We are going to start by discussing limited stage or a few issues in limited stage, and talk about the standard of care in that population. These are slides from the NCCN guidelines. As you can see, this is in very early stage.

Stage I‑IIA LS‑SCLC: Testing, Primary Treatment, and Adjuvant Therapy

Now, this is not a particularly common presentation of small‑cell lung cancer. You can see this is a slide that outlines the testing and primary treatment for stage I to IIA. Obviously, if you have an early‑stage small‑cell lung cancer or a radiographic finding that looks like a stage I or II, from a clinical point of view, obviously, the first question is the status of the mediastinum.

Pathologic mediastinal staging is done initially. Obviously if it is positive, that changes the stage to a higher stage, and in that case, with positive mediastinal nodes, the recommendation would be to pursue treatment for standard limited‑stage small‑cell lung cancer.

If it is pathologically negative, then surgical options for those patients who are both resectable and operable are options for patients. Generally, the recommendation is to give adjuvant systemic chemotherapy in this population. There may be subsets of patients that one would consider mediastinal radiation, those patients that have either positive margins or those patients who are found to have nodal disease despite a negative initial pathologic mediastinal staging.

There may be patients who are medically inoperable that are not surgically resectable. Certainly, targeted radiotherapy is an option for these patients, but probably should be followed by systemic therapy.

To make a long story short, I think that my training has always been that based on the TNM system, small cell should probably be managed similar to how we would manage early‑stage non‑small cell lung cancer.

Current Clinical Guidelines on Primary Treatment for Stage IIB‑IIIC LS‑SCLC

More commonly, we are dealing with what we frequently call limited‑stage small‑cell lung cancer. Historically, this has been defined as those patients that have a disease extent that is encompassed within a tolerable radiation port. The stages here would be closer to stage IIB or stage III. Certainly, in the good performance status patients, the standard of care, as I tell my patients in this setting, this is potentially curable with systemic chemotherapy delivered concurrently with radiation. I will show you the ADRIATIC trial, a new standard of care showing the benefit of durvalumab consolidation if patients have no disease progression during the adjuvant chemo radiation.

This is really limited to patients with good performance status. We certainly see many patients that have borderline or poor performance status, in which one may consider a sequential approach, giving up to four cycles of systemic chemotherapy. Sometimes the performance status improves, and the patient becomes a better candidate for radiotherapy, which could be done either concurrently or sequentially. If patients have significant comorbidities, and it is really not the cancer driving their poor performance status, then I think you have to really take that on a case‑by‑case basis.

ADRIATIC: Consolidation Therapy With Durvalumab for LS‑SCLC

Now, I mentioned the ADRIATIC trial before. This was a trial we saw at ASCO a year ago and published in the New England Journal, as you can see there. This was an international randomized phase III trial taking early‑stage or limited‑stage patients that received concurrent chemotherapy and radiation. PCI was allowed prior to the randomization, assuming that they had no evidence of disease progression. They were subsequently randomized, as you can see, to one of three arms, although the primary focus of the trial was the top two arms. Obviously, the standard of care was placebo because we were not aware of giving any consolidation therapy after concurrent chemo‑radiotherapy had a benefit in this population.

In the investigational arm of interest was durvalumab given at a standard every‑four‑week dose of 1500 mg, and done for two years. Patients did have to get three to four cycles of platinum plus etoposide. There was some flexibility in terms of the radiotherapy prescription, either 60 to 66 gray once a day or 45 gray twice daily. It had to start relatively early in the concurrent chemo strategy.

The coprimary endpoints were either progression‑free survival by blinded review as well as overall survival. Then you can see the secondary endpoints shown at the bottom. To my knowledge, we have not seen data from the durvalumab‑tremelimumab. If I am wrong about that, someone can correct me later on.

ADRIATIC: OS and PFS (Coprimary Endpoints)

Here are the coprimary endpoints. We have overall survival to the left, you can see that these curves separate really at about six to nine months or so. The hazard ratio here is 0.73, which is in the range of hazard ratios that we have seen in historical trials that have changed the standard of care. My personal practice has changed based upon this benefit in overall survival here. You can see at three years, 56% of the patients alive on the durvalumab consolidation arm versus about 47% on placebo. So roughly about a 10% difference in survival at the three‑year time point. Of course, we will be interested in more maturation of this overall survival curve to see what the curves look like out at five years or so.

There was a benefit in PFS. Again, a hazard ratio very similar at 0.76. At least from my perspective, this did create a new standard of care in those patients with limited stage disease treated with potentially curative chemo radiation, who are able to go on to get consolidation treatment.

Establishing Standards for Radiotherapy in LS‑SCLC

Now, I mentioned the radiotherapy prescription could have been one of two strategies, either once a day to 60 to 66 or twice daily. This is a trial done over 25 years ago, published in 1999 in New England Journal by Turrisi, exploring the effect of, for lack of different phrase, dose intensification of radiotherapy. The same dose 45 gray in both arms either delivered once daily or twice daily. You can see there was a late advantage in overall survival for the twice‑daily radiotherapy and about a 10% difference at five years.

There was a notable difference in improved local tumor control. It came at a slightly increased risk of toxicity. I think that benefit and overall survival was certainly tolerable given the benefit and survival that we saw. Surprisingly, this really has not influenced practice as most patients do not get BID radiotherapy, but certainly is an option.

Ongoing Immunotherapy and CRT Trials in LS‑SCLC

Now we have another set of ongoing immunotherapy and concurrent chemo radiation trials in limited stage small cell. We discussed ADRIATIC. There are three other listed here. We have seen the results of one of them. That was the NRG‑LU005 trial. This was presented by Kristin Higgins at ASTRO, I think, last year, and published in the JCO. You can see here this was an international randomized phase III trial.

NRG‑LU005: Atezolizumab With CRT for LS‑SCLC

The one difference here, or the couple of differences here, was the use of a PD‑L1 agent, that is different. Atezolizumab versus durvalumab. I am not quite sure they are necessarily different, like Coke and Pepsi. In this case, this agent was delivered concurrently with the chemo radiation there. You did have the option of the two different radiotherapy prescriptions shown here after the completion of the concurrent aspect of treatment with immunotherapy, chemotherapy, and radiotherapy. Patients on the atezolizumab arm were continued on maintenance therapy for up to one year.

NRG‑LU005: OS (Primary Endpoint) and PFS

In this case, the primary endpoint was overall survival. You can see the key secondary endpoints. You can see here this had a different result than ADRIATIC. Certainly, you can see these curves essentially overlap. No significant difference between the two arms in either overall survival or progression‑free survival. Obviously, a strategy that was not successful relative to the sequential use of immunotherapy demonstrated in the ADRIATIC trial.

That is our very brief review of limited‑stage small cell. I am going to turn it over to my colleague Charlie to focus on extensive stage disease. Charlie.

Dr. Charles Rudin (Memorial Sloan Kettering Cancer Center): Thanks, Mark. While I have you, it is an interesting dichotomy there between the ADRIATIC and the LU005. Similar to what we saw in non‑small cell lung cancer. Right?

