Evolving Role of B7-H3–Directed ADCs in the Extensive-Stage Small-Cell Lung Cancer Treatment Landscape

This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.

Dr. Mark A. Socinski (Advent Health Cancer Institute in Orlando): Hello and welcome to this podcast on The Evolving Role of B7‑H3 Directed ADCs in the Extensive‑Stage Small‑Cell Lung Cancer Treatment Landscape.

My name is Dr. Mark Socinski. I am the executive medical director of the Advent Health Cancer Institute in Orlando, Florida. I am joined today by Dr. Charlie Rudin. Charlie, do you want to introduce yourself?

Dr. Charlie Rudin (Memorial Sloan Kettering Cancer Center): Yes. Charlie Rudin. I am the cancer center director at Memorial Sloan Kettering Cancer Center in New York.

Dr. Socinski: Great. Thanks for joining, Charlie.

For our agenda today, we are going to talk a little bit about the clinical needs in relapsed extensive‑stage small cell lung cancer, and review the scientific rationale for targeting B7‑H3 and other tumor‑associated antigens. We will talk about some of the clinical data that is available, as well as the adverse event profile, and then some discussion about individualizing treatments for extensive‑stage small cell lung cancer, looking at patient‑specific factors in this particular setting.

So regarding clinical needs, I will give it a brief overview Charlie and you chime in in terms of giving your perspective. For decades, we have used the backbone of platinum/etoposide in extensive‑stage small‑cell lung cancer. In the late 1990s, we had the approval of topotecan as a second‑line agent. The world changed a little bit around 2019 when we had the two trials grafting PD‑L1 inhibitors, IMpower133 and CASPIAN, that changed the standard of care. It improved overall survival with a hazard ratio of about 0.7 to 0.75 or so, and that was viewed as an advance in this disease where we had not seen much in several decades.

Then, the introduction of a second‑line agent, lurbinectedin, a couple of years ago, that got moved into the maintenance setting, where we saw a positive event on survival as a maintenance strategy. Then, of course, tarlatamab in one of the DeLLphi trials compared to standard chemotherapy really replaced second‑line chemotherapy in this setting. There’s been some improvement in our options for patients, but we are still looking at a disease that remains quite a challenge. Would you add anything to that, Charlie?

Dr. Rudin: Yes, that is exactly right. Things are really accelerating now in 2026, and we have a lot of new agents that are coming on the scene that look like they have activity in small cell lung cancer patients, so an exciting time building on the recent changes that you just mentioned.

Dr. Socinski: One of those changes, and there are several you point out - and I completely agree that this is an exciting time - is a number of targets, including B7‑H3, DLL3, SEZ6. Let us just focus on B7‑H3. What exactly is it, and why is it important to target it?

Dr. Rudin: Yes, B7‑H3 is a member of a family of proteins that is part of the signaling that controls immunologic responses. It is upregulated on the cell surface of many solid tumors, including small cell lung cancer. One of the advantages of B7‑H3 as a target in small cell is it’s expressed on the large majority of small cells. We think of small cell as having somewhat different flavors, with transcription factors like ASCL1, NEUROD1, and POU2F3, and B7‑H3 is really pretty highly expressed across all of those, so it serves as a very nice target for antibody‑based therapeutics.

Dr. Socinski: My understanding is that its expression in normal tissue is quite low.

Dr. Rudin: Quite low, yes, that is correct, so it becomes a tumor‑selective antigen.

Dr. Socinski: We have a number of agents that are in clinical trials. I wonder if you could just briefly review. I know you have an intimate relationship with the I‑DXd in that setting, so just run through what is going on with these ADCs?

Dr. Rudin: Yes. I would say there is a plethora of agents right now that actually all look fairly similar in terms of strategy. I‑DXd, or ifinatamab deruxtecan, is maybe the one that has been most extensively studied to date, although there are others that are fast on its heels. This is an antibody with a topoisomerase I payload and highly specific for B7‑H3.

