Lung Cancer Podcast

Are We Ready to Use the Word 'Cure' When Talking About Small Cell Lung Cancer Treatment?

Jacob Sands, MD; Jared Weiss, MD


February 16, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Jacob Sands, MD: Hello. I'm Dr Jacob Sands, thoracic medical oncologist at the Dana-Farber Cancer Institute, where I lead our small cell lung cancer program. Welcome to Season 2 of Medscape's InDiscussion Series on Lung Cancer. Today we'll be discussing small cell lung cancer, and I'd like to start out by introducing my guest, Dr Jared Weiss. Dr Weiss is a professor of medicine at UNC's Lineberger Comprehensive Cancer Center, where he runs a joint lung and head and neck cancer section. Dr Weiss, welcome to InDiscussion.

Jared Weiss, MD: Thanks for having me here.

Sands: I'd like to build upon the discussion we had last season where we discussed immunotherapy. You mentioned at that time that you had initially thought that you would end up being a pediatric neurologist, although you took us through your course of eventually becoming a medical oncologist. That was a fascinating discussion. I encourage our listeners to go back and listen to that discussion on immunotherapy. But let's start out earlier in your course. What was the path that led you into medicine in the first place?

Weiss: Every little boy goes through some phase where he wants to be a fireman or an astronaut. I actually never did that. I saw what my pediatrician was doing and I said, "Yeah, I want to do that." And then as I got older, I quickly realized that I was a big-time nerd and I remain proud of that to this day. And then if you combine being a science nerd with the desire to help people, it just comes together for medicine to make sense.

Sands: Well, that's perfect, and this is what makes these discussions so fun. But let's dive in specifically in first-line small cell lung cancer. Let's start with that. We've seen tremendous advances in non–small cell lung cancer. And I feel like we're just getting started with small cell lung cancer. That really started, in some ways, in this era of immunotherapies. And we've certainly seen a change in the standard of care in the first-line setting. Can you give an overview of where immunotherapy fits into that or where the benefits are and potentially balance that out with the risks?

Weiss: Immunotherapy in lung cancer is a little bit glass half-full or glass half-empty or, being a New Yorker by birth, maybe who drank my water? But the glass half-full part is that it was our first improvement in survival in a long time, right? We've been waiting a long time to have an improvement in front line. Way back in the day, we went from cyclophosphamide, doxorubicin, and vincristine (CAV) to platinum/etoposide — unfortunately, not based on a survival advantage but rather based on a toxicity and convenience advantage. And we've been at a relative plateau, for survival at least, ever since. We've tried a lot of different ideas about improving care in small cell, a lot of maintenance options, and they've really never gone anywhere. So we were left with a place where we have high response rates to therapy and then it usually typically comes roaring back. And so when you enter immunotherapy, I think, yes, it's a big advance in the sense that we've improved survival and a big celebration that we've broken that logjam. But I think that the real significance here isn't just the improvement that we're able to offer patients in this moment but also the idea that, with immunotherapy, we can do better. And the idea that perhaps as immunotherapy improves and as we get new agents, we might make more dramatic advances here.

Sands: To add to that, for me, the big advance of the addition of the immunotherapy is, more than anything, the tail of the curve. It's the number of people that have years of ongoing disease control — to have people 5 years out from their diagnosis without having ever needed a second-line treatment. Unfortunately, this is not everybody and it's a smaller number of patients that go 5 years. That's a long time to not need another treatment in the setting of metastatic disease. The fact that there is the potential for not needing a second-line treatment is, in some ways, what we could call an ongoing indefinite remission is pretty exciting. And I know we discussed that concept a bit with our immunotherapy conversation and in the setting of non–small cell lung cancer, and it's even more emphasized in small cell lung cancer. Do you have some of these patients that are years out now? And what is your thought about that population?

Weiss: My primary thought is I am starting to use the C word [cure]. There's only one nice thing you can say about a malignancy as aggressive as small cell, which is that if it hasn't come roaring back quickly, it's probably because it's not there to come roaring back. If you have a low-grade lymphoma, if you have a breast cancer 10 years later, your life can be upended by having that cancer come roaring back and changing your life. I think if you have small cell and you are 5 years out, it's quite unlikely that it's ever going to come back. You can breathe more of a legitimate sigh of relief. I would go even further — I think if you're 2 years out, with no evidence of disease, no evidence of cancer growing, you may well be good. And I very much agree with you that this may not be as high a proportion of patients as we would like it to be. I think that in addition to it being wonderful for those patients who achieve it, at diagnosis, having legitimate hope of that is really rather helpful on the human side here.