Dr. Socinski: Yes, exactly. Slightly different trial designs. One, the randomization was after completion of chemo radiation, here was before. Obviously, I do not think there is much of a difference. You and I were chatting beforehand about the atezolizumab durvalumab comparison, Coke Pepsi, but you are right, the same story is true in non‑small cell. There must be some magic to doing it in a sequential way.

Dr. Rudin: In a specific way.

Dr. Socinski: Yes, exactly. At least it is consistent data, although this is not the first time we have been faced with one positive and one negative trial. Although I think the NRG trial is a very different design and should not quell the enthusiasm that we have for ADRIATIC. I do not know if you agree with that or what?

Dr. Rudin: I totally agree. I think the lesson there is really that overlapping at least standard fractionation daily radiation with immunotherapy, may be not such a great idea. Non‑small cell, small cell, and head and neck all showing a negative interaction when you overlap.

First‑line and Maintenance Therapy in ES‑SCLC: Reinforcing the Foundation or Redrawing the Map?

I am going to talk about extensive stage disease. We will start out in the first line setting, move to maintenance, second line, and then look at some of the drugs that are up and coming in the landscape of small‑cell lung cancer.

Patient Case 1

We will start out with a case. This is a 58‑year‑old gentleman, 35 pack‑year smoking history, presents with extensive‑stage small‑cell lung cancer. No evidence of brain metastases on MRI. He has a good performance status, ECOG PS of 1, and no significant comorbidities. He completes standard induction chemo immunotherapy with carboplatin, etoposide and atezolizumab, gets a partial response, typical outcome. He tolerated the treatment well with minimal toxicity, so he is doing well. During a follow‑up visit, he asks about next steps in the maintenance setting and whether adding another agent could improve outcome compared to continuing atezolizumab alone.

Pretest 1

The pre‑test question here is which of the following results from the phase III IMforte trial evaluating lurbinectedin plus atezolizumab versus atezolizumab alone as first‑line maintenance therapy would be appropriate to discuss with this patient.

1. The combination demonstrated inferior overall survival due to increased hematologic toxicity
2. The combination significantly improved PFS compared with atezolizumab alone, with a manageable safety profile
3. No difference in efficacy outcomes were observed, but toxicity was substantially higher with the combination therapy
4. The benefit of combo therapy was limited to patients with baseline brain or CNS metastases

Go ahead and choose. We will put that one in the bank for later. Interesting results.

Current NCCN Guidelines on Primary Treatment for ES‑SCLC

This is the NCCN guidelines schematically presented for primary treatment of extensive‑stage small‑cell lung cancer. For most patients who have a decent performance status or performance status that is really poor due to the disease, all the way at the left here, without localized symptomatic sites or brain metastases, they should be treated with what most people are given, which is a combination of a platinum etoposide and a checkpoint inhibitor, combination systemic therapy.

Patients, just like in limited stage, who have poor performance status that is not attributable to the disease, have to be carefully considered for whether they are appropriate for therapy and, if so, what.

Localized symptomatic sites can be treated in addition to the systemic treatment given to most patients. If patients have, for example, superior vena cava syndrome or lobar obstruction, those are complications in the chest that can be addressed usually with local radiation. Painful bone metastases similarly can be managed with radiation while pursuing standard systemic therapy.

Spinal cord compression, of course, is a somewhat different scenario. This is one of the few oncologic emergencies we face, and so standard of care there for all solid tumors, begin steroids and probably neurosurgical consultation, but likely radiation fore fronted and then systemic therapy.

Patients with brain metastases, if they are asymptomatic, can actually go ahead and begin systemic therapy. We do not hold their therapy for treatment of the brain, typically. Of course, for symptomatic brain metastases, they need to be managed. Again, this is going to be a neurosurgical consultation, radiation consultation, and probably integrating those modalities as quickly as possible for symptomatic brain metastases while also thinking about beginning systemic therapy.

Phase III Trials: Anti–PD‑L1 Immune Checkpoint Inhibitors to First‑line Platinum + Etoposide in ES‑SCLC

The standard of care has really been defined by these two trials, on the left IMpower133, and on the right CASPIAN. These trials are quite similar. The CASPIAN trial, like the ADRIATIC trial that Mark presented, had a third arm, which was durvalumab, tremelimumab on top of chemotherapy. This arm has been presented and did not show benefit relative to the other two, but had increased toxicity.

I think the key comparisons here are the control arms, which were chemotherapy, carboplatin etoposide, or with CASPIAN cisplatin was allowed, versus the same chemotherapy with the addition of the PD‑L1 antibodies, either atezolizumab in IMpower133, or durvalumab in CASPIAN, with continuation of that immunotherapy as maintenance.

IMpower133 and CASPIAN: OS

Those were two key comparisons, and these two phase III trials had actually very similar outcomes, as shown here. Again IMpower133 on the left, CASPIAN on the right. You can see there is a significant advantage to the addition of either atezolizumab or durvalumab for these patients. The benefit is not as big as we would like, of course, but it is meaningful, and there is a significant tail on the curve, maybe best demonstrated in the CASPIAN arms on the right, with about a tripling of three‑year survival here with the addition of durvalumab.

This curve really flattens out. We do have long‑term disease‑free survivors, not a lot but some, with extensive‑stage small‑cell lung cancer who get immunotherapy. This really has redefined our standard of care due to the survival advantage associated with adding a PD‑L1 agent to standard platinum etoposide backbone chemotherapy.

IMforte: Lurbinectedin + Atezolizumab as First‑line Maintenance Therapy in ES‑SCLC

Another trial that was presented in this past year was the IMforte trial. This was at ASCO this past year and has been subsequently published in The Lancet. This looked at the maintenance and took the backbone from IMpower133, chemotherapy with atezolizumab followed by atezolizumab maintenance, and asked the question, could you get benefit from adding a cytotoxic on top of the atezolizumab in maintenance, and lurbinectedin was added to atezolizumab in maintenance on this trial.

IMforte: IRF‑PFS and OS (From Randomization to Maintenance Therapy)

This was a large randomized trial to assess progression free and overall survival as coprimary endpoints. This trial did read out positive. Here are the Kaplan‑Meier curves, on the left progression‑free, and on the right overall survival. You can see that there is a benefit to the addition of lurbinectedin into the maintenance setting.

I would say a couple of caveats here. This benefit in progression‑free survival and a small benefit in overall survival, here about three months' time, comes with a price, and the price is increased toxicity with the addition of the cytotoxic lurbinectedin in the maintenance setting. I do think for patients in maintenance, avoiding those chemotherapy‑related toxicities is a real benefit. Although this is a positive trial and led to FDA approval for this regimen as an option, I think uptake has been somewhat limited because of those caveats with toxicity.

The other caveat I would put out there, a clinical trial caveat, is the patients who are on the control arm, the atezolizumab, only about 11% of them ever received lurbinectedin. The majority of patients never were given the option of getting lurbinectedin because it was largely run outside of the United States as a trial.

