Introduction: Overview of Bispecific Antibodies

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice and welcome back to “Understanding the Current Paradigm and New Approaches in the Care of Patients with Cancer.” This morning we're going to focus on a really exciting development in oncology in general, specifically in small cell lung cancer: the use of bispecific T-cell engagers.

We have a great faculty today, nurse practitioners Ms Liz Krueger and Ms Beth Sandy, and physicians Dr Anne Chiang and Dr Erin Schenk. And as in all of these programs we're doing — this is the 6^th set of 11 programs we're doing here at the ONS meeting. And in all of these programs we will be talking about the use of unapproved agents and regimens so please consult the official prescribing information for all of the products that we talk about today.

Check out our podcast Oncology Nursing Update. Just take your phone, go to podcasts, hit search, Oncology Nursing Update. We already have a couple of programs there for you to check out. One of them on bispecifics actually, in lymphoma, which we'll be talking about Saturday night as well. And all of these programs, all 11 of the programs we're doing here, we're going to be posting on that podcast feed.

Again, here are the topics we're covering this week, but we try to go beyond the topics and get into themes in medical oncology and particularly in clinical research. We're trying to talk a little bit about the strategy of clinical decision-making and management that a medical oncologist thinks about and hopefully allow you to better understand what's going on and help explain it to your patients. We're really here to make rounds. We have a fantastic faculty. We have 44 faculty members joining us here this week. It's really great to be able to just chat with them and pick their brains. That's why we're really here today.

Alright. So let's sort of jump right into this topic here today. It's great to be able to really focus down and get into more nitty-gritty and cases. Here's where we're heading today. We've asked the nurse practitioners to present cases from their practices and the physicians will go through some of the clinical research data. We'll talk about the biology of small cell cancer and clinical presentation. Then we'll get into tarlatamab, which is a bispecific antibody that's now approved in small cell lung cancer. We'll talk a little bit about where things are heading in general in the management of this challenging cancer.

But I want to just kind of start out and talk a little bit about what a bispecific is. And again, this is relevant. A lot of these CD3 bispecifics are being used now in myeloma and lymphoma, as we'll talk about. But I think this is the first one, Anne, that actually is in a solid tumor. Can you talk a little bit about your vision about what a bispecific is, the components of it, Anne?

DR CHIANG: Sure. The way that I think about it is, there's 2 heads on the antibody. One recognizes a protein on the surface of the tumor cell, and the other recognizes a protein on the surface of the T cell. So you're really physically bringing the immune system over to the tumor cell. And that's really important, for example, in small cell. It's a tumor that's kind of a cold tumor and if you look at tissue sections there are really not a lot of infiltrating lymphocytes there. So this way, you can bring the immune system, induce T-cell proliferation activation and cell death.

DR LOVE: I'm curious, Beth, how you explain it to patients? Recently I heard somebody talk about Lady and the Tramp, the scene where they share the spaghetti.

MS SANDY: Oh, I love that.

DR LOVE: I thought that was pretty good. How do you explain to a patient what a bispecific is?

MS SANDY: Yeah, I mean, I don't get to that level and start talking about the Y-shaped antibody and everything. But what I'll say to the patient is that this antibody is going to help bring your immune system, get that activated so that it can kill your cancer. So it's going to work that way as opposed to how chemotherapy may go in and kind of do a search-and-destroy mission for a lot of different things.

DR LOVE: So as I mentioned, bispecifics are being used, different types of bispecifics. These are the so-called CD3 bispecifics specifically trying to engage T cell. We see this being used in acute lymphocytic leukemia. Also as I mentioned in multiple myeloma, 2 different targets that they have on these bispecifics both approved now in myeloma, being used pretty frequently. Also in lymphoma, as I said we're going to talk about this Saturday night, we have several bispecifics now approved and several others in development. And I guess these are now offering a very similar kind of a strategy in a way, the T-cell base to CAR-T therapy, which we were talking a little bit about last night in our CLL session.

There are also other types of bispecifics that are being used in solid tumors. You see tarlatamab there and there's another one there for uveal melanoma, tebentafusp, that are again these CD3 T-cell engagers. But also in lung cancer, this is non-small cell lung cancer, we have amivantamab, Erin, and this is not immune. It hits 2 parts, EGFR and the c-MET. And you see a different spectrum of side effects. This is used in EGFR mutant disease, which again we talked about a couple of days ago. Erin, any comments about what you see with tolerability and side effects with this antibody that targets 2 parts, 2 different targets?

DR SCHENK: Yeah, absolutely. We give this pretty regularly in practice and there's a lot of challenges with both the EGFR side effects particularly the skin dermatologic toxicity. And you can also see some side effects with the MET portion of amivantamab as well, some of the swelling and edema that happens with inhibiting MET. So it's a challenging therapy to give. Not only because of the side-effect profile long term, but more immediate as well with the infusion-related reactions.

DR LOVE: So it's really amazing what's going on in oncology today. Now we spend, we've done programs just on biliary tract cancer, which we never used to talk about. And they have kind of a similar strategy with a bispecific hitting 2 parts of the HER2. On Wednesday, we were talking about T-DXd, which is used in many cancers including non-small cell lung cancer targeting HER2. But in biliary tract cancer, and probably going to be coming into other cancers, we have zanidatamab, which is a really exciting new bispecific targeting 2 parts of the HER2 molecule. So, I guess, Liz, one of the key issues here for these CD3 agents, bispecifics, like tarlatamab, is cytokine release syndrome. Again, we talked a little bit about this last night when we were talking about CAR-T therapy. When I first heard about tarlatamab in small cell I'm like, wow, interesting thought trying to — I imagine a sick patient, a smoker, cardiovascular and things you don't typically see in myeloma and lymphoma, I'm like, I wonder how that's going to work out? But can you talk a little bit, Liz, about how you visualize cytokine release syndrome?

MS KRUEGER: Sure. So this is an example of an educational slide we provide our patients with. We talk to them about the CRS symptoms being worse at the beginning, typically with treatment number 1 and treatment number 2. And those consist of potential for fever, low blood pressure, tiredness, shortness of breath and hemodynamic instability. And because of those reasons, we admit them to the hospital on cycle 1, day 1 and cycle 1, day 8 for monitoring. We found that some of the CRS symptoms can typically occur about 13 or so hours after administration of the drug. So it doesn't happen right away, it happens many hours later. So that's something that we like to prepare the patients for as well.

DR LOVE: And this will come out more. Again, it's really great to have the opportunity to spend a little — we've been rushing through so many things here this week, I feel like I'm short of breath just listening to all this stuff. But we're going to be able to present 4 cases today and really hopefully get into a little more granularity about how things play out with this interesting agent. Erin, can you discuss a little bit about sort of the pathophysiology of cytokine release syndrome, like what's going on?

DR SCHENK: Sure. Some of the information that we have what we think is happening is just the immediate activation of the immune system releases a number of cytokines that really stimulate a larger response within the body. So as my colleagues describe — the way I like to describe it is that the bispecific is 2 sticky ends and sometimes when it first goes into the patient, it's really pulling in those immune cells and activating the immune system. Some of the pathophysiology we think is around IL6 release and that's one of the things that we give an anti-IL6 antibody, tocilizumab, to help reduce the symptoms of cytokine release syndrome.

DR LOVE: So, Anne, can you talk a little bit about what tocilizumab is? How it works? When you use that? When you use steroids for cytokine release? And sort of the spectrum of what you see? These people can end up in the ICU with hypertension, et cetera.

DR CHIANG: Sure. So if you have Grade 1 or 2 CRS and you're looking for fever plus or minus hypotension or you can have hypoxia. That typically you're using supportive care, so acetaminophen, IV fluids, oxygen. If you get to Grade 3 and you really need vasopressor support or if you need — usually for Grade 2 you may also consider using steroids. So that's sort of supportive care, then steroids. Then if you get to Grade 3, that's when you usually use the tocilizumab. That's the IL6 directing, preventing the IL6 from being expressed or the actions of that. So that's sort of the level. Supportive care, then steroids, then tocilizumab. And all of these can be managed pretty well.

DR LOVE: So Erin, what about neurologic issues that come from, you know, again, in T-cell based therapy in CAR-T we see so-called ICANS that can have a variety of manifestations. We hear a lot less about that with bispecifics. I don't know if you actually can see that. Do you see neurologic issues?

