SCLC Data Drive Changes in First-Line Maintenance and Second-Line Care

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The small cell lung cancer (SCLC) treatment paradigm is experiencing unprecedented progress as emerging data about immunotherapies, maintenance strategies, and antibody-drug conjugates (ADCs) fuel optimism in the field and reinforce the vital role of multidisciplinary collaboration.

“At [the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting], we had 2 practice-changing studies,” Anne Chiang, MD, PhD, said in a recent OncLive Peer Exchange. “There [has been] more progress within the past year than there has been in the past 30 to 40 years. This is an exciting time for our patients, for our research teams, and for clinical care.”

During the panel discussion, SCLC experts discussed updates from ASCO 2025. They highlighted current treatment standards for limited-stage SCLC (LS-SCLC) and extensive-stage SCLC (ES-SCLC), practice-changing data in the ES-SCLC first-line maintenance setting, and where the future is headed regarding postprogression management strategies in the second-line setting and beyond. Multidisciplinary collaboration considerations were featured heavily in the discussion, as the panelists emphasized that the growing complexity of SCLC treatment developments necessitates frequent communication with colleagues including radiation oncologists, palliative care teams, pulmonologists, nutritionists, physical therapists, and social workers to ensure the delivery of comprehensive patient care.

Postchemoradiotherapy Duvalumab Retains its Role In LS-SCLC

In December 2024, the FDA approved durvalumab (Imfinzi) for the treatment of adult patients with LS-SCLC whose disease has not progressed after concurrent platinum-based chemotherapy and radiotherapy.1 This regulatory decision was supported by data from the phase 3 ADRIATIC trial (NCT03703297), in which patients who received durvalumab (n = 264) experienced a statistically significant overall survival (OS) benefit compared with those who received placebo (n = 266), with a median OS of 55.9 months (95% CI, 37.3-not estimable) vs 33.4 months (95% CI, 25.5-39.9), respectively (HR, 0.73; 95% CI, 0.57-0.93; P = .0104).1,2 Patients in the durvalumab arm also achieved a statistically significant progression-free survival (PFS) improvement vs those in the placebo arm, with a median PFS of 16.6 months (95% CI, 10.2-28.2) vs 9.2 months (95% CI, 7.4-12.9), respectively (HR, 0.76; 95% CI, 0.61-0.95; P = .0161).

Although ADRIATIC established durvalumab as a postchemoradiotherapy standard of care (SOC) for patients with LS-SCLC, findings from the phase 2 trial ACHILES (NCT03540420) presented at ASCO 2025 did not show a similar benefit with the use of atezolizumab (Tecentriq) in this setting.3 The median OS from randomization was 43.3 months (95% CI, 25.1-51.2) among patients who received atezolizumab (n = 85) vs 38.8 months (95% CI, 25.8-57.6) among those who underwent observation (n = 85; HR, 1.14; 95% CI, 0.76-1.71; P = .53). The median PFS in these respective arms was 21.1 months (95% CI, 9.5-43.4) vs 15.9 months (95% CI, 10.6-24.0; HR, 0.89; 95% CI, 0.61- 1.30; P = .55). Based on these data, the panelists noted that durvalumab remains the SOC for this population.

“One thing I want to emphasize here is the need for multidisciplinary care for patients with SCLC,” Christine Lovly, MD, PhD, FASCO, noted regarding the use of radiotherapy in the LS-SCLC population. “Conversations about once-a-day [radiation] vs twice-a-day radiation vs prophylactic cranial irradiation are conversations we’re having with the patients, with medical oncology, [and] with radiation oncology. [I] want to underscore the importance of that close communication with the radiation oncologists.”

Atezolizumab and Durvalumab Continue Their Footholds in First-Line ES-SCLC

In March 2019, the FDA granted approval to the PD-L1 inhibitor atezolizumab plus carboplatin and etoposide for the first-line treatment of patients with ES-SCLC based on data from the phase 3 IMpower133 trial (NCT02763579).4 The median OS was 12.3 months in the atezolizumab arm vs 10.3 months in the chemotherapy-alone arm (HR, 0.70; 95% CI, 0.54-0.91; P = .0069).

