Recent Advances in Extensive Stage Small Cell Lung Cancer

Small-cell lung cancer represents between 10% and 15% of new lung cancer diagnoses each year in the United States.^1,2 Extensive-stage small cell lung cancer (ES-SCLC) is defined as a disease that cannot be encompassed by a single radiation field. Approximately 70% of patients with small-cell lung cancer will have extensive-stage disease at the time of diagnosis.³ Without treatment, patients with ES-SCLC have a median survival of two to four months.⁴ While often initially responsive to chemotherapy, disease recurrence is the norm.⁵ Options in the second line setting and beyond are limited, and outcomes are particularly poor among patients with platinum-resistant disease and early relapse.⁶

For decades, the treatment of ES-SCLC centered on platinum-based chemotherapy. This paradigm was unchallenged until the IMpower133 phase 3 trial in 2018. Patients with ES-SCLC who were treated in the first-line setting with platinum-based chemotherapy and atezolizumab, followed by atezolizumab maintenance, had a median overall survival (OS) approximately 2 months longer than patients treated with platinum-based chemotherapy alone.⁷ The subsequent phase 3 CASPIAN trial showed that the addition of durvalumab to initial platinum-based chemotherapy, followed by durvalumab maintenance, improved median OS by approximately 3 months compared with platinum-based chemotherapy alone.⁸ The results of CASPIAN were reproduced in subsequent trials in Asian populations,⁹ and in patients with poor performance status.¹⁰ Survival benefit was seen across these trials regardless of PDL-1 status. Together, Impower133 and CASPIAN redefined standard-of-care first-line therapy in ES-SCLC. Key characteristics and outcomes of these foundational studies are summarized in *Table 1*.

Despite these advancements, most patients with ES-SCLC will develop disease relapse. Late relapse after 6 months is often treated by rechallenging with platinum-based chemotherapy.¹¹ Early relapse portends a poor prognosis, and effective treatments are limited. Topotecan was approved by the FDA in 1996 based on phase 2 trial data demonstrating an overall response rate of 39% among patients with ES-SCLC who relapsed after platinum-based therapy.¹² The oral form of topotecan was later evaluated in a phase 3 trial, which found a survival benefit, compared to best supportive care, in patients with relapsed SCLC.¹³

Second-line therapies for ES-SCLC were limited to chemotherapy until lurbinectedin changed the treatment landscape. Lurbinectedin inhibits DNA transcription by selectively binding to guanine-rich regions of the DNA helicase, resulting in tumor cell apoptosis.¹⁴ It received accelerated FDA approval in 2020 for the treatment of relapsed SCLC based on phase 2 trial data showing an overall response rate of 35% among patients with disease relapse after platinum-based chemotherapy.^15,16 The ATLANTIS phase 3 trial showed that patients with relapsed SCLC (prior platinum-based chemotherapy) who received second-line lurbinectedin and doxorubicin had a median OS of 8.6 months.¹⁷ This was not superior to patients treated with second-line topotecan or second-line cyclophosphamide, vincristine, and doxorubicin (OS 7.6 months, HR 0·97 [95% CI 0·82–1·15], p=0.70).

Lurbinectedin-based regimens are currently under investigation in the second-line setting for ES-SCLC. The phase 3 LAGOON trial will compare lurbinectedin monotherapy, lurbinectedin with irinotecan, and topoisomerase inhibitor monotherapy, among patients with SCLC who failed platinum-based chemotherapy.¹⁸ LAGOON has finished enrollment with preliminary results anticipated in 2026. Lurbinectedin is also being studied in combination with immunotherapy. The phase 1/2 2SMALL trial compared lurbinectedin with atezolizumab in the second-line setting and showed an overall response rate (ORR) of 37-44%, regardless of exposure to previous immunotherapy.¹⁹ This regimen is being investigated in the ongoing phase 3 IMforte trial.²⁰ In this trial, patients with ES-SCLC receive standard-of-care induction with platinum-based chemotherapy and atezolizumab. They are then randomized to receive either standard-of-care atezolizumab maintenance therapy or atezolizumab with lurbinectedin maintenance. IMForte is also the first prospective trial to investigate a lurbinectedin-based regimen in the first-line maintenance setting. Primary study findings presented at the 2025 American Society of Clinical Oncology (ASCO) annual meeting showed a median OS benefit for lurbinectedin and atezolizumab maintenance, compared to atezolizumab alone (median OS 13.2 months vs 10.6 months, HR 0.73, CI 0.57-0.95, p=.0174).²⁰