But an important benchmark, lurbinectedin is a good drug. It is a useful drug, whether it is used in maintenance or second line. I think it has a home for patients with small‑cell lung cancer.

DeLLphi‑303: Tarlatamab + PD‑L1 Inhibitor as First‑line Maintenance in ES‑SCLC

The DeLLphi‑303 trial looked at a T cell engager. This is a molecule that binds to the T cell and also binds to small cell lung cancer cells. That is called tarlatamab. This was a trial combining tarlatamab with a PD‑L1 inhibitor, and it was either atezolizumab or durvalumab. There were two arms on this trial to really look at whether you could combine these in the maintenance setting. The same setting that the IMforte trial was run in.

Patients got platinum etoposide with dealer's choice PD‑L1 inhibitor. The maintenance continued that same PD‑L1 inhibitor, but with the addition of tarlatamab. This was really an initial trial to look at whether this was tolerable and safe, and to look at initial clinical data outcome.

DeLLphi‑303: Survival

This is the outcome for the trial. This is actually quite impressive to me. You know, the survival curve that I just showed you, the IMpower133 and the CASPIAN trials, overall survival median was about 12 to 13 months. This is a maintenance trial, so 100% of the patients got through the initial induction chemotherapy. Nonetheless, this survival curve looks really quite impressive to me.

We have really never had a trial for recurrent metastatic small cell lung cancer with median survivals over two years, which was what we are seeing here with this combination. Early data here, I think we will have to wait for the larger phase III trial that actually compares these regimens to a standard of care, but I think this looks quite intriguing. This has been published in Lancet Oncology this past year.

DeLLphi‑303: Efficacy Summary

This is another snapshot of the efficacy. Overall response rate here was quite high. As you can see, disease control rate 82%. To me, the impressive thing is really 12 month overall survival, 80%, and median overall survival extending out over two years, and with a median that is not reached quite yet. Really quite impressive data. People are excited about this as a potential combination therapy for the future.

Future Outlooks for Tarlatamab in SCLC

The future outlook for tarlatamab in small‑cell lung cancer. There is a few important trials to know about. The DeLLphi 305 trial is bringing tarlatamab into the first‑line setting together with durvalumab as first‑line therapy for extensive‑stage small cell lung cancer, so patients will get chemo durvalumab together with tarlatamab.

The DeLLphi 306 trial will actually look at limited‑stage small‑cell lung cancer, building on the benefit that we saw with durvalumab there. This will actually look at tarlatamab and placebo after chemo, radiotherapy for limited‑stage small‑cell lung cancer. So we will see how this will read out.

Biomarker Selection in SCLC: Clinical Utility and Ongoing Challenges

Biomarker selection for small‑cell lung cancer is an ongoing problem. We do not really have good biomarkers to direct therapy for small‑cell lung cancer. There have been looks at TMB, tumor mutation burden, as a predictor. There was some initial data that there was a higher response rate associated with higher TMB in patients treated with a combination of nivolumab and ipilimumab on the CheckMate 032 trial. I would say there is limitations to these data. It really has not borne out in other data sets. There is no standard assay or cut‑off. To me, it has very limited role in clinical decision making.

I would point out re‑analysis of CheckMate 032 patients with small‑cell lung cancer, another biomarker that I think is maybe a stronger predictor is actually expression of antigen presentation machinery. You need class 1 to actually recognize antigen by cytotoxic T cells, and analysis from CheckMate 032 does suggest that antigen presentation would be an important biomarker.

DLL3 may be a biomarker for DLL3‑directed therapies like tarlatamab. Really, in clinical practice, we have no established predictive biomarkers. Patients with small cell lung cancer are largely treated similarly in standard of care.

Select Ongoing Trials on Prophylactic Cranial Irradiation

Prophylactic cranial radiation has become an area of controversy in small‑cell lung cancer. These are three ongoing trials looking at the role of PCI. In historical data, prophylactic cranial radiation clearly benefits patients with limited‑stage small cell lung cancer with a survival advantage. I would say it is still part of our standard of care in that context, although the role of it now with immunotherapy after chemo, radiotherapy is at least questionable.

It is very questionable for me in the context of extensive‑stage small cell lung cancer. There was a Japanese trial that really looked at doing MRI to detect disease and use that as a criteria to exclude patients from PCI versus giving PCI, that the PCI group actually did worse. I think in standard practice for me in extensive stage, I am not using PCI. But I think it will be interesting to see how these trials read out. These trials are looking at limited stage and extensive stage, both in the first two trials, to see if there is really a role across these stages in the modern era.

Posttest 1

Posttest. We are back to the patient with a good performance status, who had a good response to initial induction chemotherapy. He is asking you about atezolizumab maintenance and whether adding an additional agent could be of benefit. The possibilities are:

1. The combination demonstrated inferior overall survival due to increased hematologic toxicity

2. The combination significantly improved PFS compared with atezolizumab alone, with a manageable safety profile
3. No difference in efficacy outcomes were observed, but toxicity was substantially higher with the combination therapy
4. The benefit of combo therapy was limited to patients with baseline brain or CNS metastases

We will see if we had a better signal this time. Go ahead and vote.

We improved. I think the best answer here is combination significantly improved progression‑free survival compared to atezolizumab alone, with a manageable safety profile. I would say toxicity was higher, so those that voted for C, there was a difference in efficacy, so that is a wrong answer, but I think it is a consideration.

Relapse and Resistance: Sequencing Novel Agents With Confidence

Now we are going to talk about relapse and resistance. Looking at second line and beyond, and looking at some of the novel agents that have really come to the fore in 2025 and 2026.

Patient Case 2

We will start again with a case. This is a 64‑year‑old woman, 45 pack‑year smoking history, diagnosed with extensive‑stage small‑cell lung cancer 10 months ago. She had liver and bone metastases, no brain involvement. She received first‑line carbo etoposide atezolizumab. Partial response again, followed by maintenance atezolizumab.

After eight months of disease control, she now presents with progressive disease in the liver and new pulmonary nodules. A brain MRI remains negative. Her ECOG performance is good at 1.

She has not received a prior second‑line therapy, and lab studies show adequate bone marrow and organ function. She asks you about treatment options that may provide meaningful disease control.

Pretest 2

Which of the following would be the most appropriate next line treatment that you would recommend? Is it

1. Lurbinectedin monotherapy;
2. Pembrolizumab;
3. Single agent topotecan; or
4. Tarlatamab.

Go ahead and put down your nickel.

Pretest 3

Another pre‑test. Which of the following was reported from the DAREON‑9 trial of obrixtamig in patients with relapsed small cell lung cancer?

1. Durable responses observed in DLL3‑expressing tumors with T‑cell engagement
2. Significant overall survival improvement in a randomized phase III trial
3. Antitumor activity observed, underscoring need for improved patient selection
4. Superiority to platinum/etoposide in the first‑line treatment setting

I would say this is a tougher question. Indeed, answers are all over the map for this one. So that is good, that means we are in a position to teach you something now.