DR SCHENK: I have had a patient who developed ICANS long-term on a DLL3 T-cell engager on a clinical trial. What was interesting in this case is that we think of CRS as the major neurologic toxicity and, of course, it is especially if not intervened upon and treated. But there can also be ICANS that can happen later on in the course. So CRS is really a more early phase, immediate term side effect. But what the patient started experiencing was having trouble with some word finding over time and then some confusion. And she was able to come back to her neurologic baseline with steroid therapy.

DR LOVE: And Beth, you know, again in CAR-T, they want these patients to have a family member or friend available to pick up slight changes that might occur. I'm curious whether you've ever seen any neurologic issues. Also how the issue of comorbidities ties in here. Again when I think about small cell I think about a heavy smoker, chronic obstructive lung disease, cardiovascular disease. How does that play out when you're using a therapy like this?

MS SANDY: Yeah, for sure. So we're going to get into that in a couple of my case studies, but I worry sometimes about the ability to detect ICANS in our patients with small cell because many of them have brain mets, have been treated for brain mets. So there's underlying cognitive difficulties there as it starts. And I always say, you know, luckily in the clinical trials with tarlatamab, it's been a little bit less than what they necessarily see in CAR T therapy and things like that but nonetheless it occurs. And our ability to detect it may be a bit hampered by the comorbid conditions we typically see in patients with small cell.

DR LOVE: So, Anne, we're going to take a step back and talk a little bit about small cell in general and then we'll sort of get into where tarlatamab fits in. But before we do, Erin, I was just sort of flashing on the fact I hear things here and there about CAR T in solid tumors and nothing's really approved at this point. Do you see CAR T coming into lung cancer at any point?

DR SCHENK: There may be a role for DLL3 CAR T therapy. Those are being investigated in clinical trials. There's also mesothelin CARs, not non-small cell lung cancer but in mesothelioma, being developed as well.

DR LOVE: Of course some of the results we've seen with CAR T therapy, particularly diffuse large B-cell lymphoma, were these people who previously really are end-stage disease, some of them are cured. Not a small number. And we're hoping maybe this will end up in solid tumors as well, but let's see what happens.

Biology of Small-Cell Lung Cancer (SCLC) and Review of Its Initial Management

DR LOVE: Alright, Anne, let's take a step back and talk a little bit about small cell cancer, the biology and how it presents.

DR CHIANG: Sounds good. Okay. So let's start with the incidence and risk factors. Small cell is about 14% of lung cancer, the rest is non-small cell. There are around 250,000 new cases and 200,000 deaths globally each year. And in the US, that's about 16,000 new cases last year. The median age at diagnosis in the US is 69 years. It's pretty balanced between male and female. The big risk factor, of course, is smoking. 95% of patients have history of tobacco use. And I always counsel my patients around tobacco cessation because that can improve their lung function and their prognosis. There's around 2.5 to 13% of patients who are never smokers. They sometimes have a better prognosis. And then rarely we have non-small cell patients with driver mutations like EGFR that undergo histologic transformation to small cell as a mechanism of resistance.

The characteristics. This is a rapidly growing tumor. You have early development of widespread metastases and it's exquisitely sensitive to radiation and chemo. That picture is a picture of an H&E slide that shows small cell. There are small blue cells, very sparce cytoplasm. There's some nuclear molding. And 75% are IHC positive for one of those neuroendocrine markers. In the 25 that aren't, we now have other ways to subtype them including IHC markers for POU2F3.

So staging in small cell is functional. So we have limited versus extensive. Limited stage about 30% of the patients. It includes Stage 1 through 3 in the TNM staging system. And this means that you can treat everything within 1 radiation field. So that typically includes everything within 1 hemothorax and then lymph nodes you can now get include contralateral and sometimes supraclavicular. For extensive stage, that's 70% of our patients, they already have distant metastatic disease such as in the brain, liver, adrenals, bones. This can also include malignant pleural effusion and pleural disease. So the prognosis. If you're limited and you can include radiation in your treatment with systemic treatment, now actually that's improved to almost 5 years. And I'm going to show you the data for that. The 3-year overall survival with this ADRIATIC trial is 56% of our patients. In extensive stage, unfortunately the median overall survival is still just a little bit over a year; however, again because of immunotherapy advances, we do have some patients that make it out further. The 3-year overall survival in the CASPIAN trial is 18%.

So we are in the current era of immunotherapy even for small cell. I'm going to talk about these 3 trials. I'm going to start with the ADRIATIC trial for limited stage. So this trial was for patients with Stage 1 through 3 limited stage and they had already finished the concurrent chemoradiation. And they had to have had stable disease or a response. Then they were randomized to either durvalumab for 2 years, placebo or durva and treme. I'm not going to talk about that arm. Those results aren't back yet.

So the primary endpoint is overall survival. And this is the Kaplan-Meier curve. And what you're looking for here is a big separation between the blue curve, that's durvalumab, and the red curve, which is placebo. And you definitely have a separation there. The hazard ratio is 7.73. What I really tell my patients is that this improves — if you do durvalumab consolidation for 2 years after concurrent chemoradiation, it's going to improve your survival for almost 2 years. So these patients are median overall survival 56 versus 33 months.

So the PFS, progression-free survival, is also better by 7 months. And so because this study met these dual primary endpoints, this is now the new standard of care and has been approved by the FDA. This is what we're doing with our patients.

So moving to extensive stage. This is my patient, 65-year-old African American woman. She presented right before COVID with shortness of breath. There's her PET scan. A very large right lower lobe mass. Now she had axillary lymph nodes that were involved so she couldn't get radiation. So she's extensive disease. And her treatment options are systemic. So the IMpower133 trial, that's carbo/etoposide/atezolizumab x 4 cycles followed by maintenance atezolizumab until progression or toxicities. And then the CASPIAN trial does the same thing but uses durvalumab or cisplatin. Now some of these patients are sick and they present in the hospital and they can be treated with chemo.

This is the IMpower133 trial. It showed a benefit of 2 months. Very similar is the CASPIAN, again 2 months, which you think, well, we wish it could be more. But what's really important is that some of these patients actually do have a long-term effect and in this case it's the difference. We tripled the survival at 3 years between 6 with placebo and 18% with atezolizumab. And so my patient, actually going back to her, she was on maintenance atezo for 3 years. She stopped because she got COVID infection and now she's been 2 years off of therapy with no evidence of disease. So that's really what we like to, that benefit we'd like to get it to more patients. How do we do that? We really have to understand the biology and how small cell is different. There are different subtypes and then we can target some of those different subtypes with additional agents in the first line or metastatic setting and, of course, we have to improve our support of our patients through the journey. That’s it.

DR LOVE: So I'm curious, and really an amazing case. I don't know that that's typical to see that kind of response. I mean, do you see cure in small cell in limited stage, for example? Do you see people who are cured or even extensive stage? And is surgery ever used, Anne?

DR CHIANG: Yes. So the aim of treatment in limited stage is cure. So we don't see that in all the patients but long-term survival past 5 years we're thinking about 20, 25% of the patients. Your point about surgery is really key. So if they have node-negative disease, so just a spot in the lung that you can remove surgically, we do that. We have to sample the lymph nodes first to make sure there's no disease. But those patients actually do extremely well too. And I think they're cured.

DR LOVE: I was just flashing. I was like this is the first time we've ever done a program just on small cell at ONS. And when you think about it, you said 16,000 cases, that's very similar to the incidence of CLL that we talk about all the time, myeloma. So small subsets of extremely common cancers are important to consider. It's really interesting too that this tumor is so responsive to chemotherapy and yet these patients typically relapse.

We're going to go on and talk in a second about a case that Liz has from Mass General. But just one other point, Beth. We mentioned the issue of tobacco in particular, of course, the issue in general with non-small cell as well but really a big issue here. Do you attempt to try to get patients to stop smoking? And what kind of strategies have you found useful?

MS SANDY: We do. Quitting smoking not only is helpful for lung cancer but also just for all other comorbid conditions. If you think about it, I mean, they probably have underlying COPD and cardiovascular disease because they've smoked for a long time and typically the small cell patients have smoked a lot. Like these are often your 2-pack-a-day smokers. So if they can quit smoking a lot of times at least their comorbid conditions can calm down a little bit, which eases our ability to treat them. Now our strategies for that? It's hard. We love the varenicline, that's the newer oral tablet. I say newer, it's probably been around for 10, 15 years now. And we have a smoking cessation clinic that's run out of pulmonary at our institution, which uses drug therapy as well as behavioral therapy as well to try to help them quit. We refer them. Whether they continue with the clinic is up to the patient.