Tarlatamab received accelerated FDA approval in 2024 as the first targeted treatment for ES-SCLC.²¹ Tarlatamab is a bispecific T-cell engager that binds CD3 on T-cells and delta-like ligand 3 (DLL3) on small cell lung cancer cells. DLL3 is overexpressed in 85% of SCLC, with minimal expression in healthy tissue types.^22-24 The DeLLphi-301 phase 2 trial showed that Tarlatamab had a 40% overall response rate in patients with SCLC who had progressed after at least two lines of therapy.²⁵ Durable treatment responses lasting longer than six months were seen in 59% of patients. Tarlatamab has also shown efficacy in treating central nervous system (CNS) SCLC metastases. An updated analysis of early Tarlatamab trials found that, among 16 patients with ES-SCLC and central nervous system (CNS) involvement, ten (62.5%) had a ≥ 30% reduction in measurable CNS disease with Tarlatamab.²⁶ Tarlatamab is being evaluated in the ongoing phase 3 DeLLphi-304 trial.²⁷ DeLLphi-304 randomizes patients with SCLC who have progressed on one prior therapy to receive either Tarlatamab or chemotherapy in the second-line setting. Primary study findings presented at the 2025 ASCO annual meeting show that median OS is significantly longer for the Tarlatamab group (median OS 13.6 months vs. 8.3 months, HR 0.6, p<0.001). While cytokine release syndrome (CRS) was seen in 56% of patients, grade 3 CRS was rare. Immune effector-cell-associated neurotoxicity syndrome (ICANS), which is a common side effect of other bispecific T-cell engagers, was seen in only 8% of patients who received Tarlatamab.²³ Though Tarlatamab has never been directly compared to Lurbinectedin in a prospective analysis, results from DeLLphi-304 suggest that Tarlatamab should be the preferred standard of care option for eligible patients with ES-SCLC in the second-line setting.

Tarlatamab's success in the second-line setting has led to trials in the first-line setting for patients with ES-SCLC. DeLLphi-303 showed a manageable safety profile of Tarlatamab with anti-PD-L1 maintenance in the initial treatment of patients with ES-SCLC.²⁸ DeLLphi-305 is an ongoing phase 3 trial that aims to investigate whether the addition of Tarlatamab to standard-of-care platinum-based chemotherapy and durvalumab improves overall survival in patients with untreated ES-SCLC.²⁹ The trial is actively recruiting with results expected in 2028.

Other DLL3 targets are under investigation. BI-764532 is a bispecific antibody that, like Tarlatamab, targets DLL3 and CD3 and has been shown to induce tumor regression in xenograft models.³⁰ A first-in-human phase 1 trial in patients with SCLC and other neuroendocrine tumors is currently recruiting patients.³¹ HPN328 is a Trispecific T-cell engager that targets DLL3, CD3, and albumin. Binding to albumin extends the molecule's half-life and may enable less frequent dosing.³² HPN328 has shown promising efficacy in preclinical models. A phase 1/2 trial investigating HPN328 in patients with relapsed/refractory SCLC and other neuroendocrine tumors is currently recruiting patients.³³ Interim data presented at ASCO 2024 showed that HPN328 had a similar side effect profile as other DLL3-targeted therapies, with early low-grade CRS in ~ 50% of patients and relatively few grade 3 toxicities.³⁴ Interim efficacy data in patients with SCLC were not presented.

