Understanding “Paradigm-Changing” Events in Small Cell Lung Cancer Care

There is a lot of excitement surrounding the use of different immunotherapies in the frontline management of small cell lung cancer (SCLC), and various data bring “terrific news” for the maintenance setting and other phases of treatment, according to Anne Chiang, MD, PhD.

CancerNetwork^® spoke with Chiang to further understand the current treatment landscape for patients with SCLC. After providing an overview of notable therapeutic options across multiple lines of therapy, Chiang discussed ongoing initiatives intended to expand tailored treatment choices based on disease heterogeneity.She also highlighted the importance of communicating these therapeutic advances to those in community-based settings while employing patient-reported outcomes to better include patients in the treatment decision-making process.

“I hope that people get a feeling for the excitement in lung cancer, especially in SCLC. There are paradigm-changing events that are occurring in real time, [and] we have exciting agents that are active and going to move the needle for our patients,” Chiang concluded. “Moving them into the first-line setting, earlier in the limited-stage setting, is super exciting for our patients. I hope people get a sense that things are happening, that we are marrying our understanding of the biology and therapeutics with success.”

Chiang is an associate professor of Medicine in the Section of Medical Oncology at Yale School of Medicine.

CancerNetwork: What do current treatment options look like in the management of SCLC? What factors do you consider when sequencing different therapies for patients?

This is an area that we need to focus on because it's going to be changing in the near future. There's a lot of excitement around that. For frontline [therapy], right now, we still stick with our 2 trials. That's either the IMpower133 [NCT02763579] regimen—carboplatin and etoposide with atezolizumab [Tecentriq]—or the CASPIAN trial [NCT03043872]— carboplatin/etoposide or cisplatin/etoposide plus durvalumab [Imfinzi] followed by maintenance durvalumab. The exciting part is that at the 2025 American Society of Clinical Oncology [ASCO] Annual Meeting, [findings from] the phase 3 IMforte trial [NCT05091567] were read out.¹ That's a maintenance trial adding lurbinectedin [Zepzelca] to maintenance atezolizumab. That showed a positive overall survival benefit of 3 months. It was conducted in patients who did not have brain metastases, but for those patients who were fit after induction therapy, we have been talking to them about doing switch maintenance with lurbinectedin plus atezolizumab.

That's going to affect the second line. Right now, for second-line [therapy], we think about 2 options. Besides clinical trials, we think about lurbinectedin or tarlatamab-dlle [Imdelltra]. If we move lurbinectedin up into the maintenance setting, then we will be focusing on tarlatamab. Tarlatamab is a bispecific antibody that engages the T-cell system. The 2 heads of the antibody recognize DLL3 and CD3. At ASCO 2025, the phase 3 DeLLphi-304 trial [NCT05740566] showed the benefit of tarlatamab in the second-line setting, which places that as our go-to.² We are excited because the response rate is 35% to 40%, patients have a disease control rate to upwards of 70%, and the duration of response that patients stay on therapy is in the 9-month range.

We think this is a great option for our patients. There are some adverse effects [AEs] that give pause or make it, logistically, a bit more difficult right now, for the first 2 doses and the step-up dose, 1 mg/10 mg. In the first 2 weeks, the recommendation is to have inpatient monitoring for cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS]. But we're working on ways to manage that in an outpatient setting.

There are trials ongoing now that place that in the maintenance [phase], in limited-stage [disease], and in the first-line setting. At the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, the phase 1b DeLLphi-303 trial [NCT05361395] was reported out by Kelly G Paulson, MD, PhD, who said that in the maintenance setting, [patients] had an overall survival of about 2 years.³ This is terrific news for our patients. A phase 3 trial is ongoing, so there's a lot to look at in that space.

If we used tarlatamab and lurbinectedin earlier, then what are we going to do for our patients who progress? That's where the antibody drug conjugates [ADCs] are so exciting. Right now, response rates are up to 50% in the heavily pretreated setting; that's exciting. For a SEZ6 antibody, [ABBV-706], if you looked at those patients who were in their second line of treatment, that response rate went up to 80%.⁴ For that drug, they just released the design of a trial that's going to be using SEZ6 plus immunotherapy in the frontline setting, [thereby] getting rid of the platinum doublet; that's amazing. There are other trials with tarlatamab and other ADCs that are replacing different components of the platinum doublet. Our frontline strategy or algorithm for treating SCLC is going to be radically different in the next 5 to 10 years; probably 2 to 3 years.

What novel therapeutics hold the most promise in improving treatment outcomes among patients with SCLC?