DR LOVE: Do you see regret expressed by patients and families? Does that come up or people just sort of usually move on?

MS SANDY: I think less so from families. I still think with patients, I mean, typically 2 out of 3 patients with small cell are male. And I think when they experience regret that they're going to like leave their families early. I do see that sometimes because small cell is still a very aggressive disease and the majority of patients are going to die from the illness. That being said, I think for me, we are there to focus on how we can help them improve their outcomes and we try to keep a positive attitude about that.

DR LOVE: This is again a thematic issue in cancer in general to try to deal with that when people are newly diagnosed, smoking or whatever other potential issues are.

Case: 63-year-old man — Ms Krueger

DR LOVE: So Liz, I'm going to ask you to talk a little bit about some of the things you think about, particularly as it relates to small cell and tarlatamab. But just to sort of dip our toe in the water so to speak, tell us a little bit about this 63-year-old man. What happened with him? How did he present?

MS KRUEGER: Sure. So this patient is a 63-year-old man, former smoker, diagnosed with extensive stage disease in January of 2022. He presented to a local emergency room with difficulty speaking and status post falls.

DR LOVE: What was his life situation? Did he have family? Was he working?

MS KRUEGER: So, yes, he worked in accounting, well educated but lived alone. He had family but he kept them at a distance. His sister, he allowed her to come to certain important visits like scan reviews or changes in treatment planning but otherwise he preferred to manage things himself. He was often very — he was anxious and suspicious. So it made sometimes going through the treatment planning a bit difficult.

DR LOVE: How long ago had he quit smoking?

MS KRUEGER: He had quit smoking, I believe, like 5 years prior to diagnosis.

DR LOVE: Interesting. So I see he got the common first-line treatment for extensive disease.

MS KRUEGER: He did.

DR LOVE: And I assume he got radiation to the brain as well.

MS KRUEGER: He did. He started — that was the first thing that was done. He had whole brain.

DR LOVE: When you see the use of immunotherapy as part of first-line therapy you don't see what you see in some of the high PD-1 patients with non-small cell who maybe are cured. As you saw the curves there, there was a benefit but maybe not quite as much as what you see in non-small cell lung cancer. He got that treatment. How did he do? Any IO immune issues?

MS KRUEGER: So he did fairly well. He had standard chemotherapy, side effects of nausea, fatigue, appetite changes. But he did experience skin toxicity that was immune related that consisted of itchy skin, rash and then he had lichenoid plaques that required him to take hydroxyzine TID, which ultimately we worried was impacting his mentation and level of alertness.

DR LOVE: Beth, we hear a lot about skin changes with IOs. It seems like a lot of the patients have at least a little bit. What do you typically see?

MS SANDY: I mean, in lung cancer we don't typically see the severe rashes that maybe they see more commonly in melanoma especially with dual checkpoint inhibitor therapy. I think in lung cancer typically we're seeing the more mild rashes, pruritis, maybe a little bit of like flares of eczema things like that. But I haven't seen a lot of really bad significant rashes.

DR LOVE: So I see here in November actually he had progression, not too surprising. It typically happens. It seems like pretty quick here. Now he's got liver mets and he gets started on this bispecific that we talked about, tarlatamab. Anything you want to say about him as a person? You mentioned he's an accountant and that he's single. Anything else you want to say about what the flavor was of treating him compared to other patients with small cell?

MS KRUEGER: Sure. He is a bit challenging with each encounter. And so we tried from a starting point to keep him seeing the same doctor and nurse practitioner to keep a level of consistency in his care. Additionally, we considered his supports and encouraged him to involve his sister especially as we planned to admit him to the hospital in the need to monitor patients following the infusion at home.

DR LOVE: So let's talk just briefly and again we have 4 patients who got this therapy. We'll be able to compare how they did. So I guess this is just in December that he got started on tarlatamab. Can you kind of summarize what happened when he got treated?

MS KRUEGER: Sure. So cycle 1 day 1 he received the initial step-up dose, which is 1 mg. That's given in our infusion room and then patients are transferred to the hospital for observation. He did well with the treatment overall. He had mild nausea, diarrhea and some fatigue. With cycle 1 day 8, he did well during the treatment, but then upon returning home, he had a fall, which was reported several days later. So when he came back in for day 15 dosing, he was still unsteady on his feet. We were trying to assess his mental status, which was difficult in the setting of having had whole brain radiation and then multiple medications that he was taking that could impact his cognition. Because of his falls, we held the day 15 dose and brought him back to clinic the following week for consideration of more treatment.

DR LOVE: So he actually had a response?

MS KRUEGER: He did ultimately have a response, which was a little bit difficult for us to tease out because he did have some weight loss. He did have increased pain that we weren't sure. Was this malignant pain or was this an exacerbation of his underlying arthritis in the setting of receiving tarlatamab?

DR LOVE: Interesting. And what's his current situation?

MS KRUEGER: And so now he is — so we did a spine MRI that showed degenerative changes because we were working up this increased pain. It does not show any metastatic disease, but he continues to fall and most recently fell in early April with head strike and went to a local emergency room. So we're now at a point of trying to figure out, is this some neurotoxicity or are these side effects related to whole brain or other medications that he is taking? So our next step is to refer him to neuro for a more comprehensive neurologic workup.

DR LOVE: I'm kind of curious, you know, palliative care being introduced in oncology in general really came out of lung cancer at your institution, Mass General, Dr Jennifer Temel, showing that actually people who got early palliative care live longer with lung cancer. Has he gotten tied into palliative care or do you see that coming in the near future?

MS KRUEGER: So I think he certainly needs it, but he's been resistant to that.

DR LOVE: Really? So you wanted to recommend it, but he didn't want to do it?

MS KRUEGER: Yeah, so we typically recommend it early on for any of our metastatic patients whether it's to develop a relationship with the team, for symptom management or just psychosocial support.

DR LOVE: So Beth, what about at Penn? Do you use early palliative care?

MS SANDY: So we do. Our situation has been a little different because we don't have the ability to handle the volume, basically. I mean, so they really try to incorporate palliative care within our primary oncology team and then we're referring our more difficult symptom-management patients to them. But it's just not a reasonable thing to be able to refer all of our patients to early palliative care. They would be so overloaded with patients.

DR LOVE: So this is great summary of some of the issues. And again you have all the slides, you can read them, we're not going to go through every little tiny point on it. But I'm curious about some of the comments you made down here at the bottom. Operational, he prefers written communication in the EMR. That's interesting. Anything else you want to say about him and what makes it different taking care of him?

MS KRUEGER: I think the written communication piece was really important actually for providers too so everybody knew exactly what we were telling him and that there was no confusion about this person said that about my pain medications. And so ultimately having things in writing is best for him and best for the team too. Another important piece is that he lives really far away, or 2 hours, I mean, certainly others travel further. But having to come into the hospital and be monitored for a 24-hour period of time, 2 weeks in a row and then having to transition to outpatient monitoring, which can be very extensive and long. So for the first 2 cycles the observation period is between 6 and 8 hours on top of the infusion itself and then whatever clinic visit you have plus labs. So those days are very long. It takes a toll on patients. They often struggle about their time, which is limited. So that can be a tricky piece.

DR LOVE: I see also you sent visiting nurse services but yet he sort of resisted it. He sounds like a challenging person to take care of.

MS KRUEGER: He is. Despite our best efforts and recommendations, he makes his own decision, which we have been working with.

DR LOVE: So anything you want to say about some of the side-effect management issues that came up in him and come up in general in these patients?

MS KRUEGER: Yeah, so some of this is general and applies to chemotherapy as well. We make sure that all the patients have a bowel regimen, they have antiemetics on hand. We encourage them to push fluids but being mindful of fluid intake with small cell lung cancer. They can often develop SIADH and hyponatremia. So that's a caveat to that recommendation. Nutrition consults. Often patients develop taste changes on the drug so using plastic utensils and ginger for nausea can be helpful. Eating candies for dry mouth. Ibuprofen and acetaminophen as needed. However, we are very clear that patients need to tell us and call us with any fever because that could be CRS that occurs at home and just in a delayed way. So we make sure that they have our phone number, the lines of communication are open and we want to make sure that patients don't hesitate or their families hesitate to report any symptoms.