Another potential target in ES-SCLC is B7 Homolog 3 (B7-H3). B7-H3 is a transmembrane protein that is overexpressed in two-thirds of SCLC, with relatively little expression in healthy tissues.³⁵ Though its exact function is unknown, increased B7-H3 expression is associated with an immunosuppressive tumor microenvironment.³⁶ Ifinatamab-Deruxtecan (I-DXd) is an antibody-drug conjugate [ADC] that targets B7-H3 and delivers a topoisomerase inhibitor payload.³⁶ Interim results from the first-in-human trial showed that, among patients with heavily pretreated SCLC, I-DXd was generally well-tolerated and resulted in a 52% overall response rate.³⁷ IDeate-Lung01 is a subsequent phase 2 trial looking at I-DXd in patients with ES-SCLC with progression on platinum-based therapy.³⁸ Interim analysis presented at the 2024 World Cancer Conference showed that patients treated with the 12mg/kg dose had a median OS of 11.8 months and an ORR of 54.8%. Patients responded quickly, with a median time to response of 1.4 months. IDeate-Lung02 aims to expand on these previous studies.³⁹ It is an ongoing phase 3 trial comparing I-DXd versus treatment of the physician's choice in patients with relapsed SCLC. IDeate-Lung03 is the first trial investigating I-DXd in the first-line setting among patients with ES-SCLC.⁴⁰ This ongoing phase I/2 randomizes some cohorts to receive standard-of-care induction followed by maintenance with I-DXd and atezolizumab, and other cohorts to receive regimens that incorporate I-DXd into induction as well as maintenance. Both IDeate-Lung02 and IDeate-Lung03 are actively recruiting patients. Results may offer a new agent in the second line, and potentially a first-line setting for patients with ES-SCLC.

The last targeted therapy in phase 3 trials for ES-SCLC is specific to Fucosyl-monosialoganglioside-1 (fucosyl-GM1). Fucosyl-GM1 is a cell surface glycosphingolipid that is expressed on peripheral sensory neurons, dorsal root ganglia, and in 58-91% of small cell lung cancer.^41-43 Atigotatug is a first-in-class, fully humanized monoclonal antibody that binds to fucosyl-GM1 and enhances antibody-dependent cellular cytotoxicity.⁴¹ The ongoing TIGOS phase 3 trial is investigating the efficacy of Atigotatug, in combination with nivolumab and chemotherapy, in the first-line setting among patients with ES-SCLC.⁴⁴ The rationale for this phase 3 trial comes from results of the first-in-human study, which showed that Atigotatug plus nivolumab caused few grade 3 or higher adverse events in patients with relapsed/refractory SCLC and no prior exposure to immunotherapy.⁴⁵ The ORR in this phase 1 trial was 38% and the median duration of response was 26.4 months. Results in patients with ES-SCLC were not specifically reported. With TIGOS, Atigotatug joins Tarlatamab and I-DXd as targeted therapies in ongoing phase 3 trials in the first-line setting for patients with ES-SCLC.

Additional targeted agents for ES-SCLC are in earlier phases of development. Seizure-related homolog protein 6 (SEZ6) is expressed by healthy neurons, CNS malignancies and SCLC.⁴⁶ ABBV-011 is an ADC that targets SEZ6 and delivers a calicheamicin payload. Initial results of a first-in-human trial of ABBV-011 in patients with relapsed/refractory SCLC found that the most common adverse events were fatigue, nausea, transaminitis, and thrombocytopenia.⁴⁷ In the 1mg/kg cohort, the objective response rate was 25%. Final study results have not yet been reported. It is unclear if phase 2 trials are planned. A detailed overview of emerging therapeutic agents currently in clinical development is provided in *Table 2.*

In recent years, there has been a major effort to identify subgroups of SCLC that may preferentially respond to different therapies.^48,49 Gay et al. used matrix factorization on RNAseq data from 81 SCLC tumors and found four distinct SCLC subtypes based on RNA expression.⁴⁹ Subtypes SCLC-A, SCLC-N, and SCLC-P are characterized by increased expression of the transcription factors ASCl1, NEUROD1, and POU2F3, respectively. The last subtype is SCLC-I, which does not have a dominant transcriptional signature but is characterized by the increased expression of genes associated with a local inflammatory response, including genes associated with immune checkpoint regulation. Retrospective analysis of ES-SCLC samples from IMpower133 and CASPIAN suggested that patients with ES-SCLC and the SCLC-I subtype derived a greater magnitude of benefit from the addition of atezolizumab and durvalumab, respectively, compared to other subtypes.^49,50 In vitro analyses also demonstrated unique susceptibilities of the SCLC-P phenotype with cisplatin and PARP inhibitors, and the SCLC-N phenotype with multiple Aurora Kinase inhibitors. Lastly, in vitro SCLC cell lines had subtypes that evolved over time, and the emergence of the SCLC-I subtype may mediate cisplatin resistance.^49,51 This promising new area of research in SCLC may allow for a more personalized approach to treatment. Future research using larger sample sizes and potentially in prospective analyses is needed to better understand if the ES-SCLC subtype may help guide therapy.