The biology of [SCLC is something] we are learning more about. One of the aspects is, like the strategy in non–small cell lung cancer [NSCLC], where we started to understand the heterogeneity, can we start to dial in our therapies for different subtypes? I will talk about a trial that is [from] a cooperative group: the SWOG S2409 PRISM trial [NCT06769126] that I happen to be the chair of. There’s a whole slew of people who have been involved, including my co-chair Alberto Chiappori, MD, from Moffitt Cancer Center, and Carl M. Gay, MD, PhD, and Lauren Averett Byers, MD, at MD Anderson Cancer Center.

In the PRISM trial, we are going to have over 800 patients where we ask for tissue during their frontline induction therapy with [chemoimmunotherapy]. Then, based on their subtype, are they A, N, P, or I? What is their SLFN11 status by immunohistochemistry? Then, those patients will be randomly [assigned] to the biomarker-directed therapy plus [immunotherapy] vs [immunotherapy alone arm]. If you have a neuroendocrine subtype—A or N—and you are SLFN11 positive, you will get a PARP inhibitor plus [immunotherapy] vs [immunotherapy alone]. If you have subtype I, you are going to get monalizumab, which is an NK cell activator, plus the [immunotherapy] vs [immunotherapy] alone, and so forth. We are excited about that trial. It’s a prospective trial, and most of all, we are going to be getting tissue from a slew of patients so that we can really move the field forward. I am excited about that.

What can be done to further optimize the care of patients with lung cancer in community-based settings?

Education and communicating the advances that are happening are important. There’s still a bit of nihilism about the prognosis of our patients, and for SCLC, this is a disease that, 5 years ago, most patients had an overall survival of a year. Now, we are seeing with the addition of immunotherapy to the frontline regimen, that about 18% make it to 3 years, and for your 5- and 6-year overall survival, you have about 10% of the patients making it there. Obviously, we need to still push that envelope; we need to understand, explore, and leverage our understanding of the biology. How can we impart that benefit to more patients? To do that, we need to get them treated, and we need to get them treated early on. There are trials now that are much more pragmatic than before. I am seeing those trials that allow patients with brain metastases who are asymptomatic to go on. I am seeing trials that allow patients to have a first cycle of chemotherapy before they [enroll] on to the clinical trial. Both of those are classic elements of clinical trials that patients [typically] could not go on because of those [factors].

Can you speak to the importance of employing patient-reported outcomes in cancer management? What kind of role might these patient-reported outcomes play in lung cancer or SCLC, specifically?

Employing patient-reported outcomes allows us to hear directly from the patient. We do that anyway, but being able to focus on that makes sure that we are including them in the shared decision-making and that it’s a focus in clinical trials as well. Sometimes, it may not be as easy as saying, “Okay, this is what I hear, and this is what we’re going to do.” Understanding from the patient’s point of view, which is what we are trying to do nowadays, is having a patient-centric approach. It makes sense to hear directly from the patient and capture that for understanding which therapies are going to be the best for the patient. Now, we are starting to have different options for our patients with lung cancer. Understanding which patients are having which [AEs]and how that’s impacting their life is super important.

Looking ahead, where does the field need to go to further improve the prognosis of patients with SCLC?

Understanding and leveraging the biology is important. We are going to need to understand how to sequence therapies, and that involves understanding which patients are at higher risk. [That is] no. 1. No. 2, which biomarkers can we use? We are still struggling to understand how to use our biomarkers. No. 3, we need to understand the heterogeneity of which treatments will work for each group of patients and, ultimately, how to manage [AEs] as well. Those are different options.

We need to look at high-risk populations—for example, patients with brain metastases—and understand which therapies are especially useful for them. That’s an area of unmet need. We need to learn how to cure these patients, too. I want to keep that on the table. Maybe utilizing CAR T therapies or things that can teach the immune system, long-term, how to recognize cancer cells is important to keep in mind.

References

1. Paz-Ares L, Borghaei H, Liu SV, et al. Lurbinectedin (lurbi) + atezolizumab (atezo) as first-line (1L) maintenance treatment (tx) in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC): primary results of the phase 3 IMforte trial. J Clin Oncol. 2025;43(suppl 16):8006. doi:10.1200/JCO.2025.43.16_suppl.8006
2. Rudin C, Mountzios G, Sun L, et al. Tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): primary analysis of Ph3 DeLLphi-304. J Clin Oncol. 2025;43(suppl 17):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008
3. Paulson KG, Lau SCM, Ahn MJ, et al. Safety and survival update of tarlatamab with anti-PD-L1 as first-line maintenance after chemo-immunotherapy for extensive-stage small cell lung cancer: DeLLphi-303 ph1b trial. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA13.
4. Byers LA, Cho BC, Cooper AJ, et al. Safety and efficacy of ABBV-706, a seizure-related homolog protein 6–targeting antibody-drug conjugate, in R/R SCLC. Presented at: International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract OA06.04.