagonists and fosaprepitant in the context of platinum and whether you're talking about trilaciclib in terms of myelosuppression and preservation. The improvements in supportive care do shift my opinions on drugs over time and whom I'll treat.

: Experience with trilaciclib has been so limited, it's very useful for me to hear about your experience and that it's been a positive one.

To get me really excited about a drug, I really want to see a pop in survival. But when 5-HT3 antagonists came to the fore, everyone wrote them. When it came to the fourth platinum, everyone wrote it. As oncologists, we'd like to see people living longer, of course; our patients would too. But if there's a drug that can improve my patient's quality of life on treatment, preserve their counts, decrease adverse effects, it may be prescribed with yon, but I'm going to prescribe with yon for every patient. And I should patent that, prescribe with yon. The next question is about hyperprogression following radiotherapy. Do you have any thoughts on that?

: I've occasionally seen a patient who I thought might be hyperprogressing, in particular with immunotherapy and small cell lung cancer, and I have on at least 1 occasion dropped the immunotherapy from the front line because I thought that might be what was happening. But it's not something I've experienced a lot of, and I'm not familiar with any systematic data that's delved into it. I'm not sure about you.

 I think small cell is just a really nasty cancer that grows rapidly unless we do something effectively.

: Just the cancer progressing on its own without the help of anything. Probably.

I think that it's natural to ask the question of what's different as we get to new agents, but the whole idea of hyperprogression in small cell or non-small cell, I have some hesitancy about. I think they're just very aggressive cancers that sometimes grow quickly. Maybe time will prove me wrong. So there's a question about maintenance therapy. I might dispense with that quickly; every patient who gets platinum etoposide and PD-L1 should probably get the PD-L1 in maintenance. We don't really know where the benefit comes from; we just know what the trial data shows us, which is that the separation was not early. But we really don't know where it comes from. I keep it simple and keep to the trial regimen, which is to use it. Any thoughts about any one you would exclude from maintenance or do anything other than PD-L1?

: No. I'm with you and a comment you made earlier about having a pretty strict cutoff after 4 cycles of combination chemo-immunotherapy. The only downside I see is extending that to cycles 5 and 6, even though the CASPIAN trial did allow for that. I get them onto maintenance therapy as quickly as I can. I get everybody onto maintenance therapy unless there's something very unusual that's happened.

 I'm going to push this question to you because it's from one of your fellows. Can you discuss the landscape of management when there's a recurrence after concurrent chemotherapy in limited-stage disease? Does it really just depend on timing and extent of recurrence or anything else?

: I see them on the list. They're not only 1 of my fellows, but in clinic with me later this week. I appreciate the question. I think it does largely, at least in my practice, depend on the timing and the extent of the recurrence. I will say that for patients who have limited-stage disease that have an isolated recurrence, I do occasionally deploy things like consolidative radiation therapy, whereas I don't consider that much in the extensive-stage setting at a time of recurrence. Say somebody has an isolated adrenal metastasis or an isolated bone met [metastasis] after a limited stage disease, I might try to buy us some more time. I'm fooling myself a little bit with that because we know small cells are a systemic disease. We know we can detect viable circulating tumor cells in these patients, even those that appear to have a relatively limited disease. And so you probably do have to consider starting something systemically there, but maybe you don't have to think of yourself as condemning them to a life on systemic therapy. Other than that, I really base it around the duration of benefit. If a patient had a year off of therapy after concurrent chemoradiation, I'll go back to platinum. If they had a month off of therapy before they progressed, I try something different. And as I mentioned before, that's occasionally where I'll try to sneak an ipi- nivo [ipilimumab-nivolumab] past the insurer with a lot of argument and pointing to the little data that we have there. I'm interested to hear your thoughts, Jared, because I think that's a wide-open space.