The first-line treatment paradigm for this population was further expanded in March 2020 with the FDA approval of durvalumab in combination with etoposide and either carboplatin or cisplatin, which was backed by findings from the phase 3 CASPIAN trial (NCT03043872).5 In this trial, the median OS was 13.0 months (95% CI, 11.5-14.8) with durvalumab plus chemotherapy vs 10.3 months (95% CI, 9.3-11.2) with chemotherapy alone (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).

Based on these regulatory decisions, atezolizumab and durvalumab are established SOC for patients with previously untreated ES-SCLC.

“I think of them in the clinic as interchangeable, but [I acknowledge] that there are some data, if we had to pick, [indicating greater] efficacy [with] durvalumab,” Catherine Meador, MD, PhD, said. “We’re going to see more of these exciting, novel agents in the later line being moved to first-line testing in combination with PD-L1 [inhibitors]. Ultimately, that will start to affect our first-line choice of PD-L1 inhibitor.”

Shifting First-Line Maintenance Strategies Raise Questions in ES-SCLC

Data from the phase 3 IMforte trial (NCT05091567) presented at ASCO 2025 showed that in patients with ES-SCLC whose disease did not progress after first-line induction therapy with carboplatin, etoposide, and atezolizumab, first-line maintenance therapy with the combination of lurbinectedin (Zepzelca) and atezolizumab significantly improved both PFS and OS compared with atezolizumab monotherapy (Table 1).6 The median PFS was 5.4 months (95% CI, 4.2-5.8) with lurbinectedin plus atezolizumab (n = 242) vs 2.1 months (95% CI, 1.6-2.7) with atezolizumab alone (n = 241; stratified HR, 0.54; 95% CI, 0.43-0.67; 2-sided P < .0001). The median OS in these respective arms was 13.2 months (95% CI, 11.9-16.4) compared with 10.6 months (95% CI, 9.5-12.2; stratified HR, 0.73; 95% CI, 0.57-0.95; 2-sided P = .0174).

“This immediately was practice changing,” Misty Shields, MD, PhD, emphasized. “This is an area of vulnerability for patients who have extensive- stage [disease], have had a brisk or meaningful response after induction chemoimmunotherapy, and then switched to immunotherapy and relapsed. [Lurbinectedin plus atezolizumab] is a helpful option to add for patients with extensive-stage [disease] in the maintenance setting to help prevent that high risk of relapse we see with immunotherapy alone.”

Cytotoxic Chemotherapy and Targeted Agents Revamp Relapsed SCLC Management

The influx of novel treatment advances for SCLC also signals a shift away from the use of platinum rechallenge—a historical SOC—in the second-line setting. For instance, in a phase 2 basket trial (NCT02454972), data from which supported the FDA approval of lurbinectedin for the treatment of patients with metastatic SCLC, 44% of patients with a chemotherapy-free interval of at least 90 days had a duration of response of at least 6 months; this rate was 10% in patients with a chemotherapy-free interval of less than 90 days.7

“Would that have happened with platinum rechallenge?” Jacob Sands, MD, asked. “Probably not better than that. We see improved outcomes with all cytotoxic [agents] in [patients] with platinum sensitivity. Lurbinectedin and some other options are less toxic than platinum rechallenge.”

Furthermore, findings from the phase 3 DeLLphi-304 trial (NCT05740566), which were presented at ASCO 2025, showed that second-line tarlatamab-dlle (Imdelltra) generated statistically significant and clinically meaningful OS benefits vs chemotherapy in patients with relapsed SCLC (Table 2).8 At median follow-ups of 11.2 months in the tarlatamab arm (n = 254) and 11.7 months in the chemotherapy arm (n = 255), patients who received tarlatamab achieved a median OS of 13.6 months vs 8.3 months for those who received chemotherapy (HR, 0.60; 95% CI, 0.47-0.77; 2-sided P < .001).1 The 6- and 12-month OS rates with tarlatamab were 76% and 53%, respectively. In the chemotherapy arm, these respective rates were 62% and 37%.

