Small-cell lung cancer, as you probably know, is a high-grade neuroendocrine carcinoma, highly metastatic, and it is about up to 15% of lung cancers. The 3-year relative survival somewhere in the 12% range. That was from 2018. Now we are a little bit better, but the 5-year relative survival up at 2021 is around 9%. These are typically characterized by TP53 and RB1 genetic mutations. There are no clear drivers like there are non-small cell. Among veterans diagnosed with small cell, about 15% have limited stage and 85% have extensive stage when first detected.

[00:05:35]

Veterans With Lung Cancer: Strategic Initiatives

Among veterans, lung cancer is a leading cause of cancer-related death. The Veterans Health Administration launched 3 initiatives to improve outcomes for this population. This was VA-PALS, to increase access to early screening, VALOR, which was a phase III trial looking at the role of SBRT for veterans with operable stage 1 instead of surgery. Then, the VA-ROQS program, which was created in 2016 to develop national expert-derived benchmarks for quality assurance in lung cancer.

[00:06:24]

VHA: Lung Cancer Screening

The VHA lung cancer screening policy that all eligible veterans at increased risk of lung cancer be offered screening, and it is a high-quality program, utilizing shared decision making with veterans about undergoing screening and that initial low-dose CT and follow-up care. We know that low-dose CT scans can detect lung cancer at an early, treatable stage. Although we do know that it is not as useful for detecting small-cell lung cancer, although you can sometimes. Symptomatic small-cell often develops between scans due to the aggressive nature of the disease. That is why we are here talking about the treatment of it.

[00:07:10]

Approvals in Small-Cell Lung Cancer Treatment

Here is a timeline with the approvals. You can see for the 5 decades prior to 2019, it was very few and far between with our platinum doublet topotecan as, really, been notable approvals. Then in 2019, we started with immunotherapy, and we are going to talk a little bit about that. We had platinum doublet plus atezo with durva. We had lurbinectedin as second line, and then 2024 tarlatamab, and then, most recently in 2025, the IMFORTE trial. We are going to get into all of that tonight.

[00:07:51]

Selecting 1L Therapy in LS and ES SCLC

Let us start with first-line therapy in limited and extensive stage.

[00:07:56]

Patient Case 1: Treatment for LS-SCLC

I always like to start with the patient case. This patient is a 62-year-old woman. She has chest pain, shortness of breath, good PS, and the X-ray shows a right hilar mass confirmed on the CAT scan. You can see that there it is a 3.4cm right upper lobe mass. She has a 3-centimeter right hilar node, and the PET scan is positive in the right upper lobe and right hilar mass. Brain MRI is negative. She undergoes biopsy and reveals small-cell lung cancer from right upper lobe mass and the subcarinal lymph node. She has limited-staged disease. She undergoes concurrent chemo RT, and she gets cis/etoposide plus daily thoracic radiation up until 70 gray, with a good partial response and no significant toxicities.

[00:08:52]

Poll 3

Now, what is the most appropriate next step for this patient's treatment plan?

A. Close observation with surveillance imaging every 3 months:

B. Prophylactic cranial irradiation without any further systemic therapy;

C Durvalumab consolidation therapy after completing the chemo RT; or

D. Second-line chemotherapy with topotecan;

Please vote.

Speaker 3: Polling is open. Please vote. A little bit more to consider here, so we will give a little bit more time. I will give it a few more seconds, and we will go ahead and close that poll and share.

Dr Chiang: Three-quarters say durvalumab consolidation after completing chemo RT. We are going to talk about that. Exactly..

[00:09:58]

SCLC: Staging and General Approach to Treatment

A little bit more about staging and the general approach. For limited stage, they can be treated with definitive radiation. This includes stages I to III. The treatment is radiation, surgery, or chemoradiation, followed by consolidation durvalumab. You might consider radiation or surgery in node-negative patients. If they do not have any nodes, then you can consider that local therapy, followed by adjuvant chemo. The median overall survival for that approach of chemo radiation followed by consolidation durva is 56 months. That is from the ADRIATIC trial and the 3-year overall survival above 50%.

You can consider PCI before consolidation. That is still something that we discuss with our patients. Still, most of the patients do recur. Then extensive stage disease is basically stage IV disease that cannot be treated within one radiation portal. It has distant mets, or multiple lung nodules that really cannot be treated safely with definitive radiation. The treatment is systemic chemotherapy plus immunotherapy. The median overall survival is right around a year.

However, there are patients that can make it out to 3 years. In the CASPIAN trial, it was 17% and in the IMpower 133, and the patients who rolled over to the extension trial IMbrella A, they had a 5-year overall survival of 12%. We still need to do better, but we certainly have made some progress.