Others in this category, risvutatug rezetecan, generally known as Ris‑Rez is a similarly designed molecule, also with a double warhead. These essentially all have topoisomerase I inhibitors as payloads. YL201 is another agent of the same class also targeting B7‑H3, and then MHB088C is a fourth molecule also targeting B7‑H3 with a very similar design. They vary a little bit in terms of their antibody structures and the drug‑to‑antibody ratios, but really, the clinical data we have seen with them, as we will discuss, has been pretty similar.

I would say there is a broader class of these antibody‑drug conjugates in small‑cell lung cancer. As you pointed out, other targets of real interest include DLL3, SEZ6, and also TROP2, which, of course, has been explored as an ADC target across multiple cancer types.

Dr. Socinski: I have to admit, the data that we saw from Dr. Byers at ASCO that was presented at a previous meeting, also with the SEZ6 ADC, was actually quite impressive.

Dr. Rudin: Absolutely. That is one of the leading molecules in this space, and that actually was recently published in Nature Medicine, the initial trial with ABBV‑706.

Dr. Socinski: In getting back to the B7‑H3 family, we had a recent press release in mid‑July; we have seen a number of positive trials out of China. There was another positive trial with Ris‑Rez against topotecan in relapsed small cell lung cancer that was positive for overall survival, so I completely agree the clinical data with these agents looks quite similar across all these drugs, and it really is nice to have a feeling that we are moving beyond our current standards in the second‑line setting. You have done some work with I‑DXd; tell us a little bit more about that.

Dr. Rudin: This is an anti‑B7‑H3 IgG1 antibody. It has a drug‑to‑antibody ratio of 4:1, so it is carrying four payloads, if you will, on a single antibody. It has shown good efficacy in terms of response rate in patients with small cell lung cancer. These antibody‑drug conjugates in small cell have shown response rates in the 50% to even 80% range across various trials, small numbers of patients, but really impressive response rates.

These also have toxicities, and one of the things that we have been concerned about with I‑DXd is watching for interstitial lung disease, sort of an inflammatory and potentially fibrotic reaction that can happen, although, can be managed if it is recognized very early or can become really problematic later. It is not unique to I‑DXd; it is something that we see really probably across the class with a variable incidence, but almost all of the topo-I warhead antibodies have had this as a potential adverse effect.

The initial data from the IDeate‑Lung01 trial, the first trial that really explored two different doses of I‑DXd in patients in second and third‑line small cell lung cancer, showed a response rate overall of 48%. This is in patients with multiply pre‑treated disease. One of the limitations of the antibody‑drug conjugates versus, say, the T‑cell engagers is although they have a higher response rate, the durability of the responses is not as high as we might hope it would be; duration of response with I‑DXd typical for this class was 5.3 months in the initial trial published earlier in JCO.

Dr. Socinski: You did also in this trial demonstrate intracranial activity, correct?

Dr. Rudin: That is correct, and actually the intracranial activity appears to be very similar to the systemic activity, so we used to think that antibody‑based therapeutics might not get into the brain very well, but in fact, in the context of metastatic disease to the brain, maybe some breakdown of the blood‑brain barrier, we are seeing good penetration, apparently, and evident responses.

Dr. Socinski: Getting back to the safety issues, most of the toxicities with I‑DXd seem to be GI in nature, as one would expect, some myelosuppression, but focusing just on the ILD issue with that, are there patients that you think, or you are particularly concerned about, with regard to the risk of ILD? Obviously, - the small‑cell population tends to be an older population, a smoking population; many of them may or may not have had prior chest radiation in the course of their disease. What are your thoughts just around potential risk factors, if there are any that are out there?

Dr. Rudin: Yes. This has been an area of really intense focus among all the drug companies and the clinical investigators studying these agents, trying to define, can we predict this side effect? The factors that you point out are things that we think are probably associated with increased risk of ILD that is a patient who has underlying causes of pneumonitis, whether that is disease‑related, COPD, and other underlying disease; whether they have a predilection for inflammatory reactions. If they have had pneumonitis related to checkpoint inhibitors, they would be at higher risk. Those patients who have had substantial chest radiation almost certainly are at increased risk, maybe just because they have a lower threshold of pulmonary reserve, so a little bit of inflammation in the lung tips them over more quickly.