A potential new treatment strategy in ES-SCLC is using radiation in conjunction with chemoimmunotherapy to treat patients with oligometastatic disease.^52,53 The phase 3 CREST trial randomized patients with ES-SCLC who had responded to initial chemotherapy to either receive consolidative radiation to sites of residual disease in the chest or no radiation.⁵⁴ The receipt of radiation was associated with longer progression-free survival (PFS), but it did not improve one-year OS. The CREST trial, however, was done prior to the incorporation of immunotherapy as standard-of-care in the first-line induction and maintenance setting. Radiation enhances tumor neoantigen exposure and antigen-presenting cell activation and therefore acts synergistically with immunotherapy in pre-clinical models of SCLC.⁵³ An observational analysis in the post-ICI era showed that consolidative radiation was well-tolerated and associated with a median PFS of 12.8 months and 1-year OS of 80.2% in a highly selected group of patients with ES-SCLC.⁵⁵ The phase 2/3 RAPTOR aims to investigate whether the addition of radiotherapy to standard-of-care induction chemoimmunotherapy, followed by immunotherapy maintenance, improves OS and PFS among patients with ES-SCLC.⁵⁶ The trial will also look at subgroups of patients who receive radiation to all sites of residual visible disease ("complete consolidation") and those who receive radiation only to some sites of visible disease ("incomplete consolidation"). RAPTOR is actively recruiting patients. If positive, results from RAPTOR may change how we manage oligometastatic ES-SCLC.

In summary, treatments for ES-SCLC have expanded greatly in the past few years. The addition of immunotherapy in the first-line setting has changed how we think about ES-SCLC. Several targeted agents are being studied in randomized controlled trials as potential additions to the first-line chemoimmunotherapy backbone. Tarlatamab and lurbinectedin are now well-established nonchemotherapy options for relapsed and refractory disease. There are at least five targeted therapies in trials as potential novel second-line treatment options, and it is likely that we will have additional FDA-approved agents for ES-SCLC in the coming years. Despite these gains, overall survival in ES-SCLC is still poor, and only a small minority of patients achieve durable treatment responses. Further research is needed to identify novel therapeutic targets in ES-SCLC.

No relevant conflicts of interest to this manuscript. But RT reports Consulting/advisory role: Catalyst Pharmaceuticals, Nuvation, Pfizer, Johnson & Johnson/Janssen, Regeneron, Bayer, Boehringer Ingelheim and Bristol Myers Squibb. Travel support: Black Diamond Therapeutics. SR has no conflicts of interest to declare.

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This article is a narrative literature review and does not involve human participants, identifiable data, or animal subjects. Ethics approval and informed consent were not required.

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Not Applicable. This review did not generate new datasets.

Grammarly was used solely to assist with organization, clarity, and language refinement.

Not Applicable. AI tools did not generate scientific content, interpret data, or influence the conclusions of the review.

Concept and design: SR, RT

Data acquisition: SR, RT

Data analysis and interpretation: SR, RT

Drafting of the manuscript: SR

Critical revision of the manuscript: RT

All authors (SR, RT) approved the final version of the manuscript and agree to be accountable for all aspects of the work, in accordance with the International Committee of Medical Journal Editors criteria.

1. Cohen S, Brennan B, Banerjee M, et al. Temporal trends in small cell lung cancer: analysis of the U.S. Surveillance, Epidemiology and End Results (SEER) database. J Clin Oncol. 2023;41(16 suppl):e20641. doi:10.1200/JCO.2023.41.16_suppl.e20641

2. Uprety D, Seaton R, Niroula A, et al. Trends in the incidence and survival outcomes in patients with small cell lung cancer in the United States: an analysis of the SEER database. Cancer Med. 2025;14(3):e70608. doi:10.1002/cam4.70608

3. Saida Y, Watanabe S, Kikuchi T. Extensive-stage small-cell lung cancer: current landscape and future prospects. Onco Targets Ther. 2023;16:657–671. doi:10.2147/OTT.S272552

4. PDQ Adult Treatment Editorial Board. Small cell lung cancer treatment (PDQ®): Health Professional Version. In: PDQ Cancer Information Summaries. National Cancer Institute; 2002.