Sands: I agree. I tend to talk about immunotherapy more in a sports analogy as if it's swinging for the fences. And when that connects, it makes the headlines in all the papers and wins the game. But unfortunately, the majority of times it does not result in a hit and therefore is a strikeout. This to me brings up an interesting aspect of using immunotherapy in the first-line setting. Many people say, well, the best thing about using it is you're using all your best drugs upfront; if patients are going to benefit, they get the benefit. And that's true, absolutely. To me, using a drug that can be a homerun but in many cases is not effective in the second-line setting where people really need that response, you risk losing all other opportunities for treatment. And so it is swinging for the fences. And when you do that in the first-line setting, combined with a treatment that overwhelmingly works — platinum/etoposide works — you are still getting that hit while also having the opportunity of a homerun. And therefore in the second-line setting, you're not risking the majority of people really clinically declining without getting that. It's kind of backwards thinking. In some ways a justification or further reason to use that in the first-line setting that I think is relevant too because, of course, I'm also going to bring up using immunotherapy in patients who hadn't previously gotten it. So first of all, do you think that analogy holds up? And what are your thoughts about that?

Weiss: I very much agree. In listening to patients, it's not a surprise that what we hear from them is not "Doc, I want to live 2 weeks longer" but rather "Doc, I want some chance at being alive in a year, 2 years, and in 5 years." So if the values of patients should drive what we do and what we shoot for, and of course they should, then this profile fits with what patients are looking for. In terms of the relative clinical profiles, I very much agree with you that this is a nice combination and I would add a little bit, which is that the chemo is reliable for rescuing people in the short run, but it doesn't last. Immunotherapy has the opposite profile. It doesn't typically act quickly. There may be people who benefit, who you need to get a handful of doses in and have patience in order to see that maximal response. And I think that part of what the immunotherapy buys you is that patience. It keeps people safe and okay while you're giving the immunotherapy every chance to kick in.

Sands: This all forms a basis for the next aspect of discussion. The next big advance that we've had or the other FDA approval is lurbinectedin in the second-line setting. We saw from the single-arm study — this was a basket trial with 105 patients with small cell that led to FDA approval — showed a response rate of 35% among those with a less than 90-day chemotherapy-free interval, so the really poor prognosis setting, response rate was only 22%, but about 20% of patients with a 6-month progression-free survival, which in that population, I think, is meaningful, albeit we want those numbers to be higher. In the greater than 90-day chemotherapy-free interval, so a bit better prognosis but this is not the greater than 6-month that we often talk about, really better prognosis, kind of in-between: a 45% response rate, 4.6-month median progression-free survival. So, again, not enough, but 44% with ongoing disease control at 6 months. So certainly populations of patients are benefiting, although overall I think it still highlights our ongoing need for clinical trials and further drug development. Has your experience with lurbinectedin been along those lines and is there anything from the trial that you in your practice, have noticed any differences from?

Weiss: I think we have to couch lurbinectedin in [terms of] what came before it and what the alternatives are. I think the two major things that we considered in addition to clinical trials and the optimal treatment for any patient with small cell is a clinical trial, ideally at UNC but, you know, Farber would be okay too. For anyone not aware of this, those are our institutions.

But you know, that attempt at humor aside, right, what we were considering, aside from clinical trials, was either hospice or topotecan. And we do have a randomized trial of topotecan vs hospice that gives us reason to believe that in addition to a small but real survival advantage, there's a quality-of-life advantage. Now, quality of life, which I think is what's most important to our patients and, in my opinion, what's important to a good oncologist — at least physical quality of life has two major threats to the patient. One is suffering induced by the cancer (cancer grows, it hurts people), and the other is you and me. And by that I mean the side effects of our drugs. And we don't have the luxury of ever ignoring these, right? So we're going to couch our conversation about quality of life in comparing these three options: lurbinectedin, topotecan, and hospice.

We already know topotecan beats placebo for quality of life. It controls cancer better than placebo, of course, and it's worth it. The side effects are outweighed by the suffering that it prevents.