[00:11:48]

Paradigm Shifts in LS-SCLC Treatment

Not going to go into the details of the radiation. I think we can offer either BID radiation or daily radiation. That is the Turrisi New England paper. Then we do know that concurrent is better than sequential and that it is really important to start early, within 30 days of starting chemotherapy. Usually, you want to make sure to start it by the end of cycle 2. We try to start it with cycle 2. Then, prophylactic radiation. There is a survival benefit, 5% at 3 years. We do know that there is some ways to give hippocampal sparing now, but there really is a trial right now that is going to tell us whether or not, in the age of immunotherapy, it makes sense to do prophylactic cranial radiation.

[00:12:48]

Current Clinical Guidelines on Primary Treatment for LS-SCLC

Again, here you have limited stage. If you have a good PS, you offer them 4 cycles of systemic chemotherapy plus concurrent RT followed by that durvalumab consolidation. If it is poor PS that is due to small cell, you still can offer that, because they can often get better, but if it is poor PS that is not due to small cell, then you really have to figure out what are the comorbidities and developing an individualized plan, which may actually mean supportive care and not anti-cancer therapy.

[00:13:23]

ADRIATIC: Consolidation Therapy With Durvalumab LS-SCLC

Let us talk about the ADRIATIC trial, which came out at ASCO last year. This was a large phase III trial. Stage I to III, limited stage, with no progression after concurrent chemo RT, and they could have had PCI prior to randomization. There is a lot of patients – 730 - were randomized to durva-placebo or durva-treme. The durva-treme is not mature yet, so we are talking about the durva vs placebo.

[00:14:03]

ADRIATIC: OS and PFS (Coprimary Endpoint)

Co-primary endpoints of PFS and OS. You can see those here in this slide, and both were positive. Both the PFS and OS were positive for durvalumab. I really like to point out to my patients, in this case, for the OS, this is a therapy that gives you almost 2 years of benefit, OS benefit. The durvalumab arm 56 months vs 33 months in the placebo arm. Really, hazard ratio. They do not have it here. No 0.73, but really nice separation of the curve. Really positive. Also positive for PFS, but I think it is really that OS benefit of 2 years that I am impressed with.

[00:14:52]

ADRIATIC: Most Frequent AEs

If you are giving 2 extra years of therapy, you want to know whether it is well-tolerated. Here is the side effects that are for the durvalumab arm in blue on the left, and the placebo arm on the right. Basically, these are mostly all grade I, grade II, and they are pretty well tolerated. The ones of note, the radiation pneumonitis and pneumonitis are really pretty similar in both arm, and you can see that here.

[00:15:27]

ADRIATIC: Pneumonitis/Radiation Pneumonitis

About 3% maximum grade III, IV, in the durvalumab arm vs placebo, or actually 2.6 in placebo. Eight leading to treatment discontinuation vs 3 in the placebo arm.

[00:15:46]

Ongoing Immunotherapy and ChemoRT Trials in LS

That was a positive trial, and ultimately, the only other trial in this space is the NRG-LU005 trial, and that was with atezolizumab and that was concurrent with RT and a year of consolidation. That was a negative trial.

[00:16:11]

NRG-LU005: Addition of Atezolizumab to CRT for LS

Here is the trial design. You added atezolizumab to the platinum doublet, followed by atezo for a year, and that is compared to our standard of care at that time, which was just chemo RT.

[00:16:24]

NRG-LU005: OS (Primary Endpoint) and PFS

This was a negative trial, both in overall survival and PFS. Compared to the ADRIATIC trial, when you are just giving the durva for 2 years afterwards, this was a negative trial. The recommendation is not to give atezo or immunotherapy with the chemo radiation, and to stick with the ADRIATIC trial. That is important. I do not know why. There has been some theories that are floated. Maybe you are causing T cell death with the radiation, and you are not able to have that response when you are giving atezo at the same time. We still have much to learn around that, but this was a negative trial.

[00:17:12]

"Very" LS-SCLC Testing, Primary Treatment, and Adjuvant Therapy

This is just to show you again what I mentioned before that you can have very limited stage disease, that is no negative with pathologic mediastinal staging. In that case, you do lobectomy and mediastinal lymph node dissection, if they are operable candidates. Then you are going to give systemic adjuvant chemotherapy, platinum doublet either way. Then you add RT if you either have margins that are positive or if the mediastinal lymph nodes are positive. If they are medically inoperable or patient preference does not want surgery, then you can consider local radiation, and then follow that by systemic chemotherapy. So that is the very limited stage.