DR LOVE: It's interesting that you list fertility and sexuality counseling. We talked a lot about that already in our breast cancer session as well as yesterday in prostate cancer. A huge issue. Interesting that you bring this up in this scenario.

MS KRUEGER: Yeah, for women, I mean, small cell is not super common in women at younger ages, but it does happen. So we make sure that our patients know to use contraception throughout the course of treatment and then for 2 months following.

Current Role of Tarlatamab in Therapy for SCLC

DR LOVE: Alright, well, let's sort of more further into it. Now we've kind of been exposed to the issue of small cell in general, now tarlatamab. And we're going to ask Anne to talk a little bit more now specifically about tarlatamab in relapsed disease, which is, of course, where this man was treated.

DR CHIANG: Great. So we already talked about that this is a bispecific. In this case it recognizes DLL3 protein on the surface of the tumor cell. Again, brings the immune system over to the tumor and really activates the T cells and tumor cell lysis.

This is the DeLLphi-301 trial that led to the FDA approval for this drug. It was a study that had patients on 2 doses, the 10 mg dose and the 100 mg dose. I'm going to focus on the 10 because that was ultimately what was chosen for FDA approval. This is the baseline characteristics. I just want to point out that a third of these patients were heavily pretreated, so had 3 or greater lines of therapy, 73% had prior immunotherapy. So these are patients that have been treated with chemo and IO. Also noting that 23 of these patients had brain mets but they were all treated. You had to have treated brain mets before you could enroll into the study.

So the bottom line here is that 40% overall response rate. So that's terrific for this heavily pretreated population. If you add the stable disease there, then that means that your disease control rate is 70%. So that's terrific for these patients. The observed duration of response greater than or equal to 6 months was over 60 patients, 60% of the patients. So this was approved by the FDA in May. We started treating patients and then we, you know, are learning about this drug. So we talked a lot about CRS. Grade 1/2 seen in about 60% of the patients. So you really have to educate them around this. Grade 3 CRS, 3%.

And if you look here to the right, you can see that most of the side effects occur right after the first or the second dose, so week 1 or week 2. And then much lower over there. And that's why most centers actually admit the patients after those 2, in the first 2 weeks after administration for an observation stay. We really encourage our patients to be within 1 hour of a hospital for subsequent doses although it's not always possible. And you really need reliable patients and caregivers.

We talked a little bit about ICANS. So you can have confusion, cognitive deficit, or overall weakness. And that can happen anytime throughout. It was pretty low, Grade 1/2 seen in 12% of the patients and no Grade 3 seen. Other side effects, loss of taste, dysgeusia, decreased appetite, nausea, neutropenia. Again, managed by supportive care, tocilizumab or supportive care steroids, tocilizumab, oxygen vasopressor support. ICANS is managed with steroids and we always get our neurologic colleagues involved.

Looking forward, this is a cohort of 30 patients who were monitored outpatient. So in this study, all of the patients needed to be monitored in the hospital 48 hours except for this cohort. We presented it at ESMO IO, and now we published it. These patients did pretty well. Actually if you look at the green versus the blue bars, blue is the 48-hour inpatient stay, the Grade 1/Grade 2, Grade 3 is actually a little bit less, are pretty similar. So this is definitely possible to do it outpatient. There are centers that are doing this within the US and we're working on it as well.

So tarlatamab has really changed the landscape for relapsed small cell. It was approved for the second-line use and beyond. And I think on the right, that's the orange slide, that's what we're doing now. So second line we're really looking at tarlatamab and lurbinectedin and really the idea of platinum rechallenge has gone away.

So a few words about lurbinectedin. That's the other agent that we use in the second-line. This is chemotherapy. It binds to the minor groove DNA. It inhibits RNA transcription and it causes DNA damage that leads to cell death. This is the trial that led to FDA approval. It was 105 patients with relapsed small cell. The overall response rate was 35% and so this led to accelerated FDA approval. The Phase III confirmatory trial is ongoing.

So how do you balance those factors for your patients between tarlatamab or lurbinectedin? In my mind, if the patient has chemo-resistant disease, so they had a shorter platinum-free interval, that's something where I'm really going to go for tarlatamab. I'm also looking at patients that are more robust. They have a better performance status. They're reliable. They have a caregiver that lives with them that can say, they're not thinking right, they're not talking right today and calling in. Again, if they live close by that's going to be a lot easier if they have transportation. For lurbinectedin, I'm looking at, for my patients that are older, more frail, if they live alone, they have problems with transportation, this is an easy q3week IV treatment. So it's easier than what they had in first-line because it's only 1 day instead of 3 days every 3 weeks. Again, these patients, if they're responding to chemo before, this is something that they can definitely respond to and for us we always put in a central line for them.

I'm going to skip the cases because we're talking more about the case and I'll just end with the key points. I think that tarlatamab is really an exciting option to target the small cell immune desert or these cold tumors. Some of these patients overall survival 9, 10 months. That's much better than what we've seen in the past. The side effects can be managed. They're a little scary but patients, and we'll hear more about them, they've had CRS but they continue to do well. Lurbinectedin is a great tool and Erin's going to talk about other antibody-drug conjugates. I show this picture of the different cookies because we sometimes think small cell is just one size fits all, it's all the same monolithic blue cells, but now we're really understanding more about the biology that they are subtypes that you can target as well.

DR LOVE: I was trying to figure out what those cookies meant. I like it. Cool.

DR CHIANG: I've got to add food.

DR LOVE: Erin, I was just flashing on a few years ago we were presenting at a meeting for general medical oncologists and we were talking about HMA venetoclax for AML, acute myeloid — and everybody in the audience was like, we're not going to give that. And now they give it all the time. Same thing seems to be happening with bispecifics and again myeloma, lymphoma. It starts out in the community and then sort of gingerly they start thinking about moving it into community-based practice. Do you see tarlatamab at some point being initiated in a community-based setting?

DR SCHENK: I absolutely hope so. In terms of just using this agent in standard of care along with some clinical trial agents, this is a new hope for these patients. And especially, I want to highlight something that Anne brought up and mentioned in the clinical trial for tarlatamab is that these patients who have chemo, you know, platinum-resistant disease, which we classically think of as like a really aggressive bad actor, these patients don't have much in terms of survival, tarlatamab and other agents are inducing a long durable response in these patients. And that's really remarkable in terms of kind of what we now have to offer patients. So I hope that we are able to offer it to everyone who needs it whether in an academic center or the community.

DR LOVE: Another theme that we've been talking about this week is indirect comparison between different agents that haven't been compared in a trial. That happens all the time in oncology, which is challenging to do. And one of the things that's kind of, like you see lurbi having a response rate on paper that looks similar to tarlatamab. But when you actually see these patients, the duration of response, the quality of response, any difference? Do you think the responses are better with tarlatamab than lurbi? Anne, you want to comment?

DR CHIANG: Yeah. I think that for lurbinectedin the duration of response really somewhere around 5, 6 months and for tarlatamab it's much longer. It's — and we're learning more. It's getting longer as we speak. I do think that this will be able to be used in the community. I think that it's going to be a lot of education but these are side effects that you can manage through.

DR LOVE: So and we'll talk more about where this might be heading. In oncology, we start out late disease and try to move things up. Erin.

DR SCHENK: I was wondering if I could ask Anne a question about her trial with the outpatient management. Just curious. How many patients with small cell who came through the door would've been eligible for it? Because they needed reliable transportation and family members and other socioeconomic components that aren't always there for all of our patients.

DR CHIANG: It's a great point. I mean, I think clinical trials already cherry-pick patients that are robust and they have to meet all of these eligibility criteria including they had to live within an hour. So it's — but we're learning from it. I think it's important.

Case: 70-year-old woman — Ms Sandy

DR LOVE: So let's get back to a case. Beth, you have a patient who received tarlatamab. Let's hear about it.

MS SANDY: Sure. So this is a 70-year-old woman. She's deaf. She presented with chest pain, shortness of breath in January 2023. Typical with small cell is that we see the nodal mass is actually larger than the primary often. And so she gets bronched and she's positive for small cell lung cancer. She gets typical front-line therapy. She actually was limited stage to begin with so she had gotten etoposide and platinum with 4 cycles concurrent with radiation to the chest that overlapped with cycle 3 and 4. She developed progressive disease in November. And if you guys look at the timeline, that's often typical unfortunately in small cell. Even though we treated her with curative intent, 10 months later she was progressing already. And now she has a large 8 cm, so pretty large mass, in the pelvis at this point.