So, then, how does lurbinectedin stack up? We don't have a comparison between the two drugs in the same trial, but we're going to go ahead and conduct the forbidden but omnipresent cross-trial comparison, including our clinical experience. And here I would reflect that lurbinectedin, both in the noncomparative trial data and in my experience, has a greater probability of response than topotecan. And, both in the toxicity tables and in my experience, it is less toxic than topotecan.

So I'm going to go ahead and, without any comparative data, say that my opinion is that it's a better drug for quality of life vis-á-vis both cancer control and toxicity. And so now faced with that decision for maximization of quality life, it's a little bit of a transitive argument, but I'm going to argue that lurbinectedin is the best of those three options available to me. While I would not call lurbinectedin a homerun by any measure, I think there's a lot of improvement to be done for what's available to us today, which is to say, lurbinectedin, topotecan, or hospice. I think it's the best option for quality of life.

Sands: I agree. The side effect profile on that study: 46% with a grade 3 or 4 neutropenia but 5% neutropenic fever. That study did not allow for a primary prophylaxis for neutropenia. And so that was the most common side effect. It did show a 7% grade 3 fatigue, which on initially seeing that data, I thought, well, maybe that's from the small cell. Sometimes it's hard to tease those apart. But I have definitely seen that in practice. I had one patient who had gotten a few cycles of lurbinectedin with very rapidly progressive disease, even for small cell, it was pretty aggressive with a beautiful radiographic response, but had such fatigue I could not give him any more lurbinectedin and held the drug entirely. His disease was radiographically under control for more than 4 months off therapy, at which point it was rapidly progressive again. And so, in his case, the fatigue clearly was not from his disease; it really was from the lurbinectedin. And thankfully, that has not been too common. But as far as side effect profile, I agree, that's been it for the most part. Of course, there's other stuff on there. But those are the ones that I tend to highlight.

Weiss: It's a chemo profile, right? A profile we've known for a long time. I will say, if I can make a shameless plug for a trial, that we do have a phase 2 trial initiated combining trilaciclib with lurbinectedin. So trilaciclib is FDA approved with all the other small cell regimens: carbo etoposide, carbo/etopo/atezo and topotecan, where it reduces myelosuppression, reduces patient-reported fatigue. And we're studying it now in combination with lurbinectedin for two reasons. The most obvious one is to protect quality of life, avoid myelosuppression, improve patient-reported fatigue. The other one is subtler, which is that there's data on lurbinectedin that there's more of a relationship between AUC [area under the curve] exposure and probability of response, which is not what we've seen with most other small cell drugs. And so dose reductions with this agent may actually be more harmful than with other small cell agents. And it's possible that we would find a survival advantage by avoiding those dose reductions.

Sands: And maybe to flesh that out even a little further and further support what you're saying before we then discuss the data around trilaciclib, there was the combination study of lurbinectedin plus Adriamycin vs CAV or topotecan. In that study, the trial was negative, in the sense that there were seemingly very similar responses. The curves really overlapped and the dose of lurbinectedin was a bit lower. Now that's necessary: It's combined with Adriamycin, and I think we can certainly say there wasn't enough synergy to really validate using that combination, but there was some concern that the lurbinectedin dose was a bit lower and, based upon the pharmacokinetics of lurbinectedin, that actually might be a really meaningful reduction therefore, and this is why generally with lurbinectedin, I really try everything I can to not reduce the dose, which then further reinforces this concept where if using trilaciclib can help prevent dose reductions, we might see improved outcomes, and I think that makes a lot of sense.

You also led some of the earlier studies with trilaciclib, with platinum/etoposide and topotecan, in which case it is approved in those settings. And I'd say what I've seen highlighted is actually the notable reduction in neutropenia, which to me is not the appealing part about this. The most appealing part is the reduction in anemia and thrombocytopenia. These were not the primary endpoints, but I think these are the most clinically meaningful ones.

Also, you mentioned an improvement in health-related quality of life that went along with this. You've really opened my eyes in many ways in the discussion around the possibility of anemia actually causing more symptoms than we've historically appreciated probably. We've considered a lot of fatigue and such to be due to the chemotherapy, when in fact there may be a component of anemia that's playing into that. And these studies really provide some input on that. Can you discuss that a bit more?