Key Therapeutic Innovations in ES‑SCLC Over Time

These are some of the key therapeutic innovations in extensive‑stage small‑cell lung cancer. A little bit of a timeline. Platinum etoposide has been around since the 1980s, and really, very little has progressed. Since then, we have had the addition of topotecan, nobody's favorite drug, in 1998, oral topotecan coming on the scene. I told you about the first‑line extensive stage trials, bringing in atezolizumab and durvalumab in 2019 and 2020.

Lurbinectedin got an accelerated approval in second line in 2020 as well. Durvalumab maintenance for limited‑stage small‑cell lung cancer just in 2024. Tarlatamab, second line, extensive‑stage small‑cell lung cancer, accelerated approval in 2024. Full approval in 2025. Lurbinectedin maintenance also making the bar in 2025. We are beginning to see some new drugs emerge on the scene.

Phase Ib/II Trial of Lurbinectedin + Irinotecan in Relapsed SCLC

The first trial we will talk about was designed to be a confirmatory trial for lurbinectedin. This was a trial looking at lurbinectedin and irinotecan in relapsed small‑cell lung cancer. This was the initial trial, phase Ib/II, looking at this combination, and in all patients, this had a reasonable response rate 42%. Pretty good for patients with recurrent small‑cell lung cancer.

Median duration of response at seven months. Progression‑free survival, a little bit short at 4.7. Overall survival, not terrible for patients with recurrent small cell lung cancer at 9.7 months, and a 12‑month overall survival at about 45%. You can see that the chemotherapy‑free interval makes a difference. This is generally true across the board. Patients who do poorly on first‑line chemotherapy and relapse early are less responsive to second‑line therapy. No surprise there.

LAGOON: Lurbinectedin ± Irinotecan vs Topotecan or Irinotecan in SCLC

This data set up a subsequent LAGOON trial. This looked at lurbinectedin with or without irinotecan versus topotecan or irinotecan, dealer's choice on the control arm here. So really looking at lurbinectedin versus standard of care, or the combination of lurbinectedin and irinotecan. Primary endpoint of overall survival. We will see how that one reads out in the future.

Phase I/II LUPER: Lurbinectedin Plus Pembrolizumab in SCLC

This was a trial that was published in 2025. This is the LUPER trial. This is looking at lurbinectedin and pembrolizumab in the recurrent disease setting for small‑cell lung cancer. This was exclusively patients that did not get an immune checkpoint inhibitor in the first‑line setting. I think the relevance of these data becomes much less now that we have first‑line immunotherapy, but this did show a benefit from lurbinectedin and pembrolizumab with a nice waterfall plot, as you see here, and a reasonable overall response rate, particularly in platinum‑sensitive disease. This really set up the concept of bringing lurbinectedin into maintenance with immunotherapy, which was the IMforte trial, where it was combined with PD‑L1 inhibitors and showed a benefit.

DeLLphi‑301: Tarlatamab in Relapsed ES‑SCLC

The DeLLphi‑301 trial was an important trial. This was the first trial really looking at tarlatamab in the relapsed setting. So, second line and beyond. This was a dose‑finding trial. It randomized patients between 10 and 100 mg of tarlatamab given every two weeks. This was designed for Project Optimus in the NCI, that you need to find appropriate doses to carry forward in phase II, so a 10‑fold difference in dose here.

The primary endpoint was to choose the arm with the best overall response by RECIST, with key secondary endpoints as shown here. Bottom line outcome from this was very similar in the two arms, and the 10 mg dose was chosen to go forward. I will show you the data that led to this here, tarlatamab 10 versus 100.

DeLLphi‑301: Efficacy With Tarlatamab in Relapsed SCLC

Overall response rate actually numerically higher on 10 mg, although probably not statistically different. You can see the outcomes are very similar. This is not really a dose‑responsive drug, a 10 and 100 mg pretty are similar in terms of outcome, and so the lower dose is really chosen to go forward.

DeLLphi‑304: Tarlatamab vs SoC in SCLC Following Progression on Platinum‑Based Chemotherapy

This trial really set up the DeLLphi‑304 trial, which was the definitive international randomized phase III trial comparing tarlatamab versus standard of care. The standard of care arm could be topotecan, which is available in almost all countries, lurbinectedin in a more limited number of countries, and amrubicin really approved only in Japan for second‑line therapy. It was set up this way to really allow physicians to choose their best second‑line therapy, in their mind, of the available therapies versus tarlatamab. Primary endpoint here was overall survival.

DeLLphi‑304: Efficacy With Tarlatamab in Relapsed SCLC

This trial showed a clear benefit, both in terms of progression‑free survival on the left, and overall survival on the right. The overall survival hazard ratio is 0.60, quite a strong result. I would point out this trial read out at its planned first interim analysis. The median follow‑up here is only about 11 months. We really want to follow these curves out and see if there is a plateau, and if so, where does it layer out on this trial?

Although this was the definitive results and published in the New England Journal and led to full FDA approval, I would say we really want to follow these data out and see where these curves continue, because more than 11 months of follow up would be really helpful here. But a clear, definitive improvement, not only survival advantage here, but as I think Mark will probably present later in the talk, there is actually some improvements in patient reported outcomes: cough, chest pain and shortness of breath on the tarlatamab arm.

Obrixtamig (BI‑764532), a DLL3/CD3 Bispecific Antibody in DLL3‑Positive Tumors: NCT04429087

Obrixtamig is a very similar agent, at least similarly designed. It binds to DLL3 on the cancer cell, on the small cell lung cancer, and CD3 on the T cell. It is another bispecific antibody. This has been studied in an initial phase I dose‑escalation trial. About half the patients on this trial were small cell lung cancer. The other half were DLL3 positive. Other tumor types, extrapulmonary small cell and large cell, as well. Primary endpoint here was really a phase I type of endpoint.

NCT04429087: Baseline Characteristics

These are the patients that went on this trial. You can see about half the patients, again small cell lung cancer, the other half extrapulmonary small cell and large cell neuroendocrine cancer. Multiple prior lines of therapy.

NCT04429087: Responses in All Patients

This was the waterfall plot. It looks really quite good. I would say this agent and tarlatamab look pretty similar. It was nice to see that this agent actually works in neuroendocrine tumors outside of small cell lung cancer, as well as small cell lung cancer. Overall response here 36%.

Obrixtamig: Efficacy in Patients With Relapsed SCLC

This was the data in small‑cell lung cancer patients on that trial. If we just look at the small cell, the overall response rate here, 21%, many of these patients who are responding continuing to respond. This looks quite good. Mark will review some of the toxicities. I would say cytokine release syndrome, a class effect of these drugs, is an important one that we are learning how to manage.

