DeLLphi-301 - FDA Approval of Tarlatamab in Patients w/ Prev Treated Small Cell Lung Cancer (SCLC)

Terlatinimab Hello again and welcome back to another episode of the Oncology Brothers Podcast. I'm Rahul Ghassein here with my brother and Co host Rohit Ghassein. Today we're having an exciting discussion focusing on a recent approval for patients with extensive stage small cell lung cancer. Speaker 2 Rahul, a lot has changed in short time for this particular disease. Today, we are going to take a closer look at the most recent FDA approval of terlatimab, one of the first bispecific antibodies to be approved in solid malignancies. To cover this, we have Doctor Misty Shields from Indiana University who will help us breakdown the study design efficacy of the treatment. And of course, we will touch on operational challenges around this drug. Misty, thank you so much for joining us today. Speaker 3 Thank you for allowing me to be here, Rohit and Rojo. Speaker 2 It's a wonderful, wonderful opportunity for small cell lung cancer and an opportunity to spread some good news for our patients and their families. Speaker 1 Absolutely. Let's see. Welcome. Let's see. Let's start off with the drug makeup here, and then if you can also walk us through the study design itself for Delphi or Delphi three O 1. Speaker 2 Yeah, absolutely. So Delphi three O 1 was a phase two open label multi center multi. Speaker 3 Cohort study. Speaker 2 So you can see here that key inclusion criteria were patients who had diagnosis of extensive stage small cell lung cancer with prior treatments of at least two or more lines of therapy including a platinum based double chemotherapy. Performance status by ECOG was 0 or one with measurable disease and treated or in stable brain maps were allowed. Patients, 99 patients were enrolled in a one to one randomized fashion and you can see here the Part 1 and then the further dose expansion you can see here that was 10 milligrams or 100 milligrams to cohorts. These patients were then followed for primary endpoint of objective response rate and. Speaker 3 Virus cyst criteria. Speaker 2 And looking at tarlatimab serum concentration, secondary endpoints for disease for duration of response, Disease Control rate, progression free survival by blind and panic review, and overall survival. Then there was an expanded dose expansion cohort. Speaker 3 As you see. Speaker 2 Here on the 10 milligram. Speaker 3 Dose for this? Speaker 2 Study. Thank you, Missy, for laying that very important foundation for us. The approved regimen is actually 10 milligrams dose every two weeks at least for cycle 1. You start off with 1 milligram on day one followed by 10 milligrams on day 8 and day 15 and beyond that it's 10 milligrams every two weeks when walking. When talking about the study design, I'm going to reiterate what you just stated. That is the primary endpoint was objective response rate, which is rather critical as the approval here is an accelerated approval. We will need longer term data and bigger studies to ensure that there is an ongoing benefit for patients and these patients are indeed living longer because of this intervention. OK. Mr. E what did the study show? Speaker 3 Yes, so absolutely. So what we see here is the. Speaker 2 Progression free survival and overall survival so. Speaker 3 This was. Speaker 2 Reported in New England Journal last year in 2023. Speaker 3 By the investigators. Speaker 2 And what we? Speaker 3 See is that? Speaker 2 That there was an improvement in progression free survival. Speaker 3 These are two cohorts without the. Speaker 2 You know standard arm here control, but these are compared against each other with a progression free survival spanning from 3.9 to 4.9 months. Speaker 3 We say the overall survival here. Speaker 2 Dramatic this is 14.3 months and not. Speaker 3 Yet achieved here. Speaker 2 In the 100 milligram dose and so not not yet a valuable here and So what we. Speaker 3 See is that was. Speaker 2 Reported out as an overall response rate of 40% in this patient population. The median duration of response of 9.7 months. So when patients had a response, it was. Speaker 3 Very durable. Very. Speaker 2 Long lasting some patients on the study of up to 20 months and counting on this phase two open label study. Very exciting results here. Speaker 1 You know, these are exciting times. As you've mentioned, 40% objective response rate, if we've started to see a hint of overall survival benefit here already, few things to mention. Bispecific antibodies In this particular study, we had two doses, 10 milligrams and 100 milligrams, but the approval moving forward is for 10 milligrams. When we're talking about objective response. The other thing that we have to keep in mind here, this is all coming at a cost and some unique side effects that are associated with bispecific antibodies. When we're talking about bispecific antibodies here at this particular one is for DLL 3 and T cell Engager. So, Missy, can you touch a little on the makeup of this particular drug and then we'll take a dive into the side effects. Speaker 3 Yes. So this is a