[00:18:07]

Maximizing First-line Therapy for ES-SCLC

Let us go to talking about first-line therapy for extensive-stage disease. Now we have talked about limited stage.

[00:18:15]

Pretest 2

This question is in the phase III IMforte trial, that was presented at ASCO this past year, this past June, which of the following outcomes was reported with the addition of lurbinectedin to atezo maintenance for patients with extensive stage and at least stable disease after induction with carbo, etoposide, and atezolizumab?

A. Improved PFS and OS;

B. Improved PFS but similar OS;

C. Similar PFS but improved OS; and

D. Similar PFS and OS;

I hate these questions, but go for it. Let’s vote. You are all going to get this right afterwards.

Speaker 3: Polling is open. There is no wrong answers in a pre-test question, right?

Dr Chiang: Exactly. Just do your best.

Speaker 3: All right. Give a few more seconds here, and we will go ahead and close that poll and share.

Dr Chiang: We have got some votes for everybody. We have some room to go for improvement here.

[00:19:38]

Rationale for Combining ICI With Chemotherapy in SC

Now let us talk about the rationale for combining immune checkpoint inhibitor therapy with chemotherapy in small-cell. Here is chemo on the left, and we know that chemo can induce tumor cell killing. Basically, that can induce tumor antigen release and exposure to the immune system and stimulate neoantigens to be there. Then PD-L1 overexpression leads to the immune cell evasion, T cell inhibition, and then PD-1, PD-L1 axis inhibition restores that tumor-specific T cell immunity, so that you can then have active T cells attacking the tumor. Then, reversal of that immune suppression leads to deeper, more durable systemic anti-tumor response. Hopefully, cell death ultimately.

[00:20:41]

IMpower133 and CASPIAN: OS

I am just trying to get rid of my picture here. Thank you. Here are the 2 frontline trials. The IMpower133 adding atezo to the platinum doublet, and then CASPIAN adding durva to the platinum doublet. Both of these were positive trials, and they were almost exactly the same. The benefit was right around 2 to 3, or a little less than 3 months. There is the median overall survival 12.3 and IMpower133 vs 10.3 and 12.9 in the CASPIAN trial vs 10.5. Hazard ratio is almost identical 0.7, 0.75.

You see again, the curves here are separated, and ultimately, that extension trial, the IMbrella A, we have a 5-year overall survival of about 12%. In the CASPIAN, at the designated trial 3-year mark, 17.6% vs 5.8% for chemotherapy. Definitely an in-benefit for the addition of immunotherapy to our standard platinum doublet.

[00:21:56]

FDA Approvals for 1L IO Therapy in ES-SCLC: Updated Analysis

These both led to FDA approvals. There was a difference in the trial highlighted here. For the IMpower133 trial, that came first, all of their brain mets were treated. Then in the CASPIAN trial, they did allow patients with asymptomatic brain mets, as well as treated brain mets. They gave investigator choice of either cisplatin or carboplatin. Although, mostly carboplatin was used for these patients. This NTAP at the bottom it just says that you are able to use this. You get a payment for that immunotherapy if they are treated inpatient. Although we really have not had luck doing that. I think it may be different in the VA.

[00:22:49]

Overview of Key Studies of ICIs in ES-SCLC

These are the key studies. Since then, we have had a number of different studies. Also looking at anti-PD-1 strategies, including nivo, pembro, and then some studies that have been positive also in China, the ASTRUM, CAPSTONE, RATIONALE. Those actually look really good with 15.4, but they are within China and have not included patients here. They have not been approved for us, although they are approved there. In the US, it is really just the atezo and durva that are approved right now.

[00:23:06]

Current Treatment Guidelines for ES-SCLC (October)

The primary therapy then is recommended 4 cycles of cytotoxic chemotherapy. Some patients can get 6 cycles that was allowed in the CASPIAN trial. I do not usually go that far, and now, I think, with the IMforte trial, probably would not do that. Here are the preferred regimens that are basically platinum doublet plus atezo or durva. Obviously, sometimes these patients are really sick, and they can show up in the hospital and need to be treated right away with chemo. We usually just use chemotherapy in the hospital and then add the atezo or durva when they are outpatient.

[00:24:16]

Lurbinectedin

Now let us talk about lurbinectedin. This is a marine-derived tetrahydroisoquinoline alkaloid say that 10 times fast. This basically inhibits oncogenic transcription. You can see over here, basically can cause cell death and does a number of things in the tumor microenvironment. It is FDA approved now for second line, so metastatic small cell with progression, but also now approved since ASCO for first line maintenance, and we are going to talk about that right now.