DAREON‑9: Phase Ib Study of Obrixtamig + Topotecan in Relapsed SCLC

The DAREON‑9 trial looked at the combination of obrixtamig and topotecan in patients with relapsed small cell lung cancer. Topotecan is a chemotherapy backbone. Now adding the obrixtamig, the T cell engager, on top of it. This was a dose escalation trial to really look at this as a combination in the second‑line setting. There is concern about combinatorial toxicity with combining agents, and topotecan is not always the easiest agent to combine with, but the data was significant in terms of the ability to combine these drugs in the recurrent disease setting. Whether this is relevant now in the tarlatamab era, now that tarlatamab is approved, I think, is an open question.

DAREON‑9: Efficacy With Obrixtamig + Topotecan in Relapsed SCLC

This did have a nice waterfall plot, as you can see here, with the majority of the patients demonstrating a partial response rate of 65%. Essentially, all patients showing at least disease control, really no primary progressors here. So it is an interesting combination. It is hard to know exactly what its future is going to be, but obrixtamig made clearly an active agent.

First‑in‑Human Phase I/II Trial of Gocatamig (MK‑6070) in Patients With SCLC and Other Neuroendocrine Cancers

Another drug in the same class, gocatamig, actually directed against exactly the same targets, DLL3 and CD3, was also studied in initial trials including patients with small cell lung cancer, neuroendocrine prostate cancer, and other tumors selected for DLL3 expression. This trial actually included an expansion arm that looked at the combination with atezolizumab as well, which again I think the T cell engager plus checkpoint inhibitor is going to be a really interesting combinations to keep an eye on going forward.

Phase I/II Trial of Gocatamig (MK‑6070): Efficacy/Safety Summary

This was a safety and tolerability study, but really had impressive outcomes, as you can see in this swimmer plot, the majority of patients showing good responses and some patients really having extended responses as shown here. Cytokine release syndrome is a significant problem, but rarely grade 3 and above. Most patients, although they experience this toxicity in the first couple of doses with any of these T cell engagers, usually that is manageable and of relatively low grade. This agent, I would say, is an active competitor in the same space along with the other agents.

ADCs in SCLC

Beyond the T cell Engagers, the other class of agents that I will touch on that I think are looking really promising in small cell lung cancer are the antibody drug conjugates. Like all areas of oncology, antibody drug conjugates have blown up. I think there is about a few hundred now in oncology development and several of them directed into small cell lung cancer trials with a variety of targets.

The primary targets that I think are of interest here are DLL3. Again, a great target on the cell surface of small cell lung cancer. B7‑H3, where there are multiple agents in clinical development. TROP2 with sacituzumab govitecan and other agents. And SEZ6, also expressed in high‑grade neuroendocrine tumors like small cell lung cancer, with some impressive data that are emerging, and we will briefly go through some of these agents.

I think this class looks very interesting. I would say one of the problems is that they are all using a Topo‑I warhead that is very similar. If we see resistance that is related to the warhead to the payload, this may prevent across agents that may hit a different target. The one agent that was using calicheamicin has actually been discontinued in favor of the SEZ6 antibody with the Topo‑I warhead. These are all Topo‑I directed agents.

IDeate‑Lung01: I‑DXd in Patients With Pretreated ES‑SCLC

I‑DXd is one of these agents. This is an antibody drug conjugate directed against B7‑H3. This was an initial dose‑finding trial, again looking to address dose finding before expansion for registration. This looked at 8 versus 12 mg/kg of I‑DXd. This data was published this year by myself and colleagues.

IDeate‑Lung01: Response to I‑DXd

The outcome for this trial, which was looking at pick the winner by overall response rate, we saw a really nice waterfall plot. This is in patients with, again, recurrent metastatic small cell lung cancer, second and third line, and a really nice waterfall plot with a large majority of patients demonstrating benefit here. Overall response rate 48%, in the second line setting more like 55%. So a very active agent and one that we are quite interested in seeing the future of.

IDeate‑Lung02: Relapsed SCLC After 1 Prior Line of Platinum‑Based Therapy

This is the trial that has been launched subsequently, and this is an ongoing trial. This is IDeate‑Lung02. This is for patients with relapsed small‑cell lung cancer in the second‑line setting. A design very similar, actually, to the DeLLphi‑304 trial, now looking at the antibody drug conjugate ID versus dealer's choice topotecan, amrubicin and lurbinectedin. This is supposed to be second line being modified now to allow patients to have received tarlatamab, although the majority of the accruals were actually before tarlatamab was approved. This will be an interesting trial to read out. We are anxiously awaiting the data. Coprimary endpoints, overall response rate and, more importantly I think, overall survival.

ARTEMIS‑001: Risvutatug Rezetecan (HS‑20093) in SCLC

The ARTEMIS‑001 trial is looking at a drug that we are calling ‘ris rez’ for simplicity, given the length of the name here. This is another antibody drug conjugate. This is another B7‑H3 directed ADC. Same target, same type of payload, a Topo‑I warhead. Again, similar to the I‑DXd trial that I just showed you, this was a dose‑finding trial to look at an optimal dose.

ARTEMIS‑001: Efficacy in SCLC

The outcome here looks quite good. Similarly high efficacy across the board in small cell lung cancer and in extrapulmonary small cell lung cancer patients as well. 8 mg/kg and 10 mg/kg looking quite similar and good in terms of efficacy, and the swimmer's plot also looking quite promising. I think a really nice agent. Over 95% of the patients demonstrating some tumor shrinkage with this drug.

ABBV‑706 in Patients With R/R SCLC

Another exciting agent, a different target, is the ABBV‑706 antibody drug conjugate. This is directed against SEZ6, another cell surface marker that is enriched in neuroendocrine tumors, like small cell lung cancer. This was an initial trial looking at two different doses, 1.8 versus 2.5 mg/kg. A somewhat smaller trial, but a really important one, I think, in the field demonstrating a really nice waterfall plot.

Phase I Study of ABBV‑706: Efficacy

This was initial data. There is actually more extensive data for this trial now, but it shows a really nice response rate, over 50%, I think 60% on the initial data cut on this trial. Ultimately, the lower dose, 1.8mg/kg, is the dose that is going forward.

ABBV‑706: Response in R/R SCLC

Both arms demonstrating a nice response rate, and in the second line setting, really impressive response rates, 70% to 80% here, so an exciting agent.

All of these drugs do have activity in the brain, which is important. Patients with asymptomatic brain metastases were allowed on several of these trials, and we did see responses.

Posttest 2

Posttest question number two. Which of the following is the most appropriate next line treatment to recommend for a patient who has done well in maintenance but has now progressed? Would you choose as second‑line therapy for extensive‑stage small‑cell lung cancer:

1. Lurbinectedin;
2. Pembrolizumab;
3. Topotecan; or
4. Tarlatamab.

Folks did pretty well in this question at the start, so I am expecting you should do pretty well now. Indeed, you did, 82% correct. I would say the answer is tarlatamab here, based on the randomized data phase III trial showing superiority to lurbinectedin and topotecan, and pembrolizumab would not be the right choice after a checkpoint inhibitor.