So she goes back to etoposide/platinum and immunotherapy with atezolizumab for 4 cycles. And then that was followed by maintenance atezolizumab. She developed disease progression in August. So again these are pretty common timelines here. This is a fast-moving disease. She developed brain mets. Shortly after that was treated with whole brain radiation. She ended up getting radiation as well at the same time to the pelvic met. She then was put on lurbinectedin in November or she was put on lurbinectedin, sorry, back in August and then by November it was already progressing. So she started her tarlatamab in January of this year.

So a little bit of background about this patient. She comes with her son. She lives alone. They come from Delaware to Philadelphia, which I kind of laughed about because I thought, if you're not from the East Coast you might be like, where's Delaware? It's actually not that far from Philadelphia. It's only about a 40-minute drive. But people are like, oh, the whole way from Delaware to Philadelphia. It's actually not that far. But anyway, but it hasn't been an issue for her family. Her son, and she also has a daughter, they're very dedicated to her. They want the best treatment for her. Her initial treatments were actually in Delaware but when they were not able to give her the tarlatamab, they sought that out and came up to us at the University of Penn in Philadelphia.

One thing is we need to have a sign language interpreter available at these visits. And that has made this really difficult because the sign language interpreter doesn’t always show up. Typically when we're giving tarlatamab we bring these patients in really early because this is a long day. They get the infusion early in the morning. So I see them at 7:30. They come for 7:00 AM labs, 7:30 visit with me and the interpreter is not always there. And it makes it difficult. She has learned a lot of trust with me. She said she reads my lips well. She told them that and I'm like, oh alright, I guess I'll maybe wear bright lipstick. I don't know. So she now refuses to see another nurse practitioner. So even if I'm away, she will delay until I'm back. And I'm sure you guys have experience with this as well. A patient comes back to infusion and they're like, nope, I only want her. She's the only one that can get my IV. So that sometimes causes some issues.

But anyway, with her, so she got admitted for her monitoring of cycle 1. Now she had developed right arm pain that I had caught onto before we admitted her for her — we admit patients for their first day and second treatment of monitoring because it's a 24-hour monitoring timeframe. So I had sent her for an x-ray on her way over to get admitted and that showed a met in her right humerus. I'm like, okay, well we'll deal with that. We just gave you this big dose of tarlatamab now you're being admitted. Well while she was admitted, just for CRS monitoring overnight, she got out of bed in the morning, and I think of this as, you know, she's deaf, she's not in her normal setting of her home, and she fell in the bathroom and fractured her right humerus. So this ended up requiring extended hospital stay. Actually required surgery for a rod placement. She had some mild Grade 1 CRS, which was just fever, but it ended up delaying the surgery, prolonging her hospitalization. So she ended up being discharged not for 2 weeks after her first tarlatamab dose.

And so, and I'll just say the annoyance of this became, and Liz alluded to this in her first case, is that when these are delayed, we had to restart then her next dose at the step-up level at 1 mg. Because there's a timing issue here. And I made a table there to show you that. So if your time from the first dose is more than 2 weeks, you then have to go back and give that first step-up dose again because of the sensitivity and the likelihood of developing CRS again. So instead of her only having to be admitted twice for step-up dosing and CRS monitoring, this ended up having to happen for her 3 times.

I think my other big concern with her is that given that she's deaf, will I have a hard time assessing for ICANS in this patient? Because if you think about it, some of the things that we do to assess ICANS is we would say, if there's a clock in the room, we'd point to it and say, what is that? She doesn't speak well because she's deaf. So now I'm going to rely on the sign language interpreter pointing to that but not telling her what that is in a sign language. And so some of these things I'm worried I might have a hard time. Plus the fact that she's had whole brain radiation. Am I assessing her cognition well? Because I'm assessing this through a sign language interpreter. So far, so good. I don't notice anything. I think I'm really going to rely on her children also. Now they don't live with her but they check in on her frequently. They live close to her. So we really have to do a good job of educating the family about how we might identify signs of this.

DR LOVE: Really interesting she had that pathologic fracture. Was she a smoker?

MS SANDY: She was.

DR LOVE: Currently when she was diagnosed?

MS SANDY: No, she had quit — I don't remember exactly when she had quit. Because she didn't start her original care with us. It happened in Delaware. But she is not currently smoking.

DR LOVE: So we're going to go on in a second and talk about future directions and where tarlatamab might fit in. But, Beth, for these many years that we've been coming to ONS one of the themes we've had is what we call the bond that heals, which is the idea that going beyond any specific anti-tumor strategy that we might give to patients, patients really value the relationship that they have with you and it certainly sounds like this is the case here. And from my point of view it's maybe both ways. And I'm curious what it's been like for you to take care of her?

MS SANDY: Yeah, I feel like I have a bond with her too. I mean, hey anyone that says they can read my lips well, you stole my heart. But I think that we've both really developed this close bond and I think it's been really helpful. Because this drug in particular there are nuances that you have to really be able to tease out especially when it comes to ICANS and certainly CRS monitoring as well. And there's a lot of patient education and family education that goes on here when they're not here in the office with you. So I think that bond has been really particular and helpful here.

Future Directions in the Management of SCLC

DR LOVE: So we're going to move on now and talk a little bit about where things might be heading in small cell management. Erin.

DR SCHENK: Great. Thank you. This has been so exciting to see over the past few years. You saw Neil show a slide of the bispecifics that are in the hematologic space and finally it's coming to the solid-tumor space. And there are a lot of cancer types that are very deserving of breakthrough. Small cell definitely is one of them. So I'm excited to see what we've been able to develop so far for our patients. And there are a couple of themes I'll touch on. I won't go over all targets, all therapies, all response rates. But we're able to start to get more mileage for our patients from our therapies thanks to identifying new targets on the surface of the small cell lung cancer cells. So there's a number of agents in development, ADCs in particular, against several cell surface targets. I'll speak more about B7-H3 but you can kind of see a number of those targets listed as well as the associated ADC. And then, of course, there's these novel immune-based therapies, these T-cell bispecifics are one of them. But also as we mentioned briefly earlier, CAR T-cell therapy may also be coming through for our patients with small cell lung cancer.

So focusing on tarlatamab specifically a number of trials are being developed to really cement the role of tarlatamab in different spaces within the treatment paradigm for small cell lung cancer. So DeLLphi-304 really is the Phase III confirmatory trial to solidify tarlatamab as a subsequent line setting for patients with small cell lung cancer. That's underway. DeLLphi-305 is looking at the first-line setting where patients receive a chemo IO therapy appropriate for a first-line presentation of extensive stage small cell lung cancer. And then they'll be randomized to either PD-L1 alone or PD-L1 plus tarlatamab.

And then like many of these agents, the companies are very much thinking about how do we move these agents earlier on in a disease stage in a disease course? This is DeLLphi-306. And the way the trial was designed is patients would have appropriate concurrent chemoradiation for limited stage small cell lung cancer and then be randomized to either tarlatamab or placebo. And this is one of the bad things about being first out the gate is because our standard of care has since changed for limited stage small cell lung cancer since this trial was written and started. We now give durvalumab after concurrent chemoradiation in limited stage small cell lung cancer. So it'll be a little hard to interpret these results when they do come out.

There are several DLL3-CD3 T-cell engagers in development for small cell lung cancer. This is just a collection of some of them. And I think what will be really interesting over time in terms of drug development is they're able to modify the sticky end that grabs onto the T cell so that it doesn't grab so tightly. And I think this is really important because that will reduce the overall immune activation as well as the potential for CRS. But those are still in development so maybe one day we won't have to hospitalize folks or CRS will be a memory of the past.

Several other agents in development, DLL3 T-cell engagers. This is one from Boehringer. I think, it has a name, I'm not going to try it. It's too early for me. I'm from Colorado.

DR LOVE: Obri.

DR SCHENK: But you're able to see that there are good levels of response in this heavily pretreated subsequent line population. And there's ongoing trials very similar to the development strategy for tarlatamab looking at this agent in different phases of therapy. So not only small cell lung cancer but other neuroendocrine tumors also express DLL3 so that's one of the clinical trials. They're combining this agent in the first-line setting. And they're also treating it in a refractory setting with topotecan in combination.