My practice is very similar. I would add how scared I am of the recurrence as a relevant aspect of my thinking in the platinum-sensitive patient.If you give me a patient who is getting 6 months every day for conversation’s sake—or 2 patients. One of them has brutal central chest disease that is really threatening them. In this case, I care about the response rate in PFS [progression-free survival] in and of themselves because the cancer is threatening to harm that patient relatively imminently. Give me another or counter case where I have lots of smaller spots, none pressing on something critical, none causing terrible symptoms, not a high fear factor, if you will, for suffering or death, then that's a patient for whom I might look to a single agent like lurbi, instead of a platinum retreatment, to keep it gentle. Of course, patient values play in heavily. Some people are done, they've had enough; they want hospice. Some people want the most aggressive thing possible. For me, values in terms of how much they influence the end decision beyond the more aggressive, less aggressive spectrum, is also their value on trials. Are they willing to go on a trial at my institution? I have the luxury of having another major academic institution 10 minutes down the road. Believe it or not, in Carolina, some people would rather die than go to Duke [Duke Cancer Center Durham, North Carolina]. I've had that more than once, but if they have a trial that's promised, someone's got to be laughing at that one. If they have a trial that's promising for that patient, I'll recommend that. And if I don't have a trial as promising for them, are they willing to travel elsewhere? I've expressed already in our conversation my excitement about tarlatamab, the DLL3 BiTE [bispecific T-cell engager]. I don't have that open, but it's open in Baltimore Maryland, which is maybe a 2-hour drive from here. But any rate, a reasonable drive and if patients are willing, I'll refer them for that. So the values sometimes play into that—the clinical trial willingness and the travel willingness as well.

I think we've answered all your questions.

I want to thank you for this enriching and informative discussion, Dr Gay. And I'd like to thank our audience as well. Both of us hope that you found this webinar discussion to be engaging and helpful to your understanding of patients with small cell lung cancer. Personally, I hope we've gone a little past the data to give you some color on our practices and how we're thinking about making some of these decisions when there isn't level 1 data to define A or B.

: I'll echo all of that. This has really been a pleasure, Jared. And again, thanks to the audience for keeping us on our toes with some good questions.

Videos

Drs Carl M. Gay and Jared Weiss highlight several novel strategies that show promise in optimizing treatment for patients with small cell lung cancer and respond to questions from community oncologists who manage treatment for patients with lung cancer.

SCLC: Future Therapies and Advice to Community Oncologists

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?

 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.

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?

 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.

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

 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.

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.

 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.

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?

 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.

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?

 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.

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 

. 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?

 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.

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?

 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?

Less than that: once or less than once a year.

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.

 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.

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.

 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.

Available treatment options as second-line therapy for small cell lung cancer.

Treatment Options for Relapsed Small Cell Lung Cancer

Thinking about the general systemic treatment approach, we have a patient, we have gotten their PET [positron emission tomography] scan, we have gotten their MRI of the brain and we are thinking about what to do for this patient. In my practice, the first thing I think about is the brain. The brain is much more like Manhattan in terms of real estate, than it is like Houston or even further Chapel Hill, North Carolina; it’s packed in. It doesn’t tolerate much pressure or extra space. I am thinking about the brain first and if there is anything other than the very least threatening brain disease, I am going to consult a radiation oncologist and talk about doing some kind of treatment for that. Assuming that there is either no brain disease or the most minimal asymptomatic disease, my next step is to think about systemic therapy with the goal, unfortunately is not of cure, but of extending the duration of life and preserving the quality of life. And that starts with triplet therapy or chemoimmunotherapy. We’ll go over the details in a little bit. Transitions to maintenance immunotherapy, in my practice, that’s always 4 cycles in the era of immunotherapy. I have pretty strong feelings about that. There is a little bit of heterogeneity in practice. Fortunately, response rates are high, and relapse is typically early and then at that point we are talking about next-line options and if that relapse is rapid which is defined a little differently in Europe or the U.S. but however you define rapid, you move onto the next line. If it is long, and again there is controversy over what’s long, a bit of Atlantic divide, then you could either rechallenge with the original regimen or move on to a subsequent 1.

