Delving Into the Current State of Clinical Practice in SCLC

At the 43rd Annual Chemotherapy Foundation Symposium (CFS), hosted by Physician’s Education Resource®, LLC, oncologists gathered to discuss emerging developments in oncology. One session in particular, “Cases and Conversations: Transforming Small Cell Lung Cancer (SCLC) Treatment Through Emerging Evidence and Expert Insights (Spotlight CE Session),” gave an extensive overview of the state of SCLC across patients with both limited-stage (LS-SCLC) and extensive-stage (ES-SCLC) disease. Anne Chiang, MD, PhD, an associate professor of Medical Oncology and Thoracic Oncology, as well as the Associate Cancer Center Director of Clinical Initiatives at Yale School of Medicine, was one of the speakers who joined CancerNetwork® in a discussion surrounding her involvement with the session.

Initially, she provided a high-level overview of her portion of the presentation, which encompassed developments in chemoradiation and immunotherapy among patients with LS-SCLC. Additionally, Chiang touched upon findings presented by her co-speaker, Jacob Sands, MD, associate chief at the Lowe Center for Thoracic Oncology and Oncology Medical Director of the International Patient Center at the Dana-Farber Cancer Institute, who covered ES-SCLC.

Then she outlined trials evaluating chemoimmunotherapy which have contributed to the evolution of systemic therapy for the first line setting and biomarkers her team is using to better select patients for targeted therapies. Furthermore, Chiang contemplated the role of chemotherapy in the field, given the emergence of antibody-drug conjugates (ADCs) in the first-line setting.

Additionally, Chiang continued by outlining common toxicities observed with immunotherapy options in SCLC and strategies to mitigate them. She concluded by emphasizing the positive benefit-risk ratio of immunotherapy options like tarlatamab-dlle (Imdelltra) in patients with SCLC, who experience high response rates despite unique adverse effects (AEs).

What was discussed during the spotlight session on small cell lung cancer that you gave at the Chemotherapy Foundation Symposium?

Chiang: I focused on limited-stage small cell lung cancer, and I talked about the phase 3 ADRIATIC trial (NCT03703297)trial, which reported out last year, and that includes using durvalumab [Imfinzi] for 2 years after concurrent chemoradiation.² That was a positive trial, and it was an impressive overall survival [OS] benefit of almost 2 years. That was approved [in December 2024], and we have been using that ever since last year, and patients are doing well [on it]. I talked about how it was tolerated quite well in terms of [adverse] effects. We were a bit worried about adding immunotherapy after radiation, but the study showed that…if you are looking specifically at radiation pneumonitis, or at pneumonitis, the frequency of that occurring was not significantly different between the arm with immunotherapy vs without. This is a new standard of care for our patients.

There are exciting trials that are ongoing, looking at adding other agents in that space, after consolidation, or after the definitive therapy with chemoradiation. One of them is with tarlatamab vs observation. That trial is a bit hard to accrue because now, at least in the US, the standard-of-care includes durvalumab à la ADRIATIC, but that is a global study, so that should finish accrual soon.

Then there was another study, the phase 3 NRG-LU005 trial (NCT03811002) that showed that if you added atezolizumab [Tecentriq] ––immunotherapy plus chemoradiation––followed by atezolizumab consolidation afterwards, that was a negative trial.³ Right now, we do not add immunotherapy to chemoradiation and there are several different theories as to why that was negative. We do not [entirely] know, but maybe it is because you are killing off T cells that are required for that response. We are still learning about that. That was what I talked about [during the CFS presentation].

Then my colleague, Jacob Sands, MD, talked about extensive-stage [disease] and exciting new therapies there, including tarlatamab, a DLL3 bispecific, and he talked about the [phase 2] DeLLphi-301 (NCT05060016) and [phase 3] DeLLphi-304 (NCT05740566) trials that confirmed tarlatamab use is [the] standard of care in the second-line setting.^4,5 [He also] talked about the toxicities, which are manageable and include cytokine release syndrome [CRS] and, and rarely immune effector cell-associate neurotoxicity syndrome [ICANS].

Then he talked about some exciting data, looking at antibody-drug conjugates in small cell lung cancer. Response rates are somewhere in the 60% to 80% range. Sometimes, for those second-line patients, 80% and again, tolerated well. There is some interesting and exciting intracranial benefit. Those are on the horizon, and I suspect will be ultimately a better way to deliver chemotherapy more potently to the cancer and avoid some of the other [adverse] effects for standard of care chemotherapy.

How have recent trials integrating immune checkpoint inhibitors into the standard platinum etoposide backbone fundamentally changed the first-line systemic approach for both limited-stage and extensive-stage small cell lung cancer?

Small cell lung cancer is an area where you can see, within the past 5 years, how the front line, or our standard of care treatments, have changed because of research results from clinical trials. [In] 2018 was the first [phase 3] IMpower133 trial (NCT02763579) that led to including atezolizumab with the platinum doublet, followed by atezolizumab in the maintenance setting.⁶ Then shortly thereafter, in 2019 was the [phase 3] CASPIAN trial (NCT03043872) that did the same for durvalumab.⁷ Then, last year, we [received] the results of the ADRIATIC trial that showed almost a 2-year benefit of OS for patients [receiving] 2 years of durvalumab after concurrent chemoradiation. This year at ASCO, we have the phase 3 IMforte trial (NCT05091567), which showed a 3-month OS benefit by adding lurbinectedin [Zepzelca] for select patients in combination with atezolizumab in the maintenance setting.⁸

This field is changing fast. It is [quite] exciting for our patients. There are still unmet needs, but I have confidence that we are going to continue to make progress.

What predictive biomarkers are you prioritizing in early phase trials to better select patients for specific immunotherapies or targeted agents?