Dr. Socinski: there are certain situations in the management of lung cancer where we get concerned about giving certain drugs following exposure to immunotherapy? Most patients with extensive‑stage small cell are getting immunotherapy first‑line, and I assume in this study, the IDEATE-Lung 01 trial, I would say that if not all, the vast majority of patients that were entered had had prior IO exposure, correct?

Dr. Rudin: That is absolutely correct.

Dr. Socinski: Yes, so it would be hard to sort out that issue. Just for our listeners, the rate of ILD/pneumonitis in the IDEATE-Lung 01 trial overall was about 12%, but about 4% of it was grade 3 or higher, and I do believe there are a couple of grade 5 events in the trial related to pneumonitis. It certainly is something that we see, but obviously not unique to this class of drugs. We deal with ILD/pneumonitis in this population with many of the drugs that we use.

Dr. Rudin: I would say not unique to this agent within this class, and not unique to this class within the context of small cell.

Dr. Socinski: Yes. Obviously, some have argued that ADC is another way to deliver chemotherapy, and so we see many of the chemotherapy side effects: some myelosuppression, some GI toxicity. Are those, in your opinion, similar to what we manage with cytotoxic chemotherapy?

Dr. Rudin: Yes. These are topoisomerase I inhibitor drugs, and so we do see those side effects. Those adverse effects of diarrhea and other GI toxicities, nausea, vomiting, and hematologic suppression. Those we expect, and I would say that relative to, say, irinotecan, they are probably less. That is, the ADC delivers chemotherapy to the tumor selectively. Of course, we do see these toxicities, but relative to the diarrhea and grade 4 neutropenia that you can see with irinotecan, I would say these are probably a little bit more selective for tumor.

Dr. Socinski: When I look at the data from this trial, the IDEATE-Lung 01 trial, when you look at things like dose delay due to treatment‑related adverse events, in this case, it was 25%; dose reduction 15%, discontinuation about 10%, really not different than what we see with most agents in this setting, so I do not know that this is a class of ADCs that the management would be dramatically different than what we would see and what we have been talking about. Would you agree?

Dr. Rudin: I would agree, and these were dosed in phase I close to MTD, and we do see these side effects, but the benefit of a very high response rate relative to standard chemotherapy helps weigh in favor of the ADCs over standard chemotherapy, and we have begun to see that readout in some of the comparative trials that you mentioned.

Dr. Socinski: Yes. The IDEATE-Lung 01 trial led to the IDeate‑Lung02 study, and this is an ongoing ‑ I do not think it is completed its accrual yet, but it is an open‑label phase III study comparing I‑DXd at the 12 mg/kg dose every three weeks with physician's choice on the control arm. The choice would be topotecan, lurbinectedin, or amrubicin if you are in Japan. I think that is the only country that has amrubicin. I believe we have this trial open at our center and have put some patients on it. I believe the lurbinectedin cohort is full at this point, but any comments on IDEATE-Lung02?

Dr. Rudin: Yes, it would be exciting to see how this reads out. It has been accruing pretty quickly, so it is a trial to keep an eye on, for sure.

Dr. Socinski: The other drugs that we talked about, I mentioned before, about the Ris‑Rez. We saw that press release from the ARTEMIS‑008 trial, a trial done in China, and we have been facing a lot of situations in thoracic malignancies where we have positive trials done in a single country, this being China, but there is an ongoing, I believe it is called the EMBOLD‑301 trial. That is essentially the same design outside of China, that is ongoing, with overall survival as the endpoint, but as you pointed out before, all of these agents in this class ‑ the YL201, the MHB008C ‑ all in phase III at this point. - The question is, Charlie, how many of these do we need?

Dr. Rudin: Yes, that is a great question. We do not need them all, but of course a lot of drug companies are betting on their agent and developing them in very similar ways. If we look across the landscape of these phase III trials, their design is pretty similar. The two that have completed accrual are the two that have been conducted exclusively in China. Although those will be really interesting to see the final results, I would say that the population of small cell lung cancer in China is a little bit different than in the rest of the world, in the fact that about 30% of the patients on these trials are never smokers. That is very different than what we see in small cell lung cancer in the rest of the world, where the rates of never smokers are maybe 4%, so although their results will carry over, the confirmatory rest‑of‑world trials are going to be really important, certainly for Western country approvals, and also for confirmation of activity.