: I think there are a couple of interesting points here in the note section on this slide too, Jared. The role of radiation in patients that have extensive-stage disease I think remains quite controversial. It comes in 2 flavors, prophylactic cranial irradiation, which is a fairly widely accepted standard of care for patients that have limited-stage small cell lung cancer who have an excellent response to therapy and for many years was at least if not the standard of care, an acceptable form of care for patients that had excellent responses as sensitive stage setting. We are now 4 almost 5 years out from a relatively definitive Japanese study showing that patients not only failed to benefit in terms of overall survival here but, in fact, there was a trend towards worsening of overall survival. Nevertheless, I still haven’t seen it fall completely out of practice and occasionally we will have patients that I see as a second opinion who have received prophylactic cranial irradiation in the extensive stage setting. Maybe there is an occasional indication for that in an especially young patient or somebody that has a really dramatic response and is very motivated. But I’ve essentially eliminated that from my practice completely. Now that said with consolidated thoracic radiation therapy, that’s something I think there is a little bit more enthusiasm around. I agree with the note here that it’s still probably considered an investigational treatment albeit 1 with fairly strong data. I think what we don’t know about consolidated thoracic radiation is really how it integrates into the standard chemoimmunotherapy systemic therapy they are offering now. So this has not really been studied in the era of immunotherapy. There is an ongoing trial from NRG [NRG Oncology] that’s enrolling as we speak that is attempting to integrate consolidative thoracic radiation into IMpower133 atezolizumab [Tecentriq] plus chemotherapy backbone. Hopefully, we will get a somewhat definite answer there but at least in my practice even though there is not really evidence supporting it in patients who are on immunotherapy I have tried to integrate it in patients who only have residual thoracic disease. I don’t know, Jared, if you have done the same or if you’re waiting for further support.

In that setting, I absolutely do the same thing, if the only residual disease is central thoracic. The other situation is if I consider the central chest response inadequate because when you don’t do it you end up doing it as an emergency later in probably more than half of the patients.Whether it’s a response or not if there is a lot of, I was about to say bulk, but the more honest answer fear factor, which is the integration of bulk and location of the bulk. If it’s either starting to compress airways still or threatening to do so. If I have that fear factor about the central chest, I am still doing it, but I have equipoise about it. Should I be pausing the radiotherapy? Should I be going right through it? I don’t have a clue. Do you have an opinion on that?

: I approach it with almost magical thinking. I usually try to time it such that the consolidative thoracic radiation therapy happens between 2 regularly scheduled cycles of atezolizumab or durvalumab [Imfinzi], and then I convince myself I have not really given concurrent immunotherapy and radiation even though we know the half-lives of these drugs are very well. If I did pause it, I wouldn’t know for how long to pause it anyway because of that half-life issue, so I just try to keep the patients on schedule unless something really goes awry there. They are viable concerns whether or not this influences the risk for pneumonitis in these patients. I have not seen that anecdotally and I treat a fair number of small cell lung cancer patients, but I would be very interested to see not only the efficacy data from the NRG study and other smaller studies but also some of the adverse event data to see if that’s borne out.

I am really amused by your response because if you’re wrong we are wrong together, that’s what I have done with the last few as well. Hopefully, that means that it at least makes sense and time will tell us if we are doing the right thing. I am very much with you in not being a fan of PCI [prophylactic cranial irradiation] for exactly the reasons you’ve listed but also for a very happy reason which is that some of our patients are living long enough to suffer the neurocognitive effects. Back in the day, we really didn’t worry about that and now there is a small but real portion of patients who are, so that quality of life consideration has happily come to the fore