We have a great trial that has opened through the cooperative groups. It is the phase 2 SWOG 2409 (S2409) PRISM trial.⁹ It is going to include over 800 patients, and this is going to integrate biomarkers so that we can offer precision medicine for our patients [with SCLC]. In this trial, the patients will undergo induction chemoimmunotherapy during the first 4 cycles or so, and during that time, we will get tissue from the patients to figure out what subtype they are, if they are subtype SCLC-A, SCLC-N, SCLC-P or SCLC-I, and also biomarker use the what status they are for Schlafen 11 protein.

Then, based on these biomarkers, they will be [randomly assigned] to a targeted agent plus durvalumab and maintenance vs durvalumab maintenance therapy alone. This builds on [the work of] Carl M. Gay, MD, PhD and Lauren A. Byers, MD at MD Anderson, showing that there are subtypes that benefit.¹⁰ For example, the subtype SCLC-I patient benefits from the use of immunotherapy.

We are going to try to target the therapy to the patients this trial. In addition, this is going to allow patients with asymptomatic brain metastases to come on and allow them to get their first cycle off trial and then join the trial after that, in case they were [quite] sick and had to get their first trial immediately. We are making the effort to make the trial fit the patient, instead of making the patient fit the trial. Ultimately, there are a lot of patients throughout the country, because this is a cooperative group trial, so community patients who are going to be accessing novel agents for SCLC and hopefully we can learn a lot from this.

Where do you see the role of chemotherapy evolving in small cell lung cancer?

Chemotherapy is our mainstay. It has been the gold standard for years––for decades that platinum doublet. That may be changing with antibody-drug conjugates looking so good with high response rates in the 60% to 80% range. If you select out those patients who in the trials were [treated in the] second line, it is closer to 80% and they have good intracranial responses. This is a time when we are thinking about replacing that platinum doublet with a combination with an ADC in first line [setting]. This is an exciting time for small cell lung cancer.

What are some common toxicities observed with immunotherapy in small cell lung cancer, and what are some common strategies to manage or mitigate them?

We have gotten [quite] good at managing these [toxicities] with NSCLC. Typically, we use steroids to mitigate them, and often patients, even after they have been treated with steroids, and they have a treatment-free interval, you can just monitor them, and they may continue to have response. If you consider some of these new therapeutics, such as tarlatamab, which are bispecific antibodies, they have some interesting [adverse] effects that we are learning how to manage. Tarlatamab which was approved last year [in the] second line or [later], is activating your immune system––like you are getting a flu shot. You get fever, chills, aches and pains. Your blood pressure can be a bit low. You [may] not feel so well. These can be managed with acetaminophen [Tylenol], intravenous fluids, some oxygen, steroids.

There are a couple percent of patients who get grade 3 CRS, and they should be monitored in an intensive care unit setting because they might need some additional medications to support their blood pressure or [may need] tocilizumab [Actemra] to help calm down the immune system, but these are manageable, and we are learning how to do that. Now, the indication is to watch the patients for 24 hours after the infusion for the first 2 weeks. After that, the rest of the doses can be given in the outpatient office. We are working on, at Yale, ways to pilot doing outpatient administration and observation so that patients do not need to be admitted to the hospital.

The field is going to learn how to do this, certainly with the DeLLphi-304 second-line trial of tarlatamab vs investigator choice chemotherapy. That was a positive trial, and it again showed that these [adverse] effects exist but are manageable. Rarely, you can have ICANS, and that, again, is a few percent of patients, and that can manifest as confusion or disorientation, sometimes tremor shakes or some weakness in your arms or legs. Again, we treat that with steroids, and we ask our neuro-oncology colleagues to help follow these patients.

It is worth it, because the response rate for tarlatamab in the second line [setting] is around 35% to 40% and that duration of response is 6 to 10 months. [It is] important that the trial included patients with brain metastases. Patients with CNS metastases is an area of critical need. We need more therapeutics to manage that, and tarlatamab is one that we can [use] that does have clinical activity in the brain as well.

References

1. Rudin CM, Chiang A, Sands JM. Cases and conversations: transforming small cell lung cancer treatment through emerging evidence and expert insights (Spotlight CE Session). Presented at: 43rd Annual Chemotherapy Foundation Symposium (CFS); November 12-14, 2025; New York, NY.
2. Cheng Y, Spigel DR, Cho BC, et al. Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med. 2024;391(14):1313-1327. doi:10.1056/NEJMoa2404873
3. Higgins KA, Hu C, Ross HJ, et al. Concurrent chemoradiation +/– atezolizumab (atezo) in limited-stage small cell lung cancer (LS-SCLC): results of NRG Oncology/Alliance LU005. Presented at: 2024 American Society for Radiation Oncology Annual Meeting; September 29 - October 2, 2024; Washington, DC. Abstract LBA02.
4. Zuniga NM, Morgenstern-Kaplan D, Jayram DK, et al. Multi-institutional real-world experience of early tarlatamab-related toxicities for extensive stage small cell lung cancer. Presented at the 2025 International Association for the Study of Lung Cancer World Conference on Lung Cancer 2025; September 6-9, 2025; Barcelona, Spain.
5. Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. 2025;393(4):349-361. doi:10.1056/NEJMoa2502099
6. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Eng J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
7. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
8. Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025;405(10495):2129-2143. doi:10.1016/S0140-6736(25)01011-6
9. Using biomarker tests to select and test new, personalized treatments for extensive stage small cell lung cancer, PRISM study. ClinicalTrials.gov. Updated November 5, 2025. Accessed November 24, 2025. https://tinyurl.com/yc5kv9vz
10. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-360. doi:10.1016/j.ccell.2020.12.014