Posttest 3

Posttest three. This is the DAREON‑9 trial. This was the one that I thought was a little bit more challenging because the trial, I think, has gotten a little less press. This is looking at obrixtamig in patients with relapsed small‑cell lung cancer. Did this agent show:

1. Durable responses observed in DLL3‑expressing tumors with T‑cell engagement
2. Significant overall survival improvement in a randomized phase III trial
3. Antitumor activity observed, underscoring need for improved patient selection
4. Superiority to platinum/etoposide in the first‑line treatment setting

I would say the first answer is the correct one. There were durable responses in DLL3‑expressing tumors with T cell engagement on this trial. Looking at obrixtamig in this setting. Answer C is not a bad one. I think that was the most common answer. Anti‑tumor activity was observed, underscoring the need for improved patient selection. Not a bad answer. I would not disagree with that, actually. A reasonable choice.

Managing the Risks: Optimizing the Safety of New Agents

I am going to turn it back over to my co‑host here, Mark Socinski, to talk about the flip side, managing the risks of some of these drugs and optimizing safety of the new agents. Mark.

Dr. Socinski: Thanks, Charlie. That was great. Certainly, we have a number of new classes of drugs that look very promising and some phase III data that is really moving the needle a little bit in this disease. So let us talk a little bit about managing the risk.

Patient Case 4

We have a case here. T.W. is a 72‑year‑old gentleman with extensive‑stage small‑cell lung cancer with both liver and bone mets. He does have moderate COPD, well‑controlled heart failure, and type 2 diabetes. After first‑line chemo followed by maintenance durvalumab, he experienced progression at six months. He has a decline in his performance status to a PS 2, reporting fatigue and shortness of breath. He prioritizes quality of life and wishes to avoid hospital visits. He starts on tarlatamab. During the step‑up dosing. In cycle one, he develops grade 1 cytokine release syndrome characterized by fever without hypotension or hypoxia, and symptoms resolve with supportive care.

Pretest 4

The pre‑test question is here. Prior to his next scheduled dose, what is the most appropriate strategy to mitigate the risk of recurrent or more severe CRS while aligning with his preferences?

1. Proceed with the next dose without modification, as grade 1 CRS does not require preventive strategies;
2. Administer premedication with corticosteroids and antipyretics and continue step‑up dosing with monitoring;
3. Permanently discontinue tarlatamab due to the risk of recurrent CRS in a patient with comorbidities; or
4. Reduce the tarlatamab dose and eliminate step‑up dosing to minimize clinic time.

Go ahead and vote. Most popular is to administer premedication with steroids and antipyretics and continue step‑up dosing.

AEs Associated With Tarlatamab

The adverse events most commonly associated with tarlatamab are shown here. You can see cytokine release syndrome is the topic of most interest. It is an inflammatory response mediated by a number of cytokines. ICANS, which is a CNS disorder resulting from activation of endogenous infused T cells and other immune effector cells. Dysgeusia, there are DLL‑expressing taste buds that can lead to a taste disorder with T cell‑mediated destruction. And then other adverse events shown to the right. Neutropenia, fever, anorexia, constipation, asthenia, and others shown there.

CRS Grading Scale

Now the cytokine release syndrome grading system really takes into account three clinical parameters: fever, hypotension, and hypoxia. You can see based on the presence of any of these, you step up: grade 1 fever only, grade 2 some degree of hypotension or hypoxia, and then grade 3 or 4 worsening entities and requiring more supportive care, including high dose oxygen, vasopressors, and so on and so forth. CRS symptoms can be progressive, and they may progress through these symptoms here.

Key Points for Managing CRS Associated With Tarlatamab

If I go to the next slide, here are the key points for managing CRS in this particular setting. You can see for grade 1, making sure that the fever is not due to some other reason, but symptom management with Tylenol and IV fluids, and these sorts of things. Then grade 2, 3, and 4 require obviously more intensive hospital‑based strategies of supportive care, including steroids, tocilizumab, these things.

There might, as you see at the bottom, at least for grades 2 and 3, with the next planned dose a bit more prophylaxis as well as monitoring of patients, perhaps most responsibly in an inpatient setting. If grade 2 or 3 is recurrent, consider discontinuation of it. Then obviously, for grade 4, which is potentially life‑threatening, permanently discontinue the drug.

Immune Effector Cell Encephalopathy (ICE) Score

The ICE score for the encephalopathy is shown here, and obviously, I will not go through these in detail, but they have to do with orientation, ability to name, and follow commands, the ability to write, attention, these things. There is a scoring to the far right here.

ICANS Grading Scale

You can see that the ICE score is incorporated into the ICANS grading scale, as well as level of consciousness, seizure activity, motor weakness as well as intracranial pressure issues. Obviously, the more severe these are, the higher the grade is with these things. Certainly, key points for management is ruling out other causes of confusion, steroids, anticonvulsants, certainly ICU management in engagement of our subspecialists that would help us support these things.

Investigator‑Suggested Management of CRS and ICANS

There are a number of suggested management strategies for CRS and ICANS. They have to do with the support you get from facilities, having beds available when patients need them, educating patients to recognize the signs early, giving them home monitoring systems so that they can test these things: fever, blood pressure, O2 saturation, these things.

Institutions should have a dedicated protocol to manage these patients. Have the necessary supportive medications available. For instance, tocilizumab must be available to treat CRS quickly.

Then other considerations are listed at the bottom. They have to do with again monitoring system, time of day you may give these things, making sure that patients are close by, have appropriate contact information, and all of these things. At our institution, we borrowed a lot of paradigms for managing these patients from our cellular therapy group, that are actively doing CAR T cell therapies. It was easy for us to get this protocol in place relatively quickly for our patients.

Lurbinectedin Dosage Modifications for AEs

Lurbinectedin, Charlie spent some time talking about the maintenance data as well as the second‑line data with this agent. This has a toxicity profile similar to an alkylating agent for the most part. Hematologic toxicity, neutropenia, thrombocytopenia, and some liver issues. Rhabdomyolysis has been described with this agent. This is guidelines with regard to the severity of these issues. All this information can be seen in the package insert for lurbinectedin in terms of dose modification, withholding the drug, and discontinuing the drug for higher‑grade toxicities. That is all in the package insert.

Immune‑related AEs With First‑Line IO + Chemotherapy

We have been now about a decade into the immunotherapy experience in lung cancer in general. Certainly non‑small cell first, but now small cell. I do not think there is really any significant difference between those two groups with regard to the immune‑related adverse events. This is the data from IMpower133 and the CASPIAN trial with regard to toxicities. Most of these are quite similar. There may be some differences in how these patients had coded things such as dermatitis. I am not quite sure clinically that I believe that there is about a 10‑fold difference in dermatitis between atezolizumab and durvalumab. I think they are actually quite similar. This may be related to reporting, classifying, or investigator assessment, or these things. I think for the most part, these two agents are relatively similar.