“Tarlatamab is the only therapy that has the potential for a long-term, durable response,” Lovly stated. “Why would I not give a patient tarlatamab, considering the other options that we have for the second line or beyond? Tarlatamab now should be the SOC for second-line SCLC. This requires an even larger team to coordinate the hospital admissions [and] the multiple clinical visits. This will change as we learn how to operationalize the drug better. However, the operational aspect should not prevent us from giving what we believe is the best drug to patients, so we have to make it work as a systems-based team that is not just a physician-based team, but also [includes] social workers, case management, [and] hospital administration to arrange the admissions.”

Now that multiple second-line treatment options are making their way into the SCLC management arena, the panelists emphasized that individual patient characteristics and multidisciplinary collaboration will increasingly factor into decision-making in this setting. For example, in DeLLphi-304, the OS benefit observed with tarlatamab extended to patients across several prespecified subgroups, including those with previous or current brain metastases (HR, 0.45; 95% CI, 0.31-0.65).8

Furthermore, although the pivotal basket trial that led to the FDA approval of lurbinectedin for patients with relapsed SCLC did not include patients with brain metastases,7 data from the retrospective LURBICLIN study demonstrated that among a cohort of patients with SCLC who had received lurbinectedin in the second- or later-line setting, investigators observed no significant differences in lurbinectedin-related outcomes based on the presence of brain metastases.9 The median intracranial PFS was 3.1 months (95% CI, 2.6-4.1) in patients with baseline brain metastases and 8.8 months (95% CI, 4.9-not reached) in those without baseline brain metastases.

“It’s important, no matter which agent we choose for patients with or without a history of brain metastases, to be doing regular MRIs every 3 months to make sure if and when we see brain metastases develop, we can loop in our radiation oncology colleagues early to manage those brain metastases before [the patients] develop symptoms and [so we can] keep patients on systemic therapy,” Meador highlighted.

PRISM Trial Seeks to Optimize Durvalumab’s Role in SCLC

As more agents enter the SCLC treatment paradigm, future research questions will revolve around optimal ways to combine and sequence these agents, particularly following progression on prior targeted therapies.

The phase 2 PRISM (SWOG S2409) trial (NCT06769126) plans to evaluate durvalumab alone vs in combination with novel biomarker-directed therapies (saruparib [AZD5305], ceralasertib [AZD6738], or monalizumab [formerly IPH2201]) as maintenance therapy in patients with ES-SCLC.10 The trial is enrolling patients aged 18 years and older who are either treatment naive and planning to receive first-line induction therapy with platinum plus etoposide and durvalumab, or pretreated with first-line induction therapy and have completed between 1 and 3 cycles of platinum and etoposide. Patients must not have prior exposure to immunotherapy other than durvalumab and must have adequate tumor tissue available. Those with untreated brain metastases must be asymptomatic and stable without steroids prior to random assignment.

Following tissue specimen testing to determine individual SCLC subtypes and treatment eligibility, patients will be assigned to 1 of 3 cohorts, then randomly assigned to 1 of 2 arms within their assigned cohort. The primary end points include screening success rate and PFS in all 3 cohorts. Key secondary end points across cohorts include safety, OS, SCLC subtype status, and SLFN11 expression status.

ADC Development Sets the Stage For Future SCLC Treatment Strategies

Moreover, the array of ADCs for SCLC is expanding. For instance, at a median follow-up of 15.3 months (range, 0.8-20.3), treatment with the investigational B7-H3–directed ADC ifinatamab deruxtecan at a dose of 12 mg/kg (n = 42) generated an overall response rate (ORR) of 54.8% (95% CI, 38.7%-70.2%) among heavily pretreated patients with ES-SCLC; all responses were partial.11

“For the relapsed setting post tarlatamab or lurbinectedin or [other] FDA-approved agents, now we’re seeing ADCs, this trojan horse with an unassuming antibody chemotherapy payload that is introduced to the surface of the SCLC and brought in as a ticking time bomb to the SCLC to target [it], typically with a topoisomerase inhibitor payload,” Shields explained. “[ADCs are associated with] high ORRs in relapsed, heavily pretreated patients.”