[00:24:58]

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

This was the IMforte trial presented at ASCO, and this is an international phase III trial, and this is important to notice. It started at time of induction. We had 660 patients at that time with extensive stage disease, and they got platinum doublet plus atezo. If they had an ongoing response or stable disease, then they were randomized to maintenance with lurbinectedin plus atezo vs atezo. Note, they also still had to have a PS of 0 to 1 at the time of maintenance, and also note that brain mets were not allowed in this trial, patients with brain mets. The co-primary endpoints were PFS and OS, and they continued the maintenance until progression.

[00:25:54]

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

This is the OS. Sorry, PFS on the left and OS on the right. Remember that question before? Both PFS and OS are positive for this trial. The benefit of about 3 months in PFS, the benefit of about 3 months in OS. Hazard ratio 0.54 for PFS, 0.73 for OS. And just keep in mind that this is from time of randomization. It is not counting the 3.2 months of chemo upfront. It is really just from the time of maintenance. The median overall survival from that time was 13 months. This is a positive trial with a survival benefit. This is a great thing for our patients, and this was approved by the FDA.

[00:26:48]

IMforte: All-Cause AEs Occurring in ≥ 10% in Either

Here again, you can see that you are adding additional cytotoxic chemotherapy, not a platinum doublet, but lurbinectedin to atezo. You do have side effects that we know about - nausea, anemia, fatigue. Although it is really quite low in terms of the 2% to 8% over there. You have some myelosuppression, thrombocytopenia. These are all things that we can manage. The rate of grade III, IV infections was 6.6 in the lurbi-atezo arm, vs 5 in atezo. And febrile neutropenia, 1.7% in the combination arm.

[00:27:37]

Posttest 2

Here is the post-test question. In the IMforte trial, which of the following outcomes was reported with the addition of lurbi to the atezo maintenance in patients that had at least stable disease after induction therapy?

A. Improved PFS and OS;

B. Improved PFS but similar OS;

C. Similar PFS but improved OS; or

D. similar PFS and OS;

Please vote.

Speaker 3: Polling is open. Please vote. We will give it a few more seconds for incoming responses. We will go ahead and close that poll and share.

Dr Chiang: Fantastic. Improve PFS and OS for this trial. Definitely something to talk to your patient about. Keep in mind again, some of these patients are beat up by the chemotherapy, and so sometimes it is the eye of equipoise. If they say, "I really am need a break." Because we do not know whether if you add that later or cytotoxic therapy if it can be as effective. Certainly, for those patients who have had a good response and who want to know, what can I do to really improve my chances? Here is a 3-month overall survival benefit for them.

[00:29:15]

Navigating Options for Relapsed ES-SCLC

Here is now navigating options for relapsed extensive stage.

[00:29:22]

Patient Case 2: Relapsed ES-SCLC After Initial Response to First-line Therapy

We are going to go back to the patient case. Relapsed small cell. Sorry, this is a 56-year-old patient with a history of COPD diagnosed with extensive stage 6 months prior, and got first-line therapy with platinum etoposide durvalumab times 4 cycles, followed by maintenance with durvalumab for 3 months. Then you can see the PET after 3 cycles of the maintenance, durvalumab. you have progression of disease with new lymph nodes, you have chest wall, liver mets, and the MRI actually shows some 2 subcentimeter asymptomatic brain mets. PS is still really great. Labs are good, no symptoms.

[00:30:05]

Pretest 3

What do you do for this patient, this platinum-refractory patient?

A. Lurbinectedin;

B. Tarlatamab;

C. Ifinatamab deruxtecan;

F. Lurbi or tarla or;

E. IDXd or lurbi;

Please vote. I am just going to turn off this printer. Sorry about that.

Speaker 3: No problem. Polling is open. Please vote.

Dr Chiang: Go ahead.

Speaker 3: I was just going to say I will give a little bit more time because of the delay. Give about 5 more seconds here. All right. We will go ahead and close that poll and share the results.

Dr Chiang: About a third lurbi, 20% tarla, and then a third of you saying lurbi or tarla. Okay, great. Let us close this and move on.

[00:31:26]

Lurbinectedin: Marine-derived Tetrahydroisoquinoline Alkaloid

We started talking about lurbinectedin.

[00:31:31]

Phase II Basket Study (Study B-005) Lurbinectedin ES-SCLC Cohort

Let us talk about it in the second line. It was approved basically on the basis of a small trial, so really 105 patients, and the primary endpoint was response rate.

[00:31:46]

Phase II Study of 2L Lurbinectedin in ES-SCLC: Efficacy

It was not a randomized trial. It was just a one-arm trial. And they saw that the response rate was about 35%. The median duration of response 5 months, median PFS 3.5 months, and median OS is 9.3 months. This was worse in patients with platinum-refractory disease and better in patients with platinum-sensitive disease, although it still did better than topotecan in chemorefractory disease.

