Click to Enlarge: Panel A shows the time to response, the duration of response, and patient status as of the data cutoff date for all the patients who were assessed as having an objective response (complete or partial response; primary end point) to 10 mg or 100 mg of tarlatamab, as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Panel B shows the Kaplan–Meier curve of progression-free survival in the analysis population for antitumor activity, which included 100 patients who had been assigned to receive 10 mg of tarlatamab in part 1 or part 2 of the trial and 88 patients who had been assigned to receive 100 mg of tarlatamab in part 1 of the trial. Panel C shows the Kaplan–Meier curve of overall survival in the analysis population for antitumor activity. The tick marks in Panels B and C indicate censored data. NE denotes not evaluable. Source: The New England Journal of Medicine
NEW YORK — Small cell lung cancer (SCLC) is a particularly lethal form of lung cancer that progresses quickly and metastasizes early. SCLC represents about 14% of all lung cancers, but its aggressive biology and rapid development of resistance mechanisms that render treatments futile make it particularly challenging to treat—making new therapeutic approaches such as bispecific antibodies and bispecific T-cell engagers especially keenly sought.
Nowhere is that unmet need more evident than at the VA, which diagnoses 1,000 or more veterans with the malignancy each year.
Three main factors contribute to the relatively high rate of SCLC among veterans receiving VA care. In addition to higher rates of smoking among active and former servicemembers, which increases the risk of lung cancer, SCLC is recognized by the VA as a presumptive cancer for certain Vietnam, Gulf War, and post-9/11 veterans. This designation means veterans diagnosed with SCLC are assumed to have developed the disease as a result of service-related exposures, qualifying them for VA health benefits and disability compensation.
Researchers recently determined that Agent Orange exposure quadrupled the risk of SCLC in veterans after adjusting for smoking history, while burn pit exposure among younger cohorts increased the odds of developing bronchiolitis sixfold, with all veterans with bronchiolitis also having SCLC.1 Veterans exposed to ionizing radiation during military service—often referred to as “atomic veterans”—who develop SCLC are also presumed to have a service-related condition, whether the exposure occurred during the occupation of or as a prisoner of war in Japan, through nuclear weapons testing, while serving at Long-Range Navigation stations or at McMurdo Station in Antarctica’s nuclear power plant, or during cleanup operations at Enewetak Atoll, Palomares, Spain, or Thule Air Force Base in Greenland.
Age further compounds risk. The average age at SCLC diagnosis in the U.S. is nearly 70. With roughly half of veterans in VA care age 65 and older and 1 in 3 at least 75 years old, veterans represent a population concentrated in the highest-risk age group for this malignancy.
A Disease Long Resistant to Innovation
For decades, treatment for SCLC relied almost exclusively on platinum-based chemotherapy. Platinum therapy combined with etoposide and concurrent chemoradiotherapy—the standard of care for 50 years—achieved objective response rates exceeding 90% and five-year survival of up to 30% in patients with limited-stage disease, defined using the VA Lung Study Group system as confined to one hemithorax within a tolerable radiation field.2
Despite incremental advances, outcomes remain poor. Approximately 85% of patients with limited-stage SCLC relapse within five years. Although potentially curable, limited-stage disease accounts for less than 30% of SCLC cases nationally and only about 15% within the VA.
Extensive-stage SCLC remains incurable, with treatment focused on slowing progression and alleviating symptoms. Immune checkpoint inhibitors added to chemotherapy have extended overall survival only modestly, with little impact on the five-year survival rate, which remains below 5%.3 Other combination strategies have similarly failed to produce meaningful survival gains.
For patients with relapsed or recurrent disease, options historically consisted of minimally effective chemotherapies with substantial hematologic toxicity. A VA-based multicenter analysis of veterans treated between 2010 and 2017 found median overall survival remained stalled at 8 to 9 months, even as survival for non-small cell lung cancer improved markedly during the same period.4
Bispecific Antibodies and BiTEs Enter the SCLC Landscape
Bispecific antibodies, used for more than a decade in hematologic malignancies, have now begun to alter this trajectory. The FDA’s accelerated approval in May 2024 of the bispecific T-cell engager tarlatamab for previously treated SCLC marked only the second approval of a bispecific antibody in a solid tumor. Full approval followed in November 2025 based on confirmatory trials.