bispecific. Speaker 2 T cell engager It is designed to interact with CD3 on the immune cells as well as DLL 3 on the small cell lung cancer surface home and so the design of this is unique and that's a class of its own that needs to be monitored and managed. Speaker 3 Appropriately with appropriate. Speaker 2 Standard operating procedures and institutional guardrails to make sure that patients are safe and cared for. Speaker 3 Appropriately and so. Speaker 2 With that, you know we are watching for what? Speaker 3 The FDA has highlighted as black. Speaker 2 Box warnings including the cytokine release syndrome as well as the eye cans or effector cell neurotoxicity that can be potentially seen with this class of molecules. Speaker 1 Even before we go there, coming back to the same idea of the structure of this drug because of the T cell engager and looking for that DLL 3 on small cell, DLL 3 is expressed heavily on small cell lung cancer. However, here we were seeing response regardless of that expression. Speaker 3 Yeah, absolutely so. Speaker 2 What we know is that DLL. Speaker 3 3 is ubiquitous. Speaker 2 And abundant in small cell lung cancer anywhere in the reports between 70 and in the study actually was reported out at World lung this year ranging from a. Speaker 3 Positive DLL 3 of. Speaker 2 About 95% in the patients on this phase two study, so it seems. Speaker 3 Like it? Speaker 2 Is a really abundant protein potentially more enriched in an ASCL 1 subtype for neuroendocrine subtyping with small cell lung cancer and so? Speaker 3 It this is a great target. It's clearly a very efficacious target. Speaker 2 And it's needed for the small cells to survive and so therefore a nice vulnerability to target and go after. And certainly and that's what dictates the response rate itself because of the targeted option available here. Mr. Most of the patients do get treated out in the community. Rahul and I are community oncologist, though we are tied up with tertiary care center. We don't have a stand alone hospital that is attached to our Cancer Center. When you talk about the operational challenges, what you what you stated with CRS and ICANS, these are some concerning side effects. How to partner with community oncologists How are you partnering up with your community oncologist? Have you partnered up already or that is still in pipeline? Speaker 3 Yes, absolutely. So we do have. Speaker 2 Tarlatimap in active use at Indiana University where I practice at Simon Comprehensive Cancer Center here in Indianapolis and we have partnered with our. Speaker 3 Colleagues who are. Speaker 2 Practicing in rural and community. Speaker 3 Practices. Speaker 2 It is a partnership. These are patients who have been known to that oncologist and then potentially had a bad outcome on a scan and then are getting referred in for a new line of treatment. So these are patients we're meeting already in their treatment course. And so really building that rapport, building that understanding of what matters most to these patients and then being able to have an open, candid discussion about what this treatment looks like, what it all entails. And then what are the? Speaker 3 Logistics. Speaker 2 Surrounding it, what are the opportunities, what are the risks and benefits and what, what should a patient know to make a decision, an informed decision for this treatment? And so with that, you know, we don't have a prediction model to say who's going to have cytokine relief syndrome. What we know from the study was as a median time about 13 hours. It is really typically in the first cycle and the. Speaker 3 Couple cycles after. Speaker 2 That you can see. Speaker 3 Here with the with the. Speaker 2 Outcomes of the study, it was really early on in cycle one and two that we see the emergence of cytokine release syndrome and that they were majority grade zero. Grade 1 toxicities are low grade, manageable by supportive medications. Speaker 3 Such as fluids, antipyretics. Speaker 2 And monitoring in this in the inpatient setting and so it's important to have standard operating procedures in place for. Speaker 3 Safety so. Speaker 2 That we can. Speaker 3 Provide the best highest. Speaker 2 Care for patients and that may look like, you know referring a patient in from community so that they have the. Speaker 3 Opportunity of these. Speaker 2 Centers that have a higher volume and are seeing this more often, that's to help reduce any missed opportunities or any outcomes that may be unfavorable for patients. And so really having a center with a high volume that is a tertiary ordinary center to. Speaker 3 To be able. Speaker 2 To implement this, have that 22 to 24 hour observation that we're seeing with the FDA really wanting to have that in place so that we do all the safest things to provide the best outcomes for patients and their care partners. Speaker 1 Absolutely. Misty, just so that I get this right right now, are you seeing these patients from the community in your center on day one, day, 824 hour OPS and then moving forward thereafter when they're getting every two weeks treatment, they go back to their community