[00:32:21]

Phase II Study of 2L Lurbinectedin in ES-SCLC: Safety

Most of the side effects were grade I, II hematologic, although leukopenia, you can see grade III, 20%, neutropenia 20%. This is definitely something that we use growth factors with. Then some of that fatigue there.

[00:32:40]

Practical Considerations on Dosing Lurbinectedin *

This is now approved again for the IMforte trial, the maintenance, and in second line, and it is used at this 3.2mg/m², every 3 weeks IV. We use a central line for that, and definitely use G prophylaxis to reduce the risk of febrile neutropenia.

[00:33:05]

Tarlatamab: DLL3 x CD3 Bispecific T-Cell Engager

The other choice here in the second line setting is tarlatamab, and this is a DLL3 x CD3 bispecific T-cell engager and, super exciting drug.

[00:33:21]

Rationale: DLL3 Expression in Neuroendocrine Care

Again, part of it is targeting DLL3 on the surface of tumor cells, and the other is CD3, is targeting T cells. Bringing them together. No chemo involved. Just bringing the immune system to the tumor cell. Why do we think that DLL3 is a good target? In normal tissue, that expression is absent or low. In the cytoplasm and DLL3, about 85% of small cell tumors overexpressed DLL3. Interestingly enough, DLL3 is also overexpressed in other neuroendocrine tumors like LCNEC, prostate EP neck, or extrapulmonary neuroendocrine tumors like prostate, small cell, Merkel cell, and so forth. We have actually seen some good responses with tarlatamab in those patients.

[00:34:14]

DeLLphi-301: Tarlatamab in Relapsed ES-SCLC

This was the DeLLphi-301 trial that led to approval. This was an open-label phase II study with tarlatamab at 2 doses: 10 milligrams, which is the dose that was ultimately approved, and 100mg. Again, the primary endpoint was overall response rate.

[00:34:34]

DeLLphi-301: Response

Here you can see the overall response rate for the 10 milligram dose, which was approved, was 40% and additional at 30% patients had stable disease. The overall disease control rate, 70%, which is really amazing for this population. Now most of these patients were at least second line. Some of them were also third line. About 75% had had exposure to PD-L1. This is an effective drug. Let us see the duration of response. I do not see that here, but ultimately the median duration of response almost 10 months. Again, really exciting for this drug.

[00:35:24]

DeLLphi-301: Intracranial Antitumor Activity

These patients had to have treated brain mets, so they were not asymptomatic, untreated. They are looking at some of the tumor shrinkage here, but you can see almost all of them have had either whole brain or some radiation. I do not think you can say that this tumor shrinkage was due to the tarlatamab alone. It is probably the results of the radiation. However, the next trial did allow asymptomatic brain mets.

[00:35:54]

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

That is the DeLLphi-304. DeLLphi-304 was the confirmatory or is the confirmatory phase III trial with 509 patients, and this was giving tarlatamab, the step-up dose. The first week, 1 milligram, then 10 milligram dosing, and that vs standard of care investigator choice. Most patients got topotecan, although there were about 45 patients who got lurbinectedin and a few less than that who got amrubicin, that was in Japan.

[00:36:29]

DeLLphi-304: PFS and OS with Tarlatamab in Relapse ES-SCLC

These patients' second-line OS is the primary endpoint shown here. On the right, that was the OS; there is a 5-month benefit and overall survival for these patients for getting tarlatamab vs chemotherapy. The hazard ratio is 0.6. Nice separation of the curves there. The PFS also positive there, although a little bit less in terms of the benefit.

[00:36:57]

DeLLphi-304: CRS and ICANS Events with Tarlatamab

What are the side effects of tarlatamab, where you are stimulating the immune system, right? Just like when you get a flu shot, you are going to have cytokines released. You get fever, chills, some hypotension, hypoxia. However, if you look here - and most of the patients get it, 56% of the patients get some side effect CRS - most of them are grade I, grade II. Grade III was only 1%. ICANS is immune cell-associated neurotoxicity. That is confusion. Some difficulty with speech. Sometimes it can be tremors or weakness. Those patients had that at about 6%. Again, all grade I, grade II treated with steroids.

In this trial, patients were admitted 48 hours for observation after getting their dose. There was a cohort of 43 patients who were monitored in the outpatient setting for 6 to 8 hours, and were safely done that way. I think right now, most folks do monitor for 24 hours or 22 to 24 hours after the infusion, usually in an inpatient setting. I think, for example, we are developing a pilot program for selected patients who can do that outpatient too.