Weiss: Trilaciclib is a short-acting CDK4/6 inhibitor. It's designed to hold the bone marrow progenitors out of cycle while the chemo is washing by. The idea here is that because small cell is obligate Rb-null, the cancer cells won't be protected in that fashion. And that mechanism is designed to protect all of the myeloid lines, not just the neutrophils. There's data from the erythropoietin-stimulating agent (ESA) era and here I'm violating UNC religion and quoting data that came from a Dukie, but from the ESA era, we know what common sense perhaps should have taught us without needing a study — that people feel better when their hemoglobin is higher, and that's mostly driven by fatigue.

Now, every oncologist knows that fatigue is the side effect of chemo that we suck the most at addressing, right? If your neutrophils are low, I can give you Neupogen or Neulasta. If you're nauseous, I can give you Zofran or aprepitant or what have you. Fatigue, we really don't do very well at. There's some data out there that exercise can help, but to me it grossly violates common sense to tell someone who's exhausted, "Go ahead and get on the treadmill." I do tell patients to do it the best they can. I do work on hydration, I do work on diet and nutrition, but all of these things have limited impact. This is really the first thing in a very long time that we've added to our arsenal that actually works to help with the thing that patients are complaining the most about and that we're not very good at helping with.

I've actually been very surprised by the skeptical and limited embrace of an agent that makes people feel better. I've always thought this is like Zofran. Maybe you don't want to talk about it that much, but you just give it to every patient. They feel better, you hear from them less, your nurse hears from them less, everyone wins. It's, to me, a little bit odd, as in the way vaccines have become controversial. Somehow a supportive care agent has become controversial. And I've got to say, I just don't get it.

Sands: I think that's fair. I think we are very focused on outcomes and those outcomes are largely progression-free survival, overall survival-type outcomes. But as you highlight, anemia is probably an area for us to really pay a lot more attention to and, in some cases, the thrombocytopenia. I've had patients with prolonged thrombocytopenia where I had to delay doses, and particularly in patients that are already on blood thinners for previous DVT [deep vein thrombosis] or something like that or on Plavix. It's very clinically meaningful to have control of that and not have the same kind of thrombocytopenia. And so that's a compelling trial. I encourage listeners to reach out to you as far as that study or about sending patients lurbinectedin with an agent that's going to help patients hopefully stay on track a bit more, has the potential to really improve outcomes in that setting as well. Now we've really laid the groundwork for a next-level discussion.

In the clinical trial setting, there are also things being added to first line therapy. There's lurbinectedin being added to maintenance immunotherapy in the first-line setting. There are, of course, other studies as well. Now for these various trials we've mentioned, there are patients that already have long, durable responses to therapy, and might not need another therapy, although that is unfortunately a small group of patients.

So there is a lot of room for improvement in that first-line setting. What do you see going forward as far as what to potentially combine into that setting? And I'll throw in biomarkers in the second line and beyond too, where I think there's more obvious potential.

Weiss: So if you're looking for editorialization of what I think is most promising in the add-ons, I would reflect that adding on extra chemo out back has never worked. I'm a little skeptical that a slightly better drug is going to make it work. I am much more excited about doing things that are genuinely new and different in that maintenance setting. My institution has voted with our feet. I have no role whatsoever in its development, but I'm really excited about a drug called tarlatamab (AMG 757), and we voted with our feet to introduce that in the front line. Drugs like atezolizumab and durvalumab are off-the-shelf immune therapies. You hope that there's some kind of T-cell response, that you can expand that clonality and overcome exhaustion and improve clonality and result in response. But you're really amplifying an existing response.

In contrast, tarlatamab is the first of what I would call a more personalized immunotherapy, where you're actioning a neoantigen known to be present on tumors. So this agent is something called a BiTE, which, beyond being a really cool name, stands for bispecific T-cell engager. So one side of the antibody is CD3, which will bind your T cell, and the other side is the neoantigen DLL3, so that you bring the T cell and the tumor cell, which is DLL3-positive, together so the T cell can attack it. We have some late late-line data that was just updated at the World Conference on Lung Cancer. I think the last time that the response rate is creeping up, which is what phase 1 studies do as a greater proportion of patients are treated at dose. And I find that exciting both for itself — I think tarlatamab is an exciting agent — and also for this broader idea that we can action preserve neoantigens in small cell with some approach (be it a BiTE or a CAR [chimeric antigen receptor] or a TCR [T-cell receptor] or what have you), the idea that this is going to get us past incremental gains into our next big jump, I find very, very exciting.