oncologist and their community settings. Is that the work play right now? Speaker 3 So I think that is. Speaker 2 Definitely a potential option. The patients I've had from the community have come and stayed just. Speaker 3 Because of the. Speaker 2 Current logistics. Speaker 3 Of their. Speaker 2 Outpatient and community oncologist, but I think that is a very reasonable opportunity and I think I would encourage those community sites to make sure. Speaker 3 That they work. Speaker 2 With their pharmacist, it's very much a multidisciplinary approach here to have the opportunity to have those medications on board. Speaker 3 Particularly tosalisumab. Speaker 2 To have that. Speaker 3 Available. Speaker 2 So that we can, you know, if there is no emergence of a cytokine release in a later cycle, which isn't really, you know, data-driven, but just potentially for safety to have that on site as well as to, to be informed and know those. Speaker 3 Delayed toxicities such as. Speaker 2 ICANS, we know that neurotoxicity in the trial emerge with a medium time of 30 days. And so we want to really make sure that if we're sending those patients back to their. Speaker 3 Outside or. Speaker 2 Community oncologist or a rural oncologist, they feel comfortable with that monitoring and recognizing that and helping with that expected management. And I feel like, well, we've seen very similar stuff happening in our hematological space where they patients have received something at tertiary care center and once they're on maintenance or at least we have gone out of the window of CRS, then they can get this regimen out in community. So we'll see how it plays out in most of the community settings. But it's nice to see that Misty, you are already employing this. Speaker 3 Yes, absolutely so. Speaker 2 We've had a number of patients here at IUI know that other institutions like Moffett are really leading the way. I think they were the first institution in the United States to offer to our Live M outside of the expanded access program. Speaker 3 So I think there's a lot of really great. Speaker 2 Programs that are using this and having great experience with it and so I think you know, the more roll out, the more we all get familiar with. Speaker 3 It this class. Speaker 2 Of drugs and recognizing these symptoms early. I'm hoping this is going to be a great opportunity for patients to have terrible responses and best outcomes with diagnosis of small cell. Speaker 1 Absolutely. All right. So before we close bringing it back to home, what does it really mean for us in the clinic and for our patients? What does this mean for the clinic and for patients? The study design was for two agents and beyond, but the approval is actually a little more loose, which it's a, it states second line and beyond. Here we also have leuerbenectin. Misty, how are you sequencing this today in your clinic? Speaker 3 Yeah, absolutely. So I think, you know, there's a few places where. Speaker 2 You would want to think about this in your algorithm. Of course. We know based on the study that patients who are platinum resistant as well as patients who have platinum sensitive disease benefited from tarlatumab. Speaker 3 Regardless of their. Speaker 2 Initial chemotherapy free interval between first line and second line and beyond. And so that is, you know, probably not as much of A. Speaker 3 Variable here for these. Speaker 2 Patients who are going to be treated with tarlatumab, I'd like to think about a couple. Speaker 3 Of variables. Speaker 2 Things like active infection or immunodeficiencies, we don't know. Speaker 3 What? What that? Speaker 2 Is going to look like and that is not a safe patient population at this time to provide this. So patients with immunodeficiencies or active infections untreated. Speaker 3 Like hepatitis B, Hepatitis CHIV. Speaker 2 Things. Speaker 3 That were also excluded were patients. Speaker 2 Who had active non infectious pneumonitis in interstitial lung. Speaker 3 Disease as well as. Speaker 2 You know, symptomatic brain medicine. So those we. Speaker 3 Have to follow. Speaker 2 The data and follow the trial. We also want to think about patients who have a high burden of disease that may not be the best patient that might. We don't know who's going to have cytokine release, but. Speaker 3 You could postulate the. Speaker 2 Potentially more disease might result in. Speaker 3 More risk of. Speaker 2 Cytokine release syndrome and so when I think about my algorithm of these patients post platinum who have potential relapse or recurrence of their extensive stage small cell lung cancer, you know someone who has a brain metastasis. Speaker 3 As part. Speaker 2 Of their relapse that's somewhat. I'm more leaning towards tarlatamab because we know that lurve nectin is too large, it's a semi synthetic derivative from the C squirt to get into the CNS and so that might be a better patient for tarlatamab once this have been definitively managed. Speaker 3 We just saw. Speaker 2 Data from Ashwin Dilaty and the investigators showing that those patients who had brain metastases continue to have ongoing