This is MK-6070. This is also a therapy targeting small cell lung cancer, and they included other neuroendocrine tumors that express DLL3 in their cohorts. And they're seeing a level of response across these histologies and across these tumor types.

And I want to shift just briefly to talking about I-DXd. It's a B7-H3 targeting ADC. Early Phase II data in patients with extensive stage small cell lung cancer have been promising. Let me show that to you. So these were patients that already received appropriate first-line therapy. And they were comparing different dose levels of this agent in this Phase II clinical trial. And they saw a pretty good response rate. Again for subsequent line small cell lung cancer, they were seeing 26% in the lower dose cohort and 55% in the higher dose cohort. And the reason I bring this up is we hinted at this before. In very broad strokes, these new novel ADCs targeting these new targets in small cell lung cancer often have a pretty impressive response rate for our patients. Again early data but hopefully that holds true. What they don't have, and Anne referenced this, is they don't have a duration of response similar to novel immune therapies like tarlatamab. So what this particular trial is doing, and likely other companies are going to do as well, is find a way to combine the DLL3 T-cell engagers with these novel ADCs to try to get that response rate, so get more patients into response, and then allow the patients to have a more durable response with the T-cell engager. So the future is here. We're getting close. And I'm really excited for it.

Some of the barriers we've touched on. And I think I'll just go to my last slide to talk about, what are the challenges with trying to enroll patients onto the clinical trials? So we've talked a bit about the hospitalization requirement. With the combination of the T-cell engagers and the ADCs, we're still at — some are q1week, 2 week, 3 week dosing for these T-cell engagers. And then when you try to combine them with ADCs, because they can have a number of different dosing regimens. They could be day 1, day 8, every 2 weeks. This particular one, that clinical trial I highlighted, the T-cell engager once you're sort of in maintenance mode is every 2 weeks. The ADC is every 3 weeks. That's a really challenging infusion appointment scheduling. They're not all given together. They're given in a staggered fashion. So it's a lot of visits for patients and some of these other items we can talk about as a discussion, but I'll stop here.

DR LOVE: So Anne, question from the audience that I'm going to ask you to address in a second. Any other side effects of tarlatamab other than CRS and ICANS? But I wanted to just point out one thing if we can go to that, yeah, there you go. Just to clarify just again thematically. This is called a waterfall plot for those of you who don't know. And each one of these bars is a patient. And if the bar is going up, it means the tumor is getting bigger. If it's going down, it means it's getting smaller. So when you see a waterfall plot where most of the patients, again each one is a patient going down, that's favorable as well. So again, Anne, any other side effects with tarlatamab?

DR CHIANG: Yeah, you have loss of taste. That's something that really has been remarkable. Like no taste. Similar to the COVID.

DR LOVE: Really?

DR CHIANG: Yeah. And that's something that you really have to get used to because you don't have the same sort of drivers necessarily to eat. You can have decreased appetite because of that. Neutropenia in about 12% of the patients. You can have a handful of some nausea, diarrhea, but that's very low level. But that really has impressed me for my patients. They just can't taste.

DR LOVE: Interesting.

DR CHIANG: And that's gone away after they went onto another therapy.

DR LOVE: So also I noticed in one of the trials you talked about is tarlatamab plus a checkpoint inhibitor. That sounds like it might be kind of interesting from — I have no idea what kind of tolerabilities you get when you put those two together. Is there any data on that right now? I'm curious about how that plays out.

DR CHIANG: We have that open. We're going to start a patient next week actually. I think that they're overlapping in a different way. They both have to do with the immune system. But, for example, some patients who you wouldn't give our traditional anti-PD1, anti-PD-L1 immunotherapy because they have ILD or some sort of autoimmune disease, that seems to be okay with tarlatamab. We're not specifically tickling the immune system in that way to ramp that up, for example, to get a flare of rheumatoid arthritis. So they're different.

DR LOVE: So really exciting, Beth, to try to use tarlatamab as maintenance in the first-line setting but that's going to change the maintenance experience quite a bit. Right now I guess you just get an IO in maintenance. Now we're going to look at bringing in tarlatamab with all these issues. Any thoughts about how that's going to play out?

MS SANDY: Well, you're right. Logistically it would be different. Side-effect wise, it would be different. I mean, I think that remains to be seen and I don't think we're there yet. We need to see what clinical trial data shows. But, yeah, it would definitely change a lot for the patient. But I think once they would then get into the maintenance part of it. I mean, you know, once you get through those first couple of cycles where you have the overnight admission, they often are on autopilot then every 2 weeks and the drug is pretty well tolerated then at that point.

DR LOVE: I'm the eternal optimist. I always think things are going to work and sometimes they do.

Case: 81-year-old man — Ms Krueger

DR LOVE: Alright. Let's get back to another case, Liz. This is an 81-year-old man, history of prostate cancer. That's interesting. We had a whole session on that yesterday. Typical comorbidities you see in an older man. He was a smoker?

MS KRUEGER: Yes, heavy smoker, 2 packs a day for many years. And he presented to a local hospital after a mechanical fall in the context of a 20-pound unintentional weight loss, cough and found to have a mild transaminitis on labs. Imaging demonstrated a large lung mass with other subpleural nodes and significant hepatic disease burden. He had a liver biopsy that demonstrated small cell lung cancer and was started on standard therapy with carbo/atezolizumab for 4 cycles and unfortunately progressed before starting maintenance atezo. So he was then started on lurbinectedin. He progressed right around when tarlatamab was approved, but we didn't have our standard of practice developed at that point. So we put him on lurbinectedin for the time being. And unfortunately, in short order, he progressed in his liver and developed new brain metastases. So by July, we had developed our standard of practice and we were ready to start him on tarlatamab.

DR LOVE: And just pointing out similar to Beth's case this man went from first-line therapy to third-line therapy in 5 months. You don't typically see that so it reflects how aggressive this disease can be. What is his life situation?

MS KRUEGER: So he is currently a single male but the primary caretaker for his 17-year-old great-granddaughter who lived with him. He could be challenging in clinic. He was very regimented. A former marine. And if anything was late or if he wasn't seen early, it sort of, he was thrown for a loop. And then when we thought about his home life, he was the primary caretaker. There wasn't many people around to support him and to check in on him. His healthcare proxy was his landlord. And so we made contact with his landlord prior to discharge from the hospital to make sure that he would agree to check in on him daily and knew how to reach us.

DR LOVE: Did you meet his granddaughter?

MS KRUEGER: No, so I never met her. She was always in school and that also presented some challenges because once he had transitioned to outpatient therapy, he needed to get home to get her off the bus and be home. So he was very anxious. And we ultimately worked with him. Once his monitoring period was shorter, we did delinked visits. So he would come and see us and then come back the next day.

DR LOVE: One of the things we've talked about for years here at ONS is minor children and grandchildren of patients with cancer. Do you have any specialized services at MGH?

MS KRUEGER: So we involve social work. He said that he had appropriate legal support and that things were in place should he pass because she was still a minor. So we wanted to make sure that she was protected and safe during his treatment course.

DR LOVE: So what happened when he got the tarlatamab?

MS KRUEGER: So he was admitted for the step-up dosing cycle 1 day 1. He developed Grade 2 CRS with fever to 104 with associated hypotension and new oxygen requirement up to 2 liters. So at that time we supported him with acetaminophen, ibuprofen and meperidine for rigors. We gave him dexamethasone 8 mg IV q8h x 2.

DR LOVE: Was he in the ICU?

MS KRUEGER: No, he was on the floor because he did not need pressure support. His pressures came up but were still soft with the IV fluids. And so when things were not turning around quick enough, then we reached for the tocilizumab. So tocilizumab is dosed 8 mg/kg infused over an hour. It's a single dose. And he recovered and turned around and did quite well.

DR LOVE: What's his current situation?

MS KRUEGER: So now he is — I'll skip past that. We covered what tocilizumab is. So his current situation is that he's had a great response. He has had marked improvement in his hepatic disease burden as well as a response in the CNS, which is something that we're very excited about. We haven't seen it with all of our patients, but it's something that's very important given the propensity of small cell to metastasize to the brain.

DR LOVE: Yeah, we always have this concept of so-called blood-brain barrier but none of the immunotherapies, even ADCs, seem to work in the brain so that sounds like a great at least beginning here. Anything else you want to say about him and the challenges of managing this particular patient?