I think the paradigms for immune‑related adverse events are realizing the spectrum of toxicity. Pretty much any part of the body cannot be spared from a potential immune‑related toxicity. They generally occur early, but can occur late. The challenge is to recognize them early and prevent them from becoming high‑grade with the appropriate supportive care. I think these two trials were relatively similar.

Management of Immune‑Related AEs

I think I mentioned most of this on the previous slide. The management obviously, no part of the body has been spared. One must recognize that and try to identify the event early. Give steroids as indicated. The severe adverse events may lead to discontinuation and may require more intensive supportive care with other immunosuppressant therapy. Of course, supportive care is important in these patients also.

Posttest 4

The posttest. Prior to his next scheduled dose, what is the most appropriate strategy to mitigate the risk of recurrent or more severe CRS while aligning with his preferences?

1. Proceed with the next dose without modification, as grade 1 CRS does not require preventive strategies
2. Administer premedication with corticosteroids and antipyretics and continue step‑up dosing with monitoring
3. Permanently discontinue tarlatamab due to risk of recurrent CRS in a patient with comorbidities
4. Reduce the tarlatamab dose and eliminate step‑up dosing to minimize clinic time

Go ahead and vote with the posttest four, and we will look at the results in a moment.

About 70% of people got the correct strategy: administer premedication with steroids and antipyretics, and continue on. This is grade 1 CRS, and if it happens, then one must just be a little bit more vigilant in premedicate patients before the step‑up dosing.

Key Takeaways from Faculty

Key takeaways. I will have Charlie join in on some of these. Certainly I think that we over the past several years are finally beginning to budge the needle a little bit in these treatment strategies that have evolved certainly five, six years ago. The addition of immunotherapy in the first line setting, the use of maintenance therapy, the use of some of these new agents, like the tarlatamab data that we have seen.

We are beginning to see, and Charlie presented a lot of data that, when I look at it, I start to feel a little bit optimistic that we may find this. I think part of the issue, and Charlie touched on this very briefly, is that we are like we were in non‑small cell 25 years ago, where one size fits all. That pretty much was carbo‑taxol for everybody. It is obviously very different now in non‑small cell. As Charlie pointed out, in clinical practice, there are really no way to identify patients yet, who is going to get benefit from which strategy.

Charlie, do you have any optimism for biomarkers in this?

Dr. Rudin: Oncologists are an optimistic crowd. There is always hope. I do think so. I actually think there are going to be biomarkers that are going to sort out patients that really benefit from tarlatamab. I have seen some data that is emerging, not yet published, that I think looks pretty promising in that role.

Dr. Socinski: The relapse data is obviously busy with a number of ADCs, other DLL targeting agents, and these things. I personally think that the IMforte data is important data, only because one of the issues historically, and we learned this in non‑small cell years ago, is that if you have an active agent but you wait until a patient progresses, we know that about a third of those patients progress in a way that they never get a second‑line treatment. If you have an active second‑line drug, it cannot be active if the patient does not get it. I have always viewed maintenance as early second‑line therapy.

Dr. Rudin: That is exactly right. That’s what power is.

Dr. Socinski: Typically, in patients who have responded to first‑line treatment, so they are a better population, by giving them an active agent that changes the outcome. The interesting thing, too, though, we oncologists have to be a pretty flexible group of physicians because starting way back with the anti‑VEGF drugs, the anti‑EGFR drugs, we had to become cardiologists and dermatologists, and then with immunotherapy, we had to become endocrinologists to manage all these things.

Dr. Rudin: And rheumatologists.

Dr. Socinski: Rheumatologists, yes. And now with these new ADCs and T cell engagers and these things, as I said when I was talking about this, we did not try to reinvent the wheel. We just went to our cellular therapy people and said how are you managing this? Because they were several years ahead of us in this setting. We just copied their strategies in terms of how we managed these patients getting tarlatamab and other bites. Thoughts on that?

Dr. Rudin: I think leaning on our colleagues has been really helpful. A lot of these toxicities are things that other fields have dealt with, and so learning from those experiences, people have been dealing with cytokine release syndrome in the hematologic malignancy world for quite a while. Again, taking their tricks and understanding how to manage this certainly has been helpful for us.

Dr. Socinski: I wanted to also to get your perspective, just as a class of drugs, on the ADC. I am hoping ADC does not turn out to be another way to deliver chemotherapy. An antibody has a target. A biomarker strategy would seem plausible in that setting. But you actually raise the point about the payload and how important that might be in this setting in terms of the activity. Obviously, the payloads are mostly Topo‑I inhibitors that we do not use in clinical practice, because they are difficult to give without a targeted approach. Is there an opportunity to use other payloads, or what is the thinking there?

Dr. Rudin: There really is. I think there are agents that are in an earlier phase of development now that have different payloads. There is no reason they all have to be Topo‑I. Topo‑I is an active class of chemotherapy for small cell. That is irinotecan, that is topotecan. But there is a lot of options there, and it would be great for the pharmaceutical industry to diversify, I think the warheads that are being delivered.

Antibody drug conjugates have gotten the reputation of being chemo on a stick. Which they are. They are chemotherapy hooked to an antibody. These are showing higher levels of activity than what we have seen with chemotherapy alone, but they are essentially a chemotherapy delivery vehicle. It is not clear that they all concentrate chemotherapy in the tumor to the exclusion of chemotherapy elsewhere. We are seeing toxicities with these agents. I think they are better than chemotherapy, but I think there is a lot of room for improvement, both in the delivery and the specificity, and diversifying the way the chemotherapy is being delivered.

Dr. Socinski: Certainly, a lot of work to be done in identifying a biomarker for this. I am blanking on the phrase that we saw with one of the TROP2 antibodies in non‑small cell, looking at a quantitative continuous scoring –

Dr. Rudin: Very complicated.

Dr. Socinski: Yes. Is it applicable to the average pathology lab the on the corner on Main Street?

Dr. Rudin: See how much uptake that is gotten, which is not much. It is complicated, and we need simple things for clinical practice.

The other antibody drug conjugate‑like drugs that I think have some interest in small cell are radioconjugates because small cells is a very radiosensitive tumor. As you presented, we cure about a third of the patients with limited stage with radiation. We do not cure anybody with chemo. Delivering a high‑potency radionuclide is another strategy that I think will have a future in this space. It will be fun to see how those play out.

Dr. Socinski: I actually have a patient, on a trial that is now closed at our place, but was using lutathera in combination with chemo‑IO. My patient has had, by RECIST criteria, phenomenal response. He had some complications that I do not think are related to the radionuclide. But I think you are exactly right, we were and should remain open to that area as an investigative pathway, because, to your point, all the advances that we have seen up until the recent times have been at the hands of our radiation colleagues. Concurrent use of radiation, PCI, earlier radiation versus delayed radiation, they have all been radiation strategies. The chemo has been the same. It is been platinum etoposide the whole time for the most part.

Dr. Rudin: We will see how it plays out. Those are simpler in some ways because you do not need to worry about the linker cleavage. You never need to cleave it, and you can just hook the radionuclide directly to the antibody. Anyway, we will see how it plays out. I think it would be great if we had some questions.