: There is a little tale to particularly some of the immunotherapy containing regimen curves and I think we need to be mindful of that. There are also some trials evaluating whether or not either close MRI surveillance or even in the use of gamma knife in patients with small cell lung cancer, which have long been considered a faux pas for small cell lung cancer patients, might be able to spare them some of this neurotoxicity because it is certainly real. If you have given PCI to patients, it’s rare that they don’t suffer any consequence from that PCI I would say if they live long enough to see it. I think it’s something that really bears taking in mind and if you look back at the Japanese study that I reference the trend towards the overall survival was not because of the inefficacy of the prophylactic cranial irradiation those patients that got PCI in extensive-stage setting were at much lower risk of developing brain metastasis yet they still lived certainly not longer if not slightly shorter period of time. You have to imagine this is driven by adverse events and the inability to get future regimens of chemotherapy because of lingering toxicities from the PCI and so it’s not just about controlling brain metastasis it’s about controlling the overall health of the patient, I think. There is a sort of distant illusion to the new standards of care in small cell lung cancer that the use of chemoimmunotherapy, so I just want to make sure that we’re all on the same page as to which regimen we are talking about here. At least in the United States and now throughout most of the world we have several preferred regimens that are backed up by randomized phase 3 data and that’s the combinations of platinum etoposide with either atezolizumab or durvalumab. This was based on a brief snippet of the data in just a second, the IMpower133 and CASPIAN studies, respectively. For the most part, carboplatin is the law of the land for patients that have extensive-stage disease. The only time that I ever used cisplatin, and I am curious about your thoughts on this Jared because I think this is also borderline magical thinking on my part, but occasionally I will have a patient that has a myelophthisis and will have very-very weak counts coming in and I convince myself that cisplatin is slightly less myelosuppressive, so I am doing some benefit to the patient by giving them cis [cisplatin] instead of carbo [carboplatin]. These are patients that have platelet counts of 20,000 in the treatment naïve setting but I have not seen that go well and so I am not sure I am doing anybody any favors by taking that approach. Otherwise, I have a difficult time seeing any enthusiasm for cisplatin, which is generally a more difficult drug to give here, but maybe you feel differently, I don’t know.

I have magical thinking just slightly different magical thinking. In the pre-trilaciclib [Cosela] era, I was sometimes using cisplatin for just that reason if the patient’s bone marrow was beaten up in the first round. For everyone else, in case this is not overwhelmingly obvious just to be clear cisplatin is rougher for everything other than myelosuppression. But in a modern era with our modern antiemetics and renal prophylactic regimens, cisplatin to me is a much less nasty drug than it used to be but that’s titrating degree of hatred, it’s still not a gentle drug. Frankly, neither is carbo [carboplatin] it’s just less so than cis [cisplatin], so I am with you. The other magical thinking I was referencing is sometimes in a very fit, very motivated patient when I am re-treating I will have the magical thinking that if I switch up their platinum and sometimes I will switch etoposide to irinotecan that maybe I will have a little more sensitivity and I mean this as a self-criticism in calling it magical thinking. I suspect if you did a randomized study it would not be different.

: I think we have all dealt with the lack of progress in small cell lunch cancer for so long that we’ve all developed these coping mechanisms, as practitioners where you want to feel like you’re doing something or you’re not just repeating the same thing. I mean it’s hard to treat a disease where 1 of the standards of care is have you considered just trying the same thing that you did before over again? Right, there are very few. I mean, I treat a narrow range of diseases but I’m not that far out of fellowship. I can’t think of diseases where they say just go back to step 1 and try again when patients relapse. And so you know, I think we, in a self-deprecating way, we’re talking about these things but I think it’s universal you want to feel like you’re trying something different because if this patient only got 6 months of out of carboplatin and etoposide the first go around you know they’re going to get less out of it the second time through, why not try something different even if it’s just subtly different? I’m right there with you with switching between etoposide and irinotecan in those scenarios, and occasionally, switching between carbo [carboplatin] and cis [cisplatin] in those scenarios certainly without any data to back that up, but no reason to think we’re harming anyone by doing that. Some of those are listed here as well among the reasonable options for frontline systemic therapy as for the other recommended regimens, the ominously titled “Useful in Certain Circumstances,” I think that unless you have a patient that’s clearly not a candidate for immunotherapy, you know, an organ donor, solid organ transplant patient, or somebody that has a very, very brittle autoimmune disease, even there I would give yourself a lot of latitude in considering immunotherapy. I think the preferred regimens are the regimens for patients who have extensive-stage small cell lung cancer.

I would say that before a patient is excluded from immunotherapy unless they have an organ transplant because PD-1 [programmed cell death protein 1] is the projection pathway that perhaps one of us ought to be consulted to address the question of whether they really aren’t a candidate before fully excluding anyone.