MS KRUEGER: Sure. So as we touched on a lot of patients with small cell lung cancer have comorbid conditions. He was a diabetic on 5 agents but having had so much weight loss in the setting of progressive disease, he presented with hypoglycemia on the admission for tarlatamab. So he was a captive audience. It gave us the opportunity to involve endocrine and to manage some of his comorbid conditions in that short period of time. Other things that came up. So we often discuss code status or advanced directives especially in the setting of progressive extensive stage disease. And so when he was being admitted to the hospital, we talked about would he want to be DNR/DNI. But he was very hung up understandably on the reversibility of some of the side effects with CRS and ICANS that maybe he would get to the point of needing to be intubated, though unlikely, but he felt like this could be reversed and understandably. So he elected to be full code. And now that things have stabilized and he's out, he's receiving treatment as an outpatient, those risks are very low and the small cell in general is the higher risk of taking his life. So those code status discussions are ongoing.

DR LOVE: Beth, any thoughts about this full code thing? Kind of interesting. 81-year-old man, comorbidities, brain mets, et cetera.

MS SANDY: Yeah, you know, I never thought about it until this case and you just said that. And I was thinking like, wow, you're right though. These patients with CRS can become quickly really hypotensive, but we can reverse it very quickly with steroids or toci. So it's like, you know, the whole touch-and-go thing. It's like, well, yeah, you're right. I wouldn't want to just be like, well, he's DNR so we'll just let him pass peacefully when a little bit of steroids and toci could turn this around quickly. So I never thought about it until now but yeah that actually makes sense, I think, in this case. Though, I think you — what I was thinking personally is, the patient could still be a DNR but very specifically communicated in that. That if there were cardiac arrest, then they would not resuscitate him, but if he's hypotensive and even requires pressors for a short time, that may be something that he would want. So I think there would need to be a more extensive discussion about the actual DNR status.

DR LOVE: So question from the audience. Anne, do the taste changes reverse? And I'll ask you, is this similar to the taste issues you see with COVID?

DR CHIANG: Yeah, I think a little bit because they just can't taste. And, you know, my patients who have been on tarlatamab who had this side effect and then went on to another therapy did regain some of their taste. So that did come back.

DR LOVE: We have a great audience here. Somebody just sent me a paper on the Phase IB study of tarlatamab plus, what we just talked about, IO. And it looks like maybe they — oh, no, this is tarlatamab as maintenance with this study, the idea that you talked about, I guess a preliminary study to see how well it was tolerated. Really interesting strategy. It looks like these patients did pretty well.

Unique Considerations in SCLC Management

DR LOVE: Alright. So let's move on now. We're going to get into some further discussions in terms of some specific unique considerations in the management of small cell that you can see in other cancers but much more common in small cell. And when you see these kinds of issues it makes things even more interesting. Erin?

DR SCHENK: Yeah, thank you. So there definitely are some interesting ways that small cell lung cancer can manifest and present that can affect patients and quality of life and you can see it and often with chemotherapy you can help it really quickly. So that's the good news. So in speaking about small cell lung cancer, these arise from neuroendocrine cells and they, as we've kind of talked about, some of the epidemiology, often there is a significant tobacco use history, mediastinal nodes, hilar nodes, often bulky and large. And this is a disease that's highly proliferative, fast growing, fast moving. And I'll talk about a couple of these clinical issues that we can see in patients newly diagnosed with small cell lung cancer.

So some of the broad categories that we think about are paraneoplastic syndromes and these are syndromes that can come up because of the cell of origin. These neuroendocrine cells especially they're sort of adept at making various hormones, bioactive substances that can act as if they are the hormones of the target organ. They can also express shared antigens that generate an autoimmune response that can be through B-cells or autoantibody production and more severely sometimes autoreactive T cells can also be generated to these antigens. A couple of the syndromes down here that are most common, SIADH as well as Cushing syndrome.

And I want to talk through SIADH in a patient I'm taking care of right now with a rapid response. So this was a patient who was having a slow recovery from COVID about a year back with cough, dyspnea. And she also reported she was just having this low level of nausea and occasionally vomiting. And sometimes we can see long-term GI effects from COVID. But this was just persisting. Eventually, because of her history of smoking as well as her symptoms, she had imaging and a left upper lobe mass was identified. Eventually we diagnosed her with extensive stage small cell lung cancer and she was started on chemoimmunotherapy. And just before that she had a sodium of 124 and a very high urine osm about greater than 600, really inappropriate for that level of sodium. Started her on chemoimmunotherapy and I remember seeing her prior to cycle 2 and she says to me, my nausea has gone away. This is amazing. And what we saw though the initial therapy is that her sodium levels, and that's what this chart is demonstrating here, is they went back in the normal range, this blue bar. Unfortunately, some other medical issues came up and we had to interrupt her treatment because of hospitalization. Her sodium levels went down as her disease became active again. And we've restarted her on therapy and again the sodium is starting to level out. So it's a little more tricky the second time.

DR LOVE: Before you go on, can you kind of explain your vision of — you were talking about syndrome with ADH secretion. Like what's the pathophysiology that leads to the low sodium?

DR SCHENK: Yeah, so it just prevents — the way I think about it and talk to patients about it is that this extra release of hormone by the cancer cells prevents sort of the normal regulation of sodium within the body. And that really happens in the kidneys, that sodium balance. So when you have all of this extra basically hormone coming out of the cancer cells, your body can't regulate it normally. So your body can't regulate the sodium normally. So we're able to attack the cancer cells, take that extra hormone away, kind of your normal, your normal levels get restored.

DR LOVE: And in patients with severe hyponatremia do you ever use saline? Do you restrict fluids?

DR SCHENK: In my clinical experience, in other situations, yes, we absolutely can. Often with any sort of hyponatremia what you see when you look online like uptodate.com it says treat the underlying disease. And so often in small cell lung cancer treating the underlying disease with chemotherapy, chemoimmunotherapy as needed really helps to reset that osmostat, reset that level of sodium.

DR LOVE: Really interesting that when her treatment gets interrupted her sodium went back down.

DR SCHENK: And she also became nauseated and started unfortunately having some balance difficulties too.

DR LOVE: How about SVC syndrome?

DR SCHENK: SVC syndrome. So usually it's because of some sort of mediastinal mass pressing on the superior vena cava. And you can often see this and patients will report feeling swollen in the head, in the face. As you examine them, you might notice that there's some dilation of the vessels within the upper body and the arm. And they can also have upper extremity edema. This illustration really helps to capture some of those key features. There's a facial fullness and often they will tell you this. They will say, my face is swollen and it hasn't gone down on its own. As well as examining the chest wall and some extremities you can see these dilated, tortuous vessels. This is just an imaging example showing a patient with a mediastinal mass. The SVC being compressed right here. So it really prevents that normal blood flow that really causes that edema to happen within the face.

So really, again, just like SIADH other paraneoplastic syndromes treating the underlying disease, small cell lung cancer is one that responds so quickly. Sometimes we can start chemotherapy and see a response before our colleagues in radiation oncology are able to do their simulation and start their radiation therapy as well. Often in my institution we do concurrent chemoradiation especially for SVC syndrome just knowing that it needs quick, active treatment. For some of the other diseases, for example, if this was a lymphoma, steroids make sense. Occasionally stenting can be done as well. But again, it all depends on what is the underlying disease or etiology of why the SVC is compressed.

So this one is one of the final major considerations with management of patients with small cell lung cancer. A lady I take care of, she lives about an hour away from campus and she's really scared of driving on the freeway. So she actually hides in the back of the car while her husband drives to campus. But her family is very dedicated and they bring her and she has someone with her all the time. But she was going through lung cancer screening based on her smoking history and a left upper lobe nodule was identified. Eventually it was determined she had small cell lung cancer and because of osseus metastases it was extensive stage. And she received first-line therapy in April, you know, just on the dot with the progression-free survival that we see with the chemo/IO therapies in first-line. She then developed a recurrence of her disease. And I enrolled her on a clinical trial for a T-cell engager as you see here. And again, look at that duration of response. She had a full year of response on this T-cell engager therapy. And as you remember back to Anne's one of her initial presentations, these patients with extensive stage small cell lung cancer really are only thought to live about a year with the chemoimmunotherapy when that came out.