5. Kim SY, Park HS, Chiang AC. Small cell lung cancer: a review. JAMA. 2025;333(18):1906. doi:10.1001/jama.2025.0560

6. Gong J, Salgia R. Managing patients with relapsed small-cell lung cancer. J Oncol Pract. 2018;14(6):359–366. doi:10.1200/JOP.18.00204

7. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–2229. doi:10.1056/NEJMoa1809064

8. 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 randomized, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929–1939. doi:10.1016/S0140-6736(19)32222-6

9. Cheng Y, Wang J, Yao W, et al. Final results and subgroup analysis of ORIENTAL: a phase IIIB study of durvalumab plus platinum–etoposide in first-line treatment of Chinese patients with extensive-stage small-cell lung cancer (ES-SCLC). Ann Oncol. 2023;34(suppl 5):S1673. doi:10.1016/j.annonc.2023.10.598

10. Asao T, Watanabe S, Tanaka T, et al. A phase II study of carboplatin and etoposide plus durvalumab for previously untreated extensive-stage small-cell lung cancer patients with a poor performance status: NEJ045A study protocol. BMC Cancer. 2022;22(1):1135. doi:10.1186/s12885-022-10222-1

11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Small Cell Lung Cancer. Version 4.2025. Published 2025. Accessed July 15, 2022. https://NCCN.org

12. Schiller JH, Kim K, Hutson P, et al. Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 1996;14(8):2345–2352. doi:10.1200/JCO.1996.14.8.2345

13. O'Brien MER, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol. 2006;24(34):5441–5447. doi:10.1200/JCO.2006.06.5821

14. Santamaría Nuñez G, Robles CMG, Giraudon C, et al. Lurbinectedin specifically triggers the degradation of phosphorylated RNA polymerase II and the formation of DNA breaks in cancer cells. Mol Cancer Ther. 2016;15(10):2399–2412. doi:10.1158/1535-7163.MCT-16-0172

15. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645–654. doi:10.1016/S1470-2045(20)30068-1

16. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with first-line treatment. Lung Cancer. 2020;150:90–96. doi:10.1016/j.lungcan.2020.10.003

17. Aix SP, Ciuleanu TE, Navarro A, et al. Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicenter, randomized, open-label, phase 3 trial. Lancet Respir Med. 2023;11(1):74–86. doi:10.1016/S2213-2600(22)00309-5

18. PharmaMar. A randomized, multicenter, open-label, phase III study of lurbinectedin single-agent or lurbinectedin in combination with irinotecan versus investigator's choice (topotecan or irinotecan) in relapsed small cell lung cancer patients (LAGOON trial). ClinicalTrials.gov. Published 2025.

19. Ponce Aix S, Navarro A, Olmedo Garcia ME, et al. Safety and efficacy of lurbinectedin plus atezolizumab as second-line treatment for advanced small-cell lung cancer: results of the 2SMALL phase 1/2 study (NCT04253145). J Clin Oncol. 2025;43(16 suppl):8013. doi:10.1200/JCO.2025.43.16_suppl.8013

20. Paz-Ares LG, Borghaei H, Liu SV, et al. Lurbinectedin plus atezolizumab as first-line maintenance treatment in patients with extensive-stage small cell lung cancer: primary results of the IMforte phase 3 trial. J Clin Oncol. 2025;43(16 suppl):8006. doi:10.1200/JCO.2025.43.16_suppl.8006

21. US Food and Drug Administration. FDA grants accelerated approval to tarlatamab-dlle for extensive-stage small cell lung cancer. Published 2024.

22. Rojo F, Corassa M, Mavroudis D, et al. International real-world study of DLL3 expression in patients with small cell lung cancer. Lung Cancer. 2020;147:237–243. doi:10.1016/j.lungcan.2020.07.026

23. Matsuo K, Taniguchi K, Hamamoto H, et al. Delta-like 3 localizes to neuroendocrine cells and plays a pivotal role in gastrointestinal neuroendocrine malignancy. Cancer Sci. 2019;110(10):3122–3131. doi:10.1111/cas.14157

24. Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3-targeted antibody–drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med. 2015;7(302):302ra136. doi:10.1126/scitranslmed.aac9459

25. Ahn MJ, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389(23):2063–2075. doi:10.1056/NEJMoa2307980

26. Dowlati A, Hummel HD, Champiat S, et al. Sustained clinical benefit and intracranial activity of tarlatamab in previously treated small cell lung cancer: DeLLphi-300 trial update. J Clin Oncol. 2024;42(15):3392–3399. doi:10.1200/JCO.24.00553