[00:38:28]

DeLLphi-304: Treatment-Emergent AEs with Tarlatamab

Here the side effects. More frequent with chemo, what we expect, myelosuppression, etc. More frequent with tarlatamab, site CRS. There's dysgeusia, so the lack of taste that can be really significant, and I have had patients now on tarlatamab for 6 to 9 months, and that is an issue because they are losing weight or they have to be careful not to lose weight. That is the side effects.

[00:39:02]

CRS and ICANS With Bispecific Antibody Therapy: Grading and Management

Let us talk a little bit more about CRS and ICANS, the grading and management, but let us start with the pretest.

[00:39:09]

Pretest 4

Patient with recurrent small cell receiving tarlatamab experiences grade 2 CRS with fever and hypotension. Which of the following initial management steps would you recommend?

A. Anakinra or siltuximab;

B. Dexamethasone and IV fluids;

C. Dexamethasone and anakinra; or

D. Dexamethasone and tocilizumab;

Please vote.

Speaker 3: Polling is open. I will give it a few more seconds for incoming responses, and we will go ahead and close that poll and share.

Dr Chiang: It looks like most of you said dex plus IV fluids, and then the next answer was dex plus toci. Let us talk about that. All right.

[00:40:22]

Practical Considerations on Dosing Tarlatamab

Just starting here on the left in the red. Basically, you do the step-up dosing. There is 3 weeks in a row, 1 milligram, the first week, and then 10 milligrams next week, and then 10 milligrams the third week. Then you just dose 10 milligrams every 2 weeks. That was what was approved.

[00:40:44]

Consensus Guidelines: CRS Management

I think we are going to get further into the CRS management here. Grade 1 is fever. Grade 2 is fever plus hypotension, and/or hypoxia. Grade 3 is fever plus higher grade hypotension hypoxia. For grade 1, you can just have oral hydration Tylenol. For grade 2, then we are admitting patients for this inpatient grade 2 management. You get Tylenol. You get fluids, oxygen if you need it, and then you start the steroids, dexamethasone. Then, if they persist, then you would consider tocilizumab.

Now, in the grade 3 and 4 case, now you need to have them in the ICU and monitor them there because they may need pressors for grade 3, multiple pressors for grade 4. O₂ high flow that is the setting that where you need to manage that. Then you treat with dexamethasone. If that is not working, you do tocilizumab. If that tocilizumab is not working, then you would think about anakinra or siltuximab.

Steroids first, then toci, then something else. These are all very manageable. If you have the first 2 doses, you can have CRS, and then you are done. Third dose, they are fine, you treat them in the outpatient setting. If you have issues with, for instance, the 10 milligram dose, then you can go ahead and monitor them for the next dose and see how they do.

[00:42:29]

DeLLphi-305: Tarlatamab ± Durvalumab as First-line Maintenance in ES-SCLC

All right. This is just to say, in lung cancer, if you have active agents, you want to move them up earlier in treatment. This is active in the second line, so let us see how you do in the maintenance, and then there is also a trial looking at frontline, another trial looking at limited stages consolidation. This is DeLLphi-305. This is a maintenance trial.

Again, those patients who get their first cycles of platinum etoposide with durva and then they do not have disease progression. They do not have brain mets. Their PS is still good. Then they go on to tarla-durva vs durva alone. The primary endpoint is overall survival. This is an ongoing trial right now.

[00:43:16]

Summary Data for FDA-Approved Agents for Relapsed ES-SCLC

Again, here you are looking at the difference between lurbinectedin, which is overall response rate of about 35%, tarla. 30%. But the median duration of response is really where they differ a little bit. It is 5 months for lurbi, 10 months for tarla. I think you have 2 good choices, but I think tarlatamab now, because of that positive second-line trial, we need to learn how to use it. It is a really good drug for our patients.

[00:43:48]

Patient Case 2: Relapsed ES-SCLC After Initial Response to First-line Therapy

Let us revisit our patient. Let us go back here. 56-year-old patient, COPD, extensive stage, got first-line therapy with the platinum doublet durva and maintenance. Then 3 months later has progression, also 2 subcentimeter asymptomatic brain mets, good PS, no symptoms. Now what are you going to treat them with? Lurbi, tarla, IDXd, lurbi or tarla, IDXd or lurbi.

Please vote.

Speaker 3: Polling is open. Please vote. We will get a few more seconds for incoming responses.

Dr Chiang: See how I am doing for time here, okay.

Speaker 3: Looking pretty good so far. We will go ahead and close that poll and keep moving along.