:Yeah, I think that’s fair. Even though it’s a minority of patients that are benefiting from immunotherapy there is still, as I mentioned, a tail to that curve. These are the only long-term survivors that you’re going to get with small cell lung cancer, right? We were not getting any long-term survivors in the pre-immunotherapy era, and so yeah I think it’s a chance that you have to take for those patients even if they carry a rheumatoid arthritis diagnosis you’d rather just sort of manage the consequences of the toxicity than cheat them out of the chance at a long-term response. I think this goes back to the inability to predict who will benefit from immune check blockade in small cell lung cancer where PD-1 and a mutational burden has not worn out. There have been some hints here and there but when push came to shove those things were not predictive of benefit, so you have to treat everybody to get maybe 10% to 15% of patients that are going to benefit from it. That’s where we are now. Some of the specifics in these regimens and some of the attempts I guess to validate some of the other perhaps more familiar to our audience immune checkpoint blockade agents are listed here. I mentioned the IMpower133 and the CASPIAN studies. I think this is a fun question for discussion, Jared. Do you have any rationale for choosing between these 2? Once upon a time, durva [durvalumab] was offered every 4 weeks and so slightly more convenient, and then atezo [atezolizumab] nipped that in the bud. Is there anything that drives you toward 1 or the other here?

The curves for these 2 trials are almost eerily superimposable, which to me just reflects that they were large well-conducted trials. They did their homework right and there was no luck intervening to make them different. To my mind, having 2 positive studies really just confirms the principle that PD-1 inhabitation adds to chemotherapy. If I had small cell lung cancer of extensive-stage and you were flipping a coin between the 2 agents, I wouldn’t be rooting for heads or tails. In practice, it’s not Schrödinger's cat, you have to choose 1 or the other.And to not totally cop-out, I do use atezolizumab and the reason is actually not related to a feeling about superior efficacy of atezolizumab, it’s because I really like trilaciclib, which we’ll get to, for preserving quality of life and it’s only approved in combination with atezo [atezolizumab]. It’s a very mundane reason but that’s what drives my practice.

: I think that that’s the only reason that 1 could choose between them now. I agree with everything you say about the sort of 1 validating the other and vice versa. It’s also nice to sort of have 2 building blocks for clinical trial development. This keeps 2 companies very invested in the extensive-stage small cell lung cancer space and that’s a good thing for patients. If 1 company has something in their pipeline that might pair well with an immune checkpoint blocking agent then you don’t have to jump through the hoops that it takes to bring 2 companies together in a trial design. I tend to use atezolizumab. I will say, and I’m curious to hear your thoughts on trilaciclib later because I saw that on your slides and I’ve read a bit on your commentary before, our utilization of it at our institution has not been broad, to say the least, but that may not be fully justifiable at this point. I think it is worth mentioning here the other trials. Essentially, every immunotherapy has attempted this extensive-stage space and while atezolizumab and durvalumab I guess are the de facto winners there’s really not a lot to distinguish the outcomes from these trials. Pembro [pembrolizumab; Keytruda] fell a little short in the KEYNOTE-604 [clinical trial] but realistically the hazard ratio was not all that different than the others and could’ve just been a little bit of bad luck in trial design. Then, the nivo [nivolumab; Opdivo] was a phase 2 trial, but was just a little late to the punch, but had relatively similar outcomes. I’ll jump ahead to the first polling question that I’ll open up to the audience. I’ll read this and then Jared and I can talk about it a little while your answers come in. Of the following, which is the key factor you consider when selecting first-line therapy for patients? As options, we have patient fitness, progression-free survival data for the regimen, toxicity, or adverse events of the regimen.

It’s interesting because most of these aren’t that different between the 2 choices we’re making. To my mind, philosophically, we treat extensive-stage or any incurable cancer for quality of life and duration of life, and I don’t know if either of those were directly up there. Quality of life is probably the most important for me but very challenging to measure. So for trial data, I’d say survival but that wasn’t up there.