Dr. Socinski: Yes, I believe our regulatory agency embraces multi‑regional trials done in more than one country rather than single‑country trials. Just as a bit of a sidebar, Charlie, you mentioned about 30% of non‑smokers in China diagnosed with small cell – any link to EGFR mutations? We know there is a small percentage of EGFR patients that transform into small cell. I have had at least one or two cases where that was really their presenting histology with an EGFR mutation, so I wonder.

Dr. Rudin: Yes, Mark, it is an excellent question because, of course, EGFR‑mutant lung cancer adenocarcinoma is super common in Southeast Asian populations, including China. There could be one factor – is tumors that essentially started as an adenocarcinoma but were diagnosed as de novo small cell, but with an underlying adenocarcinoma history, maybe with an EGFR mutation. However, the numbers seem to ‑ and the analyses that have been done to date suggest that there is a different biology independent of EGFR, of never‑smokers developing small cell lung cancer in China. I do not think we know the etiologic association that is responsible for that, whether it is underlying genetics or whether it is environmental exposure or what.

Dr. Socinski: Just getting back to when we were talking about the standard of care, I am interested in your perspective on how your practice of small cell has changed, say, over the past five years, and what you are doing now, and what patient factors may influence you to do strategy A versus strategy B? Have you embraced the lurbinectedin maintenance strategy? Are you doing that in your patients? Where do you place tarlatamab in the overall setting? What is your prediction for these new ADCs as they pass the phase III test how they are going to be integrated? We cannot forget about the DeLLphi trials with tarlatamab that are rapidly coming at us.

Dr. Rudin: Yes, Mark, your practice and mine, I think, we are generally treating patients with chemoimmunotherapy almost across the board. I really feel there are a few exclusions for giving patients the opportunity to respond to immunotherapy because, even though it provides a relatively small benefit as a population, there are durable responders to immunotherapy - rare but real. I feel like we owe our patients the opportunity to respond to that drug, and so chemoimmunotherapy is our first‑line in almost all patients. Maintenance immunotherapy, with the addition of lurbinectedin based on phase III data, certainly a reasonable strategy. That trial did not allow patients who were on the control arm to get lurbinectedin afterward.

There is an open question about whether combining immunotherapy with lurbinectedin is really better than sequential, but you can’t argue with a good hazard ratio and a positive survival phase III trial. It is certainly something to discuss with our patients. It adds some toxicity into the maintenance phase, but a real survival advantage.

And frankly, similar to first‑line immunotherapy, I think unless there is a really good reason not to give tarlatamab, I am tending to want to give that for patients with recurrent disease because there is good phase III data that it beat chemotherapy. It is the agent of choice.

As you pointed out, the tarlatamab trials, the DeLLphi trials, are now pushing tarlatamab into maintenance and into first‑line. We will see how those read out, but those could really change the landscape. Then the ADCs, if they are super active in third‑line, all of the companies are really trying to push them up to see can they actually replace some of the chemotherapy?

Dr. Socinski: Getting back to the maintenance strategy, even when we go back 20 years, when we started to embrace maintenance therapy in non‑small cell lung cancer, we typically took agents that we would use in the "second line" and used them as maintenance in patients who did not progress or did well during the first four cycles, so the best of the best patients. I have always viewed it as early use of second‑line agents in good patients. They got through the four cycles; they had a response; they did not progress; they got an active agent that we knew was active in second line, and we just moved it up because you know as well as I know, many of these patients, when you wait for progression, they have disease or comorbid complications that make a good treatment candidate a poor treatment candidate, and they might not get next‑line therapy.