response with tarlatimab. So this is showing this intracranial response. So those are patients that you know, they have brain metastases. I'm leaning more towards tarlatimab in the second line once those have been definitively managed. Otherwise, you know if they have a high burden disease. Speaker 3 Let's. Speaker 2 Try a few cycles of larbenectin and we have durable responders who have been on larbenactin. I have several myself, you know, 20 cycles, 25 cycles and ongoing. So we don't want to deny a patient who could potentially have a durable response to lurbinectin as well, so. Speaker 3 Really. Speaker 2 Having that conversation, thinking about these parameters and really having an open discussion with patients as to what that might look like. Speaker 3 If you were to. Speaker 2 Start a treatment that is going to require hospitalization and potentially referral to another, you know, town or city or even potentially another state depending on your location and access to those care. And we want to make that, you know, open and as equitable and fair to patients and remove any. Speaker 3 Barriers to that. Speaker 2 As much as we can and and getting this out in centers that feel comfortable with managing this and have that opportunity for inpatient monitoring on cycle one day, one cycle one day. Speaker 1 Absolutely Miss Dave. As a generalist, I get to see GI GU1. Question that's going to come up is now I have access to this, can I use this for a high grade neuroendocrine tumor from other sites, especially knowing that DLL 3 is overexpressed in that particular population? Have you, would you use it outside clinical trial? Speaker 3 Yeah, I. Speaker 2 Think you know? Speaker 3 That is definitely where the. Speaker 2 Field is going. There's a cousin molecule to this with Boranger Ingelheim that that was just given a name and presented a world lung this year. You know that. Speaker 3 Is particularly. Speaker 2 Looking at this high grade neuroendocrine, large cell neuroendocrine, extra pulmonary small cell carcinomas and so they are looking at this in the trial setting I think without. Speaker 3 A trial. It's going to be a little bit dicey to get this probably approved for the. Speaker 2 Outside the indication. Speaker 3 By the FDA. Speaker 2 Since it was 4 extensive stage small cell lung cancer, but I think that's where the field is going. We really want to see this you know expand especially for those patients with large cell in our endocrine who have potentially maybe run out of treatment options as it is a more difficult. Speaker 3 Disease to treat. Speaker 2 And so I think that's where the field is going. I don't think we have. Speaker 3 That just yet. Speaker 2 Misty, before we close, any last minute starts from your end, please. Last Minute Starts Yes, absolutely. So just a. Speaker 2 Small shameless plug for a patient advocacy group that's partnership with Longevity Small Cell Smashers. It's a new patient advocacy. Speaker 3 Group to help. Speaker 2 Patients and their care partners. Speaker 3 Who are diagnosed? Speaker 2 And living with small cell lung cancer. We want to support you if you can find us on Facebook, on Twitter, tell your patients about it. Speaker 3 We would love to. Speaker 2 Have opportunities to provide good education, information, hope and a voice and a future for these patients and their care partners. We have an upcoming speaker series coming up this month with Doctor Ann Chang. We have Doctor Christine, Lovely, Doctor Shroponisen, a lot of exciting speakers coming up talking about the biology, the treatments, the outcomes, the, you know, multimodal multidisciplinary therapy for small cell lung cancer. So give us. Speaker 3 A follow give us a like. Speaker 2 And listen to us on Facebook or on podcasts For more information and more support for patients with small cell Doctor Shields, Thank you so much for taking the time to dissect this recent approval and sharing your valuable insights for our listeners. Summary Let us go over a quick recap from today's discussion. Speaker 1 In today's discussion with Doctor Misty Shields from Indiana University, we had a chance to focus on the recent approval of Terlatimab in extensive stage small cell lung cancer based off Delphi three O 1 study. This accelerated approval is based off exciting objective response seen with terlatimab if by specific antibody towards DLL 3 and CD3T cell. DLL 3 is expressed heavily in small cell lung cancer, but this approval is for all extensive stage small cell lung cancer patients regardless of this expression. Speaker 2 Yes, the current approval is based off of the objective response rate, but we need to be very mindful about the side effects we see with this by a specific agent, cytokine release syndrome or CRS and immune cell associated neurotoxicity syndrome. ICANS can be serious and managing these for now an inpatient setting is extremely important. We will eagerly await on more mature data and larger studies using this agent. Thanks for joining us. Stay tuned noon for more discussions around the recent approvals and practice change data. We are the oncology brothers.