Dr Chiang: Yes. 20% tarla, or lurbi or tarla. Excellent. All right. That is really the answer lurbi or tarla, based on our guidelines right now, either would be a viable second line. IDXd is not yet approved, although it looks really good in clinical trials, and I expect probably will be approved sometime within the next year or 2.

[00:45:24]

Posttest 4

Then a patient with recurrent small cell receiving tarla experiences grade 2 CRS with fever hypotension. Which of the initial management steps would you recommend? Grade 2 fever, hypotension.

A, Anakinra or siltuximab;

B. Dex plus IV fluids;

C. Dex plus anakinra; or

D. Dex plus toci;

Speaker 3: Polling is open. Please vote. We have a few more seconds for incoming responses, and we will go ahead and close that poll and share.

Dr Chiang: Yay! Excellent. The correct answer is dex plus IV fluids for grade 2 CRS. If they have persistent symptoms that does not go away - we were talking about the initial treatment - but if it does not go away, then you can use tocilizumab. If that does not work, then you can consider anakinra or siltuximab.

[00:46:51]

Ongoing Trials of Novel Agents in ES-SCLC

Then these are the ongoing trials for novel agents. Obrixtamig is another T cell engager. There is obrixtamig plus topo. There is gocatamig, that is also T cell engager from Merck, and that is a trispecific. It actually has a domain which recognizes albumin and that extends the half-life. IDXd is a B7H3 antibody drug conjugate that has nice response rates, and some of these have response rates in the 60% to 80% range. IDXd also works in the brain. ARTEMIS and TROPICS is another TROP2 ADC that you guys may know from the breast realm. That actually also has some nice response rates there.

[00:47:52]

Posttest 1

Now, how confident are you in implementing strategies or guideline recommended therapy for your patients with small cell?

A. Not at all confident;

B. Slightly confident;

C. Moderately confident;

D. Mostly confident; or

E. Very confident;

Please vote.

Speaker 3: Polling is open. Please vote.

Dr Chiang: Do not undersell yourself.

Speaker 3: All right. We will give a few more seconds, and we will go ahead and close and share.

Dr Chiang: Excellent. 25%, mostly confident. Great. We have definitely moved the needle here.

[00:48:43]

Poll 5

Do you plan to make any changes in your clinical practice based on what you learned in today's program?

1. Yes;

2. No; or

3. Uncertain;

Again, please vote.

Speaker 3: Polling is open. We will go ahead and close this one.

Dr Chiang: Yes, 55%. Excellent.

[00:49:20]

Poll 6

Then, please take a moment to enter one key change that you plan to make in your clinical practice based on this education, and you can scan this QR code to text your response, and appreciate you doing this.

Speaker 3: For our live group, you can scan the QR code and text in your response. For our Zoom group, please use the Zoom window provided. We will leave this up for a little bit, and then, doctor, you can move on to the Q&A whenever you are ready.

[00:49:54]

Q&A

Dr Chiang: Okay, great. That is great. We have about ten minutes left for Q&A. I would love to hear any questions you have. This is an opportunity to ask, and I would love to have some interaction. It is hard to do these things online, so please tell me you are out there.

Speaker 1: We are now taking questions for Dr Chiang. Please use the Q&A function in Zoom to submit your questions. While you do so, actually, Dr Chiang, can you forward the slide one more?

Dr Chiang: Yes. I do not know if I can, can I?

[00:50:40]

Thank You For Attending Our Program!

Speaker 1: There you go. Right there. I want everyone to please note the QR codes on the screen and the chat panel, which contain 2 important links: a downloadable slide deck from today's presentation, as well as the program evaluation link to complete and claim credit. I can see one question in the Q&A.

Dr Chiang: Can you ask it because I cannot see?

Speaker 1: It says is there any consideration for shortening the LDCT interval scanning in patients that are higher risk for small cell?

Dr Chiang: Oh, that is a really good question. I think not right now. I think, those recommendations come out from different groups, like the US Preventive Task force and so forth. It is really a population approach. Right now, I do not think there is any plans to change that, but I do think that is why people are working, or why people are so excited about some of these AI approaches, radiomic, [inaudible [00:52:04] to determine characteristic patterns as well as potential blood tests that could help us detect lung cancer beforehand, and specifically small-cell lung cancer.

I do not think we are there yet, and so right now, I do not think that the bulk of lung cancer, 85%, is non-small-cell lung cancer. I think that really forms the basis for the screening recommendations. Although, I would tend to agree with you that maybe we could move it up a little bit, but right now… That is a great question. Thank you.

Speaker 1: There is another one that says thoughts on maintenance, tarlatamab, and atezo question mark? Does Atezo add anything if we are doing maintenance tarlatamab?