Dr. Socinski: We encourage anyone in the audience to submit questions. We are happy to take them. We have a few more minutes left in our time here, so we would be happy to answer those questions.

Poll 3

Do you plan to make any changes in your clinical practice based on what you have learned in today's program? You can go ahead and vote. You will have the opportunity to note that in the chat or whatever access you have. I think it is the next slide.

Poll 4

You can go ahead and cast your vote here in terms of changes you may make in your clinical practice based on the information that we have presented at this point. Let us see, Charlie, if we earned our keep tonight.

Q&A

Dr. Rudin: I did find some questions that are in the chat. I had to figure out how to get to them, but I got them.

Dr. Socinski: Maybe I do not know how to get to them.

Dr. Rudin: The Q&A button at the bottom. Mark and I are old school but we are figuring it out.

Dr. Socinski: Now I see it. Okay.

Dr. Rudin: I will just run down some of these. Tim Quill asks, any idea if a patient with limited stage on durvalumab consolidation, who gets less than two years due to intolerance, gets a similar benefit? A good question. If the patient has to go off of immunotherapy because of toxicity, do they still derive a benefit?

Dr. Socinski: Yes. I do not think we have seen data specifically from ADRIATIC. We do know from the PACIFIC trial. If I remember correctly, the average patient got about nine months. There seemed to be a little bit of advantage for those patients that completed the full year in the PACIFIC trial, but of course, is that because they were just more robust patients, or is it because they got those three extra doses? Obviously, that is an unanswerable question. But have you seen data in this regard, Charlie?

Dr. Rudin: I do not think we have data. I think you are right. I would say most of us who give immunotherapy feel like we do not know how much to give, and when can you stop. There have not been many discontinuation trials in oncology to answer the question. My sense is patients who benefit from immunotherapy benefit early. If you stop for toxicity, they can continue to benefit. There is some education and some memory in the immune system that probably happens.

Dr. Socinski: I think there is data out there to suggest that a little bit of immune adverse events is a good thing, to the extent as long as you do not have high‑grade toxicity with these things. Let me ask you this. You presented some of the DeLLphi trials with regard to tarlatamab. I think they are moving into first line and into the limited stage disease. I think you presented at least the trials that are ongoing. We do not have any outcome data yet from these trials. To be honest with you, I am pretty optimistic about these agents moving into first line if it works. I was impressed with the second line trial, tarlatamab easily beat standard chemotherapy. I think moving it into first line, I think the benefits could be at least the same, if not greater, in these populations.

Dr. Rudin: Yes, I share your enthusiasm. I think we need to wait for the trials. We have been wrong before, but I think these data are looking really good. I do think they will have a home there. We will see. I am certainly optimistic that that will be the case. Limited stage, I think, is a tougher place to position them. You do not want to mess with the success that we have achieved there. I think we will first see it in extensive‑stage first line and see how that reads out, and then make decisions about where to go from there.

Dr. Socinski: What is your thinking when you see a newly diagnosed patient with extensive‑stage small cell, in the absence of any clinical trial data? I always like to think of what am I going to do first. Is there a role for maintenance? What is next? I try to get as many shots on goal as I can with these patients. Is that your thinking in terms of how you sequence these things?

Dr. Rudin: Yes, that is exactly right. I agree with you about IMforte, by the way. I think there is benefit there, but it comes with a price. It is not for everybody, but it is certainly worth a discussion with patients. If they are in great shape and they want to do everything they can to maximize their outcome, I think it is phase III data. It shows a survival advantage, and we should.

Dr. Socinski: Yes. I would say in my practice, the last couple extensive stage patients I have had, I have been impressed, at least in this couple of patients, most recently with the tolerability of lurbinectedin plus atezolizumab and maintenance. My plan is to transition these people to tarlatamab when they progress, but so far, both of them have received eight, nine doses on the maintenance part. Four induction and then eight, nine. They are out close to a year or so, and doing well and seem to be tolerating it well. I also feel like I have a good option with tarlatamab following that. I think we are going to see better improvements, not for every patient, but in selected patients.

Dr. Rudin: This is an interesting question. If someone had PCI, do you have concerns about more risks for ICAN?

Dr. Socinski: That is a good question. I have not seen any correlation. Of course, ICANS is a relatively uncommon event and we are still in the early days of the use of tarlatamab. I must say, certainly in extensive stage disease, I have shied away and so have our radiation oncologist about considering PCI, and doing brain monitoring with MRIs as a strategy rather than expose them to PCI. But I do not know in that setting.

Dr. Rudin: Dr. Subramanian asks, is there further research across the pond in this disease? More smokers over there and in Asia. That is right. Actually, a lot of the research is going on, both in Europe, and most of the lurbinectedin trials initially were European trials. And I would say the drug development in China is just exploding right now: lots of agents, and lots of pretty interesting agents, being developed there. This is definitely a global field, not only lung cancer, but cancer research has certainly become global, with major efforts in Asia, I think, in many ways leading the field right now.

Dr. Socinski: I would say the question about recommendations for community oncologists, over the past five, six years, we have added immunotherapy, we have added lurbinectedin maintenance, we have added tarlatamab. My goal, my advice or recommendation to the community oncologist is when you see a new patient with extensive stage, you should think, how can I give the patient the potential benefit of all of these drugs?

That requires vigilance in terms of monitoring for progression, selecting patients correctly for maintenance therapy, and managing the side effects of each of these. I think that would be my recommendation. Again, I am not young enough to think that every patient is going to get all of these therapies. I think the recommendation would be to think, I want to give these patients every shot on goal that I can and give them the best chance at as good an outcome as we could possibly see.

Dr. Rudin: I think that is right. I think for the community oncologists, the NCCN guidelines are, of course, a very important source. Some of the data I presented you do not need to know because these drugs are not yet approved, they are not available. But understanding the role of immunotherapy, understanding the role of tarlatamab now, understanding the role of lurbinectedin, I think these are the drugs that are really changing and that have become a standard of care, and that the community oncologists should be aware of. For later, for patients who are not responding to those agents, maybe that is a context where you consider referral to a tertiary care center that is doing some of these experimental therapies. But I think understanding those basics is probably where you really want to concentrate.

Dr. Socinski: Then lastly, we have two minutes, Charlie. The question about vaccines, what is your thoughts on vaccines in this setting?

Dr. Rudin: I think the approach of grinding up the tumor and using that as a vaccine, we have tried that, does not work. Not in small cells so much, but in oncology in general. That approach is not so good. There is a ton of interest now, actually, in cancer vaccines designed around antigens that the cancer has. Actually, some of the same mRNA technology that was used to develop the COVID vaccines is deployed in the context of cancer. It is early days for that stuff. We will see where it plays out. I think it is a pretty interesting area. It is an area where the basic immunology is coming to the fore. We are beginning to understand more about how to actually stimulate an immune response in a cancer patient. I would say watch this space over the next decade because this is really going to be an area that could take off and explode.