I wanted to get your perspective on one other thing, and that is that brain metastases are like so common in this population and one of the impressive things we saw at ASCO was an analysis of the tarlatamab data where tarlatamab really erased the poor prognostic aspect of brain metastases in that trial, which was pretty impressive, which we do not see with chemotherapy, but we did see with that bispecific T‑cell engager. I am wondering: we did make the point that these B7‑H3 ADCs do have CNS activity, but I do not know if that has been looked at with, say, I‑DXd or any of the other ones at this point.

Dr. Rudin: Yes, we have looked at that in terms of activity in the brain, but you are absolutely right: the tarlatamab data was pretty striking that it seemed that the relative benefit for patients with brain mets of tarlatamab versus chemotherapy is actually greater than the overall benefit in patients who did not have brain mets. It is quite clear that these agents get into the CNS and are active there, so both the T‑cell engagers and ADCs seem to have good activity in the brain.

Dr. Socinski: I was taught that the vasculature for brain metastases comes from the systemic and is really not privy to the so‑called blood‑brain barrier. It is not a surprising observation that these things may work in the brain; the clinical evidence is compelling that they actually do at this particular point.

Dr. Rudin: Yes, they do. Yes, they do for sure.

Dr. Socinski: I want to present you a case. This is a patient that I am currently managing, and I would like your perspective on whether B7‑H3 ADC be part of his management. I do not know about New York, Charlie, but in Orlando, about 30% of our extensive‑stage small‑cell lung cancer patients present to the ER with symptoms, get admitted, and are diagnosed in the hospital, and for this gentleman that is what happened. He was about a 65‑year‑old African American gentleman, smoking history, of course, who presented with widespread disease, including something I had not seen in quite a while, and that was pancytopenia.

He had a bone marrow biopsy, and he had extensive infiltration of small cell lung cancer. he also had a liver biopsy that showed the same disease, and he got his first cycle of carboplatin and etoposide as an inpatient and responded very well. It was dosed ‑ I think it was about half a dose. I cannot remember exactly what they did in the hospital, but amazingly, when he showed up in my clinic about a week before he needed his second cycle, his CBC was normal, so he had a very nice response to his first cycle at dose attenuation.

Since his CBC was normal, we continued cycle two at full dose because his CBC was fine. Added atezolizumab to that regimen; got four cycles, had a great response in his chest and his liver. Everything looked good, I did not obviously repeat a bone marrow because his CBC returned to normal, but had a great PR not a CR, but a great PR. We continued on. I did add lurbinectedin as maintenance therapy. He did get his first dose with growth factor support, and his major complaint was bone pain after that, so he was not having problems with cytopenias, and so I discontinued the growth factor and just gave him atezolizumab/lurbinectedin, which he did fine with; he never really had blood count issues. he got five or six cycles of the lurbinectedin with atezolizumab.

Before he was on routine screening, he was still asymptomatic, but his CT suggested that he clearly was worsening with worsening liver disease. His marrow seemed to still be fine with regard to his CBC, but his disease was progressing at this point. This type of patient would have been the type of patient that would have gone on the IDeate‑Lung01 trial, correct?

I recommended that we treat him with tarlatamab, which he got really only about a week or so ago, but much to my surprise ‑ I am still struggling with the grading of the ICANS, but somewhere between grade 2 and grade 3 ICANS. He did get observed in the ICU overnight because of his neurologic changes, but then has now recovered. About a week ago, we decided to delay day 8 for a week just to get him out of the hospital for a few days and make sure he is back to normal before we rechallenge him. I had not seen any ICANS yet until this patient, and so I just wanted to get your perspective on it and see what your experience has been.

Dr. Rudin: Yeah, that is a great case and a fairly typical one except for the initial presentation with the pancytopenia ‑

Dr. Socinski: Yes. When is the last time you saw pancytopenia with a small cell and ‑

Dr. Rudin: Pretty rare, I would say. It certainly is a disease that goes to bone marrow; we saw that in the old days, when they did bone marrow biopsies for staging, that was ‑

Dr. Socinski: Bilateral bone marrow biopsies.