27. Rudin CM, Mountzios GS, Sun L, et al. Tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer: primary analysis of the phase 3 DeLLphi-304 trial. J Clin Oncol. 2025;43(17 suppl):LBA8008. doi:10.1200/JCO.2025.43.17_suppl.LBA8008

28. Lau S, Ahn MJ, Moskovitz M, et al. Tarlatamab with a PD-L1 inhibitor as first-line maintenance after chemoimmunotherapy for ES-SCLC: DeLLphi-303 phase 1b study. J Thorac Oncol. 2024;19(1 suppl):S31–S32. doi:10.1016/j.jtho.2024.09.058

29. Amgen. A phase 3, open-label, multicenter, randomized study of tarlatamab in combination with durvalumab vs durvalumab alone in subjects with extensive-stage small-cell lung cancer following platinum, etoposide and durvalumab (DeLLphi-305). ClinicalTrials.gov. Identifier NCT06211036. Published 2025.

30. Hipp S, Voynov V, Drobits-Handl B, et al. A bispecific DLL3/CD3 IgG-like T-cell engaging antibody induces antitumor responses in small cell lung cancer. Clin Cancer Res. 2020;26(21):5258–5268. doi:10.1158/1078-0432.CCR-20-0926

31. Boehringer Ingelheim. A first-in-human phase I, non-randomized, open-label, multicenter dose-escalation trial of BI 764532 administered by parenteral route in patients with small cell lung carcinoma and other neuroendocrine neoplasms expressing DLL3. ClinicalTrials.gov. Identifier NCT04429087. Published 2025.

32. Molloy ME, Aaron WH, Barath M, et al. HPN328, a trispecific T-cell activating protein construct targeting DLL3-expressing solid tumors. Mol Cancer Ther. 2024;23(7):1294–1304. doi:10.1158/1535-7163.MCT-23-0524

33. Harpoon Therapeutics, Inc., a subsidiary of Merck & Co., Inc. A phase 1/2 open-label, multicenter, dose escalation and dose expansion study of the safety, tolerability, and pharmacokinetics of HPN328 monotherapy and HPN328 with atezolizumab or ifinatamab deruxtecan (I-DXd) in patients with advanced cancers associated with DLL3 expression. ClinicalTrials.gov. Identifier NCT04471727. Published 2025.

34. Beltran H, Dowlati A, Jain P, et al. Interim results from a phase 1/2 study of HPN328, a tri-specific, half-life extended DLL3-targeting T-cell engager, in patients with neuroendocrine prostate cancer and other neuroendocrine neoplasms. J Clin Oncol. 2024;42(4 suppl):121. doi:10.1200/JCO.2024.42.4_suppl.121

35. Carvajal-Hausdorf D, Altan M, Velcheti V, et al. Expression and clinical significance of PD-L1, B7-H3, B7-H4 and tumor-infiltrating lymphocytes in human small cell lung cancer. J Immunother Cancer. 2019;7:65. doi:10.1186/s40425-019-0540-1

36. Getu AA, Tigabu A, Zhou M, et al. New frontiers in immune checkpoint B7-H3 (CD276) research and drug development. Mol Cancer. 2023;22:43. doi:10.1186/s12943-023-01751-9

37. Patel MR, Doi T, Koyama T, et al. Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with advanced solid tumors: updated clinical and biomarker results from a phase 1/2 study. Ann Oncol. 2023;34(suppl 5):S481–S482. doi:10.1016/j.annonc.2023.09.1876

38. Rudin CM, Ahn MJ, Johnson M, et al. Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer: interim analysis of IDeate-Lung01. J Thorac Oncol. 2024;19(suppl 1):S15–S16. doi:10.1016/j.jtho.2024.09.033

39. Owonikoko TK, Byers LA, Cheng Y, et al. IDeate-Lung02: a phase 3, randomized, open-label study of ifinatamab deruxtecan (I-DXd) vs treatment of physician's choice in relapsed small cell lung cancer. J Clin Oncol. 2024;42(16 suppl):TPS8126. doi:10.1200/JCO.2024.42.16_suppl.TPS8126

40. Daiichi Sankyo. A phase 1b/2, multicenter, open-label study of ifinatamab deruxtecan (I-DXd), a B7-H3 antibody–drug conjugate, in combination with atezolizumab with or without carboplatin as first-line induction or maintenance in subjects with extensive-stage small cell lung cancer (IDeate-Lung03). ClinicalTrials.gov. Identifier NCT06362252. Published 2025.