DLL3 is another attractive target for the development of SCLC ADCs, the panelists agreed. The DLL3-targeted ADC ZL-1310 is under investigation in an ongoing, global phase 1 trial (NCT06179069) in patients with ES-SCLC.12 Updated data from the dose-escalation portion of the trial presented at ASCO 2025 showed an ORR of 68% and a disease control rate of 93% among 28 evaluable patients. The best ORRs among patients who had received 1 (n = 33), 2 (n = 26), and 3 or more (n = 15) prior lines of therapy were 49%, 27%, and 27%, respectively. Investigators observed responses across all tested dose levels and DLL3 expression levels. Additionally, among patients with brain metastases (n = 22), the ORR was 46%.

The panelists concluded their discussion by noting questions regarding the potential for and causes of acquired resistance with the serial use of therapies directed at the same target. With the ubiquitous use of the DLL3-targeted agent tarlatamab for all-comers with SCLC, the speakers emphasized that further research is necessary to determine how DLL3 expression changes over the course of the disease and in the presence of each agent. Although the SCLC treatment armamentarium is accumulating an array of novel agents, biomarker biology and target expression remain ripe points for further therapeutic evolution through innovative clinical research.

“There are more drugs in development for SCLC than there ever have been in the past,” Meador summarized. “Please refer your patients for trials, because the only way we’re going to advance the field is by continuing to get patients on trials, enroll on these studies, and learn. We cannot do that unless we’re getting patients onto studies.”

References

  1. FDA approves durvalumab for limited-stage small cell lung cancer. FDA. December 4, 2024. Accessed June 20, 2025. http://bit.ly/4lfHOPY
  2. Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5
  3. Gronberg BH, Aanerud M, Dumoulin DW, et al. Randomized phase II trial investigating whether atezolizumab after chemoradiotherapy (CRT) prolongs survival in limited stage (LS) small cell lung cancer (SCLC). J Clin Oncol. 2025;43(suppl 17):LBA8005. doi:10.1200/JCO.2025.43.17_suppl.LBA8005
  4. FDA approves Genentech’s Tecentriq in combination with chemotherapy for the initial treatment of adults with extensive-stage small cell lung cancer. News release. Genentech. March 18, 2019. Accessed June 20, 2025. https://bit.ly/2Y5jVkw
  5. FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. Updated March 30, 2020. Accessed June 20, 2025. http://bit.ly/4k60FvT
  6. Paz-Ares LG, 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
  7. Singh S, Jaigirdar AA, Mulkey F, et al. FDA approval summary: lurbinectedin for the treatment of metastatic small cell lung cancer. Clin Cancer Res. 2021;27(9):2378-2382. doi:10.1158/1078-0432.CCR-20-3901
  8. Rudin CM, Mountzios GS, 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
  9. Girard N, Guisier F, Swalduz A, et al. Lurbinectedin in extensive-stage small-cell lung cancer: a brief report of the IFCT-2105 LURBICLIN study. ESMO Open. 2024;9(12):103968. doi:10.1016/j.esmoop.2024.103968
  10. Using biomarker tests to select and test new, personalized treatments for extensive stage small cell lung cancer, PRISM study. ClinicalTrials.gov. Updated March 28, 2025. Accessed June 20, 2025. https://clinicaltrials.gov/study/NCT06769126
  11. Rudin CM, Ahn MJ, Johnson M, et al. Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): interim analysis of IDeate-Lung01. J Thorac Oncol. 2024;19(suppl 10):S15-S16. doi:10.1016/j.jtho.2024.09.033
  12. Patel MR Wu YL, Wang Z, et al. ZL-1310, a DLL3 ADC, in patients with extensive stage small cell lung cancer: ph1 trial update. J Clin Oncol. 2025;43(suppl_16):3041. doi:10.1200/ JCO.2025.43.16_suppl.3041

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