: I tend to agree with you. I included progression-free survival, which I think is an interesting thing to include there because progression-free survival is not really something where you can distinguish any of the small cell lung regimens. And frankly, on IMpower and CASPAIN you cannot distinguish the experimental from the control arms because the response rates are very similar through these patients. The progression is going to happen. It’s virtually inevitable in both arms. That overall survival tale is really the only thing I think that’s driving us towards adding immunotherapy to everybody. I guess if forced to choose the toxicity data is something you bear in mind, but as you said, for a very, very limited number of patients, it’s the only thing I can think to distinguish the frontline trials. As you said, taking into account the trilaciclib approval, sort of mitigating toxicity in 1 of the regimens vs the other might be a fair way to settle it. It looks like that audience was relatively split among several of these options. A lot of them thought about patient fitness, which I think is always, in small cell, is as relevant in any disease that thoracic medical oncologists [are] going to treat because these are often not fit patients who are getting progressively less fit by the day. Some others consider progression-free survival, which, I think, in general, is a good rule of thumb, but in small cell lung cancer it’s hard to choose something based on PFS [progression-free survival]. And then some consideration of toxicity there as choice C. Sort of like us, Jared, not a clear-cut winner, not a clear-cut driver of choice here.

Current considerations that affect the choice of frontline therapy for patients with small cell lung cancer with the availability of novel systemic therapies.

Small Cell Lung Cancer: Frontline Treatment Decisions

® webinar titled “Updates in Small Cell Lung Cancer: Treating Relapsed Disease.” I’m Jared Weiss. I’m a medical oncologist who focuses on thoracic cancers and cancers of the head and neck, and I run a joint section of thoracic and head and neck oncology at UNC Lineberger Comprehensive Cancer Center [at the University of North Carolina School of Medicine in Chapel Hill, North Carolina]. I’m joined by Dr Carl Gay, also a thoracic head and neck medical oncologist and an associate professor at [The University of Texas] MD Anderson Cancer Center [in Houston, Texas]. Welcome.

The treatment of small cell lung cancer continues to evolve as we learn how to incorporate new agents and improve the use of established agents. Through our discussion, we hope to review the landscape of small cell lung cancer and factors that make it an aggressive disease, to compare and contrast the first-line therapy options, to obtain insight on strategies for monitoring patient response to treatment, and to discuss second-line therapy options and indicators to change therapy. Let’s begin. Dr Gay, start by showing an overview of the landscape of small cell lung cancer, incident rates, and risk factors.

 In terms of risk factors for small cell lung cancer, unlike non–small cell lung cancer, the etiology of small cell lung cancer is relatively straightforward, so the vast majority of patients have a history of not just smoking but heavy smoking. You’re looking at upward of 95% of patients who will have a heavy smoking history. That’s evolving a bit as our targeted therapies become more effective as small cell lung cancer transformation from driver mutation. Driven adenocarcinoma is emerging as a real entity, but still, if you have a patient that carries a diagnosis of small cell lung cancer without a history of smoking, you want to make sure you have a repeat pathologic review of that at this point in time.

Yes, that’s my practice as well. If it really is small cell [lung cancer], then that’s the 1 incidence where I am sequencing small cells for exactly the reason that you described. We think of these as resistant change, but I have seen a de novo diagnosis of small cell [lung cancer] in a never-smoker who had EGFR transformed before selection pressure from TKI [tyrosine kinase inhibitor]. But that’s not our typical presentation. What’s our more typical presentation?

 The typical presentation is rapid onset of symptoms. These are usually patients who present with pulmonary symptoms, often cough or shortness of breath. These are often centrally located tumors, so they develop symptoms there rapidly. But because the disease metastasizes early on in the process, you also see systemic symptoms like weight loss; bony pain if they have bone metastasis, which is common; and various other symptoms that might be related to the sites of the distant metastasis, liver, brain, adrenal glands, etc. These are not patients who you’ve scanned for a pulmonary nodule 5 years ago and they’ve had a slow-growing evolving tumor that you’re going to finally biopsy. These are patients who say, “I felt fine 3 months ago, and now I’m in the hospital on the border of going to the ICU [intensive care unit] and in desperate need of systemic therapy.”

In the tobacco belt, a lot of our diagnoses are through the emergency department [ER] with fairly acute pulmonary symptoms just as you described, and we often end up giving cycle 1 in patients far out of proportion to other cancers.

 We have the same—1 of the interesting challenges with designing clinical trials around small cell lung cancer is exactly that. Many trials require cycle 1 day 1 to be given on protocol, and these are patients who are often treated emergently in the ER or even the ICU in some cases, so it’s an interesting challenge for somebody who designs trials for small cell lung cancer.