41. Ponath P, Menezes D, Pan C, et al. A novel, fully human anti–fucosyl-GM1 antibody demonstrates potent in vitro and in vivo antitumor activity in preclinical models of small cell lung cancer. Clin Cancer Res. 2018;24(20):5178–5189. doi:10.1158/1078-0432.CCR-18-0018

42. Brezicka FT, Olling S, Bergman B, et al. Immunohistochemical detection of two small cell lung carcinoma-associated antigens defined by monoclonal antibodies F12 and 123C3 in bronchoscopy biopsy tissues. APMIS. 1991;99(8):797–802. doi:10.1111/j.1699-0463.1991.tb01262.x

43. Brezicka FT, Olling S, Nilsson O, et al. Immunohistological detection of fucosyl-GM1 ganglioside in human lung cancer and normal tissues with monoclonal antibodies. Cancer Res. 1989;49(5):1300–1305.

44. Paz-Ares LG, O'Byrne KJ, Johnson ML, et al. The TIGOS trial: a randomized, double-blind phase 3 trial of atigotatug plus nivolumab fixed-dose combination with chemotherapy vs atezolizumab with chemotherapy in patients with first-line extensive-stage small cell lung cancer. J Clin Oncol. 2025;43(16 suppl):TPS8127. doi:10.1200/JCO.2025.43.16_suppl.TPS8127

45. Chu Q, Leighl NB, Surmont V, et al. BMS-986012, an anti–fucosyl-GM1 monoclonal antibody as monotherapy or in combination with nivolumab in relapsed/refractory small cell lung cancer: results from a first-in-human phase 1/2 study. JTO Clin Res Rep. 2022;3:100400. doi:10.1016/j.jtocrr.2022.100400

46. Wiedemeyer WR, Gavrilyuk J, Schammel A, et al. ABBV-011, a novel, calicheamicin-based antibody–drug conjugate, targets SEZ6 to eradicate small cell lung cancer tumors. Mol Cancer Ther. 2022;21(6):986–998. doi:10.1158/1535-7163.MCT-21-0851

47. Morgensztern D, Ready N, Johnson ML, et al. A phase I first-in-human study of ABBV-011, a seizure-related homolog protein 6–targeting antibody–drug conjugate, in patients with small cell lung cancer. Clin Cancer Res. 2024;30(18):5042–5052. doi:10.1158/1078-0432.CCR-24-1547

48. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47–53. doi:10.1038/nature14664

49. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of small cell lung cancer with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346–360.e7. doi:10.1016/j.ccell.2020.12.014

50. Xie M, Vuko M, Rodriguez-Canales J, et al. Molecular classification and biomarkers of outcome with immunotherapy in extensive-stage small-cell lung cancer: analyses of the CASPIAN phase 3 study. Mol Cancer. 2024;23:115. doi:10.1186/s12943-024-02014-x

51. Ireland AS, Micinski AM, Kastner DW, et al. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer Cell. 2020;38(1):60–78.e12. doi:10.1016/j.ccell.2020.05.001

52. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259–1271. doi:10.1084/jem.20052494

53. Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Trends Cancer. 2016;2(6):286–294. doi:10.1016/j.trecan.2016.05.002

54. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive-stage small-cell lung cancer: a phase 3 randomized controlled trial. Lancet. 2015;385(9962):36–42. doi:10.1016/S0140-6736(14)61085-0

55. Li L, Yang D, Min Y, et al. First-line atezolizumab/durvalumab plus platinum-etoposide combined with radiotherapy in extensive-stage small-cell lung cancer. BMC Cancer. 2023;23:318. doi:10.1186/s12885-023-10784-8

56. National Cancer Institute. Randomized phase II/III trial of consolidation radiation plus immunotherapy for ES-SCLC (RAPTOR trial). ClinicalTrials.gov. Identifier NCT04402788. Published 2025.

57. International Association for the Study of Lung Cancer. Antibody–drug conjugate I-DXd shows clinically meaningful response in patients with extensive-stage small cell lung cancer. IASLC News. Published 2025. Accessed October 24, 2025. https://www.iaslc.org/iaslc-news/press-release/antibody-drug-conjugate-i-dxd-shows-clinically-meaningful-response