Their overall survival was about a year. But this patient was able to get a year of survival from this therapy. She had progression and just a single site of progression. We're the wild west out here in Colorado so she actually underwent surgical resection because she had no evidence of disease anywhere else. So continues on surveillance. And I should say, surveillance includes full body imaging as well as brain MRIs. And unfortunately, not too long ago, she presented to a local ED for left-sided weakness and confusion. And what was seen and she previously at diagnosis did not have brain metastases but had since developed brain metastases. And she is and has completed SRS to the lesions that were found.

So the really challenging thing about small cell lung cancer is the propensity for brain metastases to develop. Over half of our patients will likely develop brain metastases. Why other than the diagnosis of small cell lung cancer, that's a huge risk factor, but what else influences who does develop metastases, who doesn't , isn't clear. And it's more likely, just like in my patient case I just presented, to have multiple metastases. We continue to think about something called prophylactic cranial irradiation. There was an older study that randomized patients receiving basically whole brain radiation therapy prophylactically or not. There was a suggestion from the data that overall survival was improved in the patients that received whole brain radiation therapy. But if you really want to get an academic thoracic oncologist, like me, to get their feathers ruffled, there were some trial design issues. Patients weren't appropriately staged in their CNS prior to trial enrollment, which had to do with the error of this trial.

So we're really trying to think about how do we improve control of brain metastases while balancing this side effect profile that can happen with prophylactic whole brain radiation therapy? A trial is going on right now through a cooperative group to understand whether in the modern setting PCI is necessary or whether just regular brain MRI imaging is sufficient to help watch for brain metastases. While we have some promising data coming out with tarlatamab and ADCs, we don't have a great agent that we give systemically that we know can guarantee will take care of brain metastases. And with radiation, of course, we're shifting towards SRS based on some noninferiority data. But, you know, the challenge is of course radiation necrosis when you need whole brain radiation therapy and just trying to reduce that side effect profile for whole brain.

DR LOVE: What do you typically see in terms of side effects or effects of whole brain radiation and when do you see it, Erin?

DR SCHENK: So I have a patient who remarkably has survived for a number of years post needing whole brain radiation therapy. I think one of the first things that he started having challenges with was dry mouth. So, of course, some of the radiation fields can affect the salivary glands. So there was dry mouth. There was a little more trouble with word recall that he's had and he also developed cataracts. This gentleman has been out for a number of years from whole brain radiation therapy. So he needed to have cataracts taken care of. So again all of these long-term side effects. But he's had great CNS control.

DR LOVE: A couple of quick questions from the audience. Anne, does vaping impact the risk of lung cancer? Do we know anything about that?

DR CHIANG: Oh that's interesting. There's a lot of data that’s starting to come out of that and I think it does affect your lung function. The direct tie to lung cancer I think is not yet, at least I'm not aware of it. But it's actively being studied. Great question.

DR LOVE: Another question from the audience, Liz. A question of the use of remote home monitoring for CRS. Is that something you ever use or you think might be useful?

MS KRUEGER: I think that's a great idea. It's not something that we're using, but it's something that makes a lot of sense. We've thought about making sure the patients have an automatic blood pressure cuff at home, a thermometer, a way to check those vital signs so we know, is it just a fever or is it a fever with hypotension at home, which requires a different intervention. So I think that's a great idea.

Case: 67-year-old woman — Ms Sandy

DR LOVE: Alright, well, let's finish out with another case. I feel like we're making rounds here today. And you know all of our work is based on rounds. Like when I was an intern I loved going on rounds and that's the way we designed our program. So Beth, let's hear about this 67-year-old woman.

MS SANDY: Yeah, so a lot of this case tags off of what we all just talked about. So this is a 67-year-old female diagnosed with extensive stage small cell in June of 2022. Her presentation was facial swelling and cough that was not necessarily out of the ordinary, but she had a scan and you can see it there. There's a large mass. And I put the heart there because sometimes we kind of forget where the superior vena cava was because we've been in oncology so long. So this large centralized mass, which is very typical of what we see in small cell lung cancer, was impacting this woman's superior vena cava. So she was bronched and found that this was small cell and she had superior vena cava syndrome. So that tumor is pressing on that superior vena cava. There's basically a backflow of blood flow to the upper extremities and the face causing her symptoms. She was inpatient at the time of this so they were able to get her really quick palliative radiation. But Dr Schenk made a really good point. We could have just started chemo as well. Chemo works very quickly with these patients. But she was there, they were able to hit this with 3 fractions of radiation really quickly to get her some symptom relief. She was also found to have brain mets at diagnosis as well and she had stereotactic radiosurgery to 3 of these brain lesions.

Again just a quick recap of her treatment. So in September of 2022 she had chemoimmunotherapy followed by maintenance immunotherapy. She progressed in June of 2023 and had a new brain met at progression. So, again, that was treated. She started lurbinectedin chemotherapy in October. Shows a response to the lurbinectedin and resolution of the brain met without radiation at that time. February 2024, she progresses and we went back to chemoimmunotherapy at this point. Progressive brain met she developed. Now she got whole brain radiation. So she first had stereotactic, now she's had whole brain. So she's had 2 brain radiation treatments. And then October of 2024, progression in the chest, a new liver met. And we started tarlatamab on her in December of last year.

So we reviewed with her family the risk of CRS and what it may look like and ICANS. We reassured them this most commonly occurs within the first 2 doses and she will be monitored inpatient. The ICANS, again similar to my first patient, I didn't voice this out loud but I'm thinking in the back of my head, she's had stereotactic brain radiation and whole brain radiation. At baseline, her cognition was definitely off to some degree. I mean, she could answer questions appropriately but she wasn't real sharp. A lot of times she would look at her husband when I would ask a question. Sometimes he would answer, sometimes she would. So she gets her first treatment on December 10 and tolerated it pretty well. There were no side effects. The second treatment, which is now the step-up dose of the 10 mg, she developed CRS while admitted for overnight monitoring. She had fever that was complicated by hypotension. She developed lethargy as part of this. And though she was admitted, her daughter was actually the one who stayed overnight with her, and her daughter was like really sort of traumatized by watching this even though she was in an inpatient setting. She was treated with acetaminophen, dexamethasone, IV fluids and she did quickly improve in 24 to 48 hours. And she actually was discharged on the third day. So and then after that we treated her, you can see on Christmas Eve, and she tolerated treatment number 3 very well as an outpatient.

So going back to this, her CRS response and her experience with it, you know, this is why we do the step-up dosing, the 1 mg on day 1, the 10 mg on day 8. And you can see that I used the same slide that you did Dr Chiang. I did use the same graphic here to show from the paper that the majority of it happens either on day 1 and then day 2. It's very rare to be Grade 3/4 so the majority of it is going to be that Grade 1/2. It did occur in over half of the patients. Grade 1 is fever only. Grade 2 is fever plus one of these complicating factors.

So I would just say the thing that took me by surprise with this one was that her daughter, when they came in for dose 3, I said, oh I saw she had CRS but she got better quickly. And the daughter was like, that was really upsetting, I was so worried, she couldn't even like talk to me properly. And here I was thinking, well I warned you about it. But I probably learned from that experience that I warn the families a little bit more. This may look scary to you. Even though they're inpatient and I'm thinking, well they're inpatient, we'll take care of it. The family doesn't know that. This is their first experience with this. And when they see their mother not being able to respond and talk and you know the machines are beeping. It was really upsetting to her. And she wasn't like mad but she was just sharing that experience. So I'm a little bit more now when I say, hey, the CRS it actually can be serious and frightening, but we know how to manage it. Generally almost all the time we're going to be able to make this go away and get better very quickly.

DR LOVE: That's a great point. What happened with her severe vena cava syndrome incidentally going way back to the beginning?

MS SANDY: Oh yeah, that got better very quickly.

DR LOVE: And she just had facial swelling?

MS SANDY: Hers was mostly facial swelling though I do feel like the irritating cough may have been part of it as well.

DR LOVE: Liz, any final comments hearing Beth talk about the family involvement?

MS KRUEGER: No, I think just emphasizing just the education can't just be to the patient it needs to be to a supportive family member. Everybody needs to hear it. Because if the patient's doing unwell at home, there needs to be that support and they need to be able to recognize symptoms and know who to call.

DR LOVE: So I want to thank the faculty for this really exciting session. Come on back here today at 12:15. We're going to be talking about ovarian cancer, PARP inhibitors, et cetera, et cetera, ADCs. And incidentally, in terms of antibody-drug conjugates, if you weren't at our program on Wednesday, we did an entire program there on antibody-drug conjugates so check it out when we post it online. Thanks so much to the faculty.