Maybe we can blame our slow progress over the past several decades on that, taking ownership for failure to understand biology until recently. Patients are in the office or in the emergency department. How are we or our emergency department, internal medicine, or pulmonary colleagues working these patients up? How do they get from shortness of breath to X-stage small cell lung cancer?

 There’s not a lot of nuisance to staging small cell lung cancer. Once you have a confirmed pathologic diagnosis of small cell lung cancers, so if you have a mass that gets biopsied and returns consistent with small cell carcinoma, every patient deserves a PET [positron emission tomography] scan, if not a CT of the chest, abdomen, and pelvis and bone scan as well as an MRI of the brain. These patients are at very high risk for having distant metastasis. Two-thirds or more are going to have extensive-stage disease at diagnosis, so they need to be staged as such.

All of us in academia worship at an altar of biomarkers. At MD Anderson, what are the cutting-edge biomarkers for small cell [lung cancer]?

 We certainly lag in non–small cell and that arena. Most of the folks following us will be aware that there are no standard biomarkers integrated into the care for patients with small cell lung cancer. That said, some clinical trials are integrating them. There’s a biomarker called Schlafen-11 that has been shown to be predictive of several things, most notably PARP inhibitor sensitivity. There’s an ongoing cooperative group study where the patients are randomized only if they’re Schlafen-11 positive. There are some other biomarkers that are another experimental arena: DLL3 expression for DLL3-targeted therapies, NIK expression for ROR kinase inhibition, as well as the recent appreciation of the transcriptional subtypes that lie within the small cell lung cancer landscape. We and certainly others are working on CLIA [chemiluminescent immunoassay]–validated assays to be able to use those for select patients or at least retrospectively review outcomes for patients on trials.

 I’m very impressed by that work. For those who aren’t familiar, transcription profiling shows these 4 distinct biologics, and they’re rather distinct. I was joking earlier about our progress being a lack of biological understanding until recently. These transcription subtypes to me are a legitimate promise that we’re getting there and heading toward subtyping this heterogeneity. It’s not applicable to current practice, as Dr Gay has directly stated, but I have real hope that these are going to make a difference. I’m impressed by that work. In the span of 5 years, we’re going to see therapies that are more or less effective in groups and hopefully speeding of drug design as a consequence.

Unfortunately, in the current time for standard practice, there’s nothing. PD-L1, in particular, is not helpful for telling us whom to treat. There we are for now. For anyone who’s still a trainee, on your board is technically the same TNM [tumor, node, metastasis] system used for non–small cell [lung cancer]. But I’m with Dr Gay and nearly 100% of lung cancer doctors in using this simple extensive-stage or limited-stage system. It’s so practical. You’re limited-stage if you can incorporate everything into 1 acceptable radiation portal; everything else is extensive-stage. What I love about our small cell system is that we use it in practice, as compared with many of the other staging systems. Dr Gay and I both treat head and neck, where the staging system doesn’t cut off to tell you what to do. What’s nice is that if you’re limited-stage, you’re doing chemo-rads [chemotherapy and radiation]; if you’re extensive stage, you’re doing a systemic regimen, which we’re going to talk about. I like that about the small cell system. It’s 1 of the few that does that cleanly for you, where it’s practical. I did just see 2 new patients with small cell [lung cancer], and they both asked me the same questions that every newly diagnosed patient asks: “What’s the prognosis here?”

 Unfortunately, that’s a very difficult conversation to have out of the gate because even with some of the improvements that we’re going to talk about later in terms of systemic therapy options, the prognosis remains very poor. That’s all comers regardless of the stag—in particular for extensive-stage patients where the overall survival even with the addition of immunotherapy is bordering on about a year or maybe a month or 2 longer than that. It’s a little better in limited stage. If you look at 5-year overall survival for patients across all stages, you’re getting close to 5%, which is really dismal, especially compared with the strides that we’ve made in non–small cell lung cancer.

Symptoms and risk factors associated with small cell lung cancer, and recommendations for staging patients with newly diagnosed disease.

Carl M. Gay, MD, PhD

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