Dr. Rudin: I would say even though he had ICANS, I would not necessarily give up on the tarlatamab. These toxicities, the CRS and ICANS tend to be transient, and if you can get folks through the first two or three doses, oftentimes we do not see it anymore. Those patients can get good durable benefit from the therapy, so it scares patients, it scares doctors, it scares nurses, it scares everybody, but if the patient is willing to keep going, I might stay at the 1 mg/kg dose, not escalate as we typically do for day 8, but I might continue with the tarlatamab. Down the road, he would be an appropriate candidate for an antibody‑drug conjugate if his performance status allows it. These drugs are not approved for use, so these are not prescribable agents yet, but if there were an opportunity to get that, it would certainly be on my list of options for him.

Presenting the case, I wondered about trilaciclib, a different agent, but just to think about, patients who present with marrow insufficiency are really ideal candidates. I did not use it a lot, but ‑

Dr. Socinski: Yeah, I might have used it in this case. I might have used it just out of caution with him for those cycles two through four.

I do agree the CRS stuff and ICAN stuff seem to be a first couple of doses issue, and then that seems to go away for the most part. Given the activity that we have seen, I really do not have anything else for him at this point that I would be enthusiastic about, so we are planning to move ahead. He is going to come in for the next dose, and we will make a decision whether it is the 10 mg/kg or the 1 mg/kg, but you would say 1 mg would be your strategy.

Dr. Rudin: I might say 1 mg/kg. I do not honestly know that it is that dose‑dependent, but yes, that is generally what we would do, and we would again hospitalize the patient to make sure that we are monitoring him closely.

Dr. Socinski: At some point in the future, when we may have B7‑H3 directed ADCs, what is your recommendation on how they are going to be integrated? What patient education things? What things would you want physicians to know in terms of recognizing toxicity and assessing any patients that may be at increased risk, for instance, for ILD?

Dr. Rudin: The initial indication for these drugs is very likely to be recurrent disease setting. That is really where the drug companies are pushing for accelerated FDA consideration. I currently would see them as drugs that would sequence after tarlatamab. Of course, as we mentioned, the newer trials are looking at them earlier in the patient's journey, and we will see how those trials play out. Initial indications are that they may be quite exciting, but we will have to wait for the data. There will be, initially, in patients who have had prior chemo‑IO and prior T‑cell engager.

The things to look out for in those patients: do they have underlying evidence of pneumonitis or pulmonary limitation? I would not necessarily not treat a patient if they had poor pulmonary function. The truth is in small cell lung cancer, the vast majority of our patients are not going to have great PFTs, but I would be really cautious and watch closely in patients who we think might have increased risk.

Dr. Socinski: Yes, I agree. It is an exciting time. This has been a great discussion, Charlie. I appreciate you joining us for this podcast. For the first time in a very long time, there is a degree of optimism with all of these new agents starting with tarlatamab and continuing on with these B7‑H3 agents, and SEZ6, DLL3, TROP2. We have got a lot of things going on, so hopefully we will be able to see some progress in extensive‑stage disease and move that into limited‑stage disease. How to incorporate it into a combined modality treatment. There are other challenges there, but certainly it is almost an incredible couple of years with these new agents coming into presentations at national meetings and international meetings. You focused on small cell for much of your career, so your perspective as a small cell, Doctor?

Dr. Rudin: Yes, I totally agree. It is a very exciting time, and it is great to see these trials rolling out, and you do not score if you do not shoot on goal, and now we are taking a lot of good shots. We have some really good shots on goal. We will see how they play out, but I am pretty optimistic that the standards of care will continue to change over the next few years.

Dr. Socinski: Yes, and it is important for our listeners to really embrace clinical trials. We really need to get a greater percentage of our lung cancer population to participate in clinical trials. I always say it starts with the doctor thinking about a clinical trial portraying it to your patient as the standard of care plus, and we cannot make these advances unless we have patients participate in clinical trials. Again, this starts with the physician, and the physician has got to believe that we need to continue to make progress.

So, I want to thank everyone for listening today, and hopefully this evolving role of B7‑H3‑directed ADCs in the extensive‑stage small cell treatment landscape was useful for your practice, and looking forward to the future as these agents become available for clinical practice. Thank you.

Dr. Rudin: Yes. Thanks, Mark. Great discussion.