Dr Chiang: That is a great question. Right now, our choices that are FDA approved are either continuing the immunotherapy or, as I mentioned about the IMforte trial, adding lurbinectedin. We do not have tarla maintenance yet. It is only in clinical trial. Now, that being said, the World Lung data showed a phase I trial of maintenance with tarlatamab. Adding tarla to the immunotherapy and that actually showed in this small phase I, but showed a median overall survival of 25 months with the tarla maintenance. I think that phase III trial with tarla plus durvalumab is going to be positive.

That has already finished accrual, and I think we will get those results sometime within another year or so. At that time, if that is positive with that effect. In other words, so just to compare, the lurbinectedin plus atezo overall survival from start of maintenance is 13 months. If the randomized phase III trial for tarla maintenance looks like the phase I, and is anywhere near 25 months, then that is definitely going to be our new standard of care. Right now, I would not use it. It is not yet approved, and I think we are waiting for the trial results. But that is a great question.

I also think that in maintenance there are a number of other approaches happening. I will take this opportunity to talk about the S2409 PRISM trial. That is a cooperative group trial that just opened, so you guys can open it. I am the national chair, and this is the largest trial that is going to be looking at targeted therapy for small cells. The idea here is that we are going to have over 800 patients who we get their tissue from during induction chemo, so platinum doublet plus durva.

Then, based on their subtype, so if they are A and P or I and the Schlafen 11 status, they will be randomized to durva in maintenance, or durva plus the biomarker-directed therapy, the subtype-directed therapy. That is a really super exciting trial. It is going to be the largest precision medicine trial for small cell, and I think we will learn a lot from that. There is some really exciting drugs in that trial as well. The newest latest PARP inhibitor, ATR inhibitor, and NK cell activator, plus durvalumab vs durvalumab. Please look into that trial. We just activated it, and you would be getting in early.

Speaker 1: Excellent. We have a question here from Hillary Wall. How do you educate patients/ED staff reawareness on ICANS, I-C-A-N-S?

Dr Chiang: That is a great question. It is a lot of education with the patients, as you know, their caregivers, as you know, because if they are confused, they really have to have their caregivers be able to advocate for them. Then the ED staff is super important because that is where they are going to go. We are actually doing education sessions with our trainees, fellows, hospitalists, and ED staff around that. There are patient wallet cards that are available that you can ask for. I think this is the thing. We are on Epic. We have a care signature pathway so that if you type in ICANS, that is what comes up, and it helps to manage that. Basically, steroids are the most useful way of managing mostly grade 1, grade 2. Great question.

Speaker 1: Thank you. That is all I am seeing online at the moment. Do we have any questions from the live audience?

Dr Chiang: Can I take down the slides now, or do you want me to leave it up?

Education Host (CCO): We got a question. One second.

Speaker 1: Oh, you can leave it up for now.

Education Host: He is making his way here.

Speaker 5: What is the future of Keytruda compared to these newer medications?

Dr Chiang: That is a good question. Do you mean in small cell or in non-small cell?

Education Host: Hey. Come back. She asked you a question. Can you repeat? Go ahead. Hello.

Dr Chiang: Let me answer. I will answer for both. Keytruda is not something that we are using a lot for small-cell. I think the overall question of immunotherapy vs bispecific antibodies, and I think that the future is really going to be the combination, honestly, because they work differently. The T cell engagers are basically taking the immune cell, the immune system to the tumor cell. That actually works really well in small cell, because if you do biopsies, there are very few T cells there. It is like an immune desert. Being able to bring the T cells over will help them to work more.

Then the immunotherapy, anti-PD-1, PD-L1, that works by taking off the checkpoints, or basically allowing again, your T cells and your immune system to recognize the antigens on the surface of the tumor cell and then destroy them. There are 2 different mechanisms, and so I think that the future is going to bring them together. You are going to need both of them to be able to get the most effective.

Speaker 5: Thank you.

Dr Chiang: Great question.

Education Host: Any other questions? All right. One more.

Speaker 6: You spoke about the life-threatening complication in patients with a recurrent disease, like fever, shock, hypoxemia, requiring vasopressor. What is the prevalence of those complications?

Dr Chiang: Over half of the patients have grade 1 or grade 2 cytokine release syndrome. That means that they can be managed with supportive care, Tylenol, oxygen, IV fluids, and steroids. Only 1% in that trial actually had grade 3, which meant that they needed to go to the ICU for more intense treatment, for example, oppressor. It is really pretty manageable. Obviously, that the 1% you want to be able to have them come in right away, or if they are in, that they can be transferred to the unit to manage them. I have not had any issues with grade 5, patients that did not make it. We have been able to really manage the symptoms.