Sands: I agree. This is an exciting class of drugs that are bispecific and trispecific. They all seem to bind DLL3 but then in some cases CD3 and albumin and trispecifics.

Weiss: We have here a GD2 CAR, I'm sure others have other CARs they're looking at. There are other targets than DLL3.

Sands: You're talking about a CAR or you're talking about…

Weiss: I'm talking about personalized immunotherapy in general. So, DLL3, we started with an antibody-drug conjugate. That did not go very well, but the BiTE experience is going better. And so I think that there are many ways to action a target depending on whether it's in the immunopeptidome or in the surfaceome. CAR is another category that does that for surfaceome targets. And what's nice there is that you bypass the need for HLA on tumor. We know that over time, tumors lose HLA, tumors lose beta-2 microglobulin, other elements of the antigen presentation machinery. And when you have an antibody-based mechanism, whether it's a BiTE or a CAR, you can overcome that.

Sands: The CARs I find particularly exciting and that's probably further down the line. Tarlatamab, in that class of bispecifics/trispecifics, is a very exciting next step that is really already happening, I agree. I think that we see more of those homerun-type scenarios with those really durable responses, patients doing exceptionally well. And the exciting thing about tarlatamab is that we see patients who have previously gotten therapy already that now at progression are having really durable responses. And when you're talking about second or third line having durable responses, that is even more impressive than right in the first-line setting. And so now incorporating that in the first line, of course, there's data [from] second or third line and now ongoing trial in the first-line setting. This is an exciting class.

Now briefly then, if we look at the subtyping of small cell lung cancer that has been proposed, of course, this is Dr Charlie Rudin, and Drs Lauren Byers and Carl Gay have proposed different subtypes that really have quite a bit of overlap to them. Within the inflamed subtype, we tend to see a higher percentage of patients in the first-line setting that have immune responses, although we see immune responses in all four of the subtypes. So right now, I don't think that that subtyping necessarily would change anyone's management in the first-line setting by our current standard of care. But do you see a place for that subtyping and how that might influence future decisions of first-line therapy? And of course, I mean, we'll just say that there are various proposals of a second line and beyond where that could be clinically meaningful right now. But let's focus on the first line.

Weiss: What I find most exciting about this subtyping is that it shows us four types of small cell lung cancer that have very discrete biologic themes. The biology of what's going on in each of these cancer types is rather different. And so while it may have absolutely no applicability to the next patient who comes into the office for standard of care, it's entirely possible that, as we develop new therapeutics, they're going to be uniquely active in one or more of the subtypes and not in others. I consider this kind of subtyping absolutely mandatory for any small cell lung cancer study. And I consider it exciting for understanding which patients are going to benefit more from our existing therapeutics.

Sands: Well, I could go on and on. I feel like we could talk for more than another hour. There is so much to discuss. It is an exciting time academically and it's wonderful that we're starting to be able to offer improved outcomes for our patients with small cell lung cancer. It's a lot of fun to be able to talk with you, Dr Weiss, about this today. To our listeners, thank you for tuning in. If you haven't done so already, take a moment to download the Medscape Mobile App to listen and subscribe to this podcast series on lung cancer. This is Dr Jacob Sands for InDiscussion.

Listen to additional seasons of this podcast.


Immunotherapy and Lung Cancer Treatment

Small Cell Lung Cancer (SCLC)

FDA Grants Accelerated Approval to Lurbinectedin for Metastatic Small Cell Lung Cancer

Lurbinectedin as Second-Line Treatment for Patients With Small-Cell Lung Cancer: A Single-Arm, Open-Label, Phase 2 Basket Trial

Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Cancer

Study of Trilaciclib and Lurbinectidin

PL02.03 Lurbinectedin/Doxorubicin Versus CAV or Topotecan in Relapsed SCLC Patients: Phase III Randomized ATLANTIS Trial

Erythropoiesis-Stimulating Agents in Oncology: A Study-Level Meta-Analysis of Survival and Other Safety Outcomes

First-Line Tarlatamab in Combination With Carboplatin, Etoposide, and PD-L1 Inhibitor in Subjects With Extensive Stage Small Cell Lung Cancer (ES-SCLC)

Bispecific T-Cell Engager (BiTE) Antibodies

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