As a bispecific T cell engager (BiTE), tarlatamab binds DLL3 on tumor cells and CD3 on T cells, bringing cytotoxic immune cells into range of SCLC cells and enabling targeted immune-mediated killing. This mechanism addresses a core limitation of prior therapies by directly redirecting T-cell activity against a tumor long considered immunologically evasive.
In the pivotal DeLLphi-301 trial, patients receiving 10 mg tarlatamab achieved a 40% objective response rate. At a mean follow-up of 10.6 months, 57.5% of responders maintained responses for six months or longer, and 30% sustained disease control for at least nine months. Median overall survival reached 15.2 months.5
Extended follow-up from the DeLLphi-300 study further supported durability of benefit. Among patients receiving the same dose, objective response was 35.3%, median duration of response reached 14.9 months, and median overall survival extended to 20.3 months. Nearly 30% of patients remained on treatment for at least one year. Importantly, among patients with central nervous system lesions of 10 mm or greater at baseline, 62.5% experienced tumor shrinkage of 30% or more, including patients with progression after prior brain radiotherapy—a clinically significant finding given that 40% to 70% of patients with SCLC develop brain metastases.6 7
The phase III DeLLphi-304 trial provided head-to-head evidence comparing tarlatamab with standard chemotherapy in patients with extensive-stage SCLC progressing after platinum therapy. In this 509-patient study, tarlatamab reduced the risk of death by 40%, with a median overall survival of 13.6 months compared with 8.3 months for chemotherapy (HR, 0.60; 95% CI, 0.47-0.77; P < .001), in results presented at the European Society of Medical Oncology Congress in Berlin in October and published in the New England Journal of Medicine in July.8 9
Managing Toxicity in Practice
As with other bispecific therapies, cytokine release syndrome was observed, primarily during the first two treatment cycles. Among patients monitored for at least six hours, 37% experienced CRS, most commonly Grade 1 or 2. Grade 3 events occurred in 7%, with no treatment discontinuations required. Treatment-emergent adverse events (TRAEs) led to discontinuation or dose reduction in 19% of patients treated with tarlatamab and 55% given chemotherapy. TRAEs caused one patient (0.4%) death in the tarlatamab group and four patient deaths (2%) in the chemotherapy group.
The investigators emphasized that these data also validate toxicity management strategies for BiTE therapies, underscoring the importance of specialized monitoring and multidisciplinary care during early treatment cycles. “The data from DeLLphi-304 mark a major milestone for people with relapsed small cell lung cancer. Tarlatamab is associated with significant improvements in both overall and progression-free survival over standard chemotherapy in patients with recurrent or progressive disease,” said Charles Rudin, MD, PhD, deputy director, Sloan Kettering Memorial Cancer Center, and DeLLphi-304 investigator.
“This study also provides confirmatory data on the management of potential toxicities associated with bispecific T-cell engager therapies in a large patient cohort, which is crucial to continuing to improve the experience of patients treated with these medicines,” Rubin added.
Implications Beyond SCLC
Experience gained from the DeLLphi program is informing BiTE and bispecific antibody development across other solid tumors. A separate BiTE targeting uveal melanoma demonstrated improved overall survival compared with standard therapy, highlighting the broader applicability of targeted T-cell engagement.¹⁰ Ongoing studies are evaluating bispecific antibodies across breast, pancreatic, melanoma, and pediatric cancers.
For a disease marked by decades of therapeutic stagnation, SCLC has become a compelling case study in how bispecific antibodies and BiTEs can translate immunologic precision into clinically meaningful survival gains. As lessons from SCLC inform development across other refractory solid tumors, these agents may reshape expectations for cancers long considered resistant to innovation—particularly for veterans, where disease burden remains disproportionately high.
- Salacup C, Roberson R, Kenyon J, Segal J, Fagan K. Occupational, operational, and environmental exposures in veterans: the implications for small cell lung cancer. Poster presented at University of Maryland School of Medicine; 2024.
- Khurshid H, Ismaila N, Bian J, Dabney R, Das M, Ellis P, et al. Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline. J Clin Oncol. 2023 Dec 10;41(35):5448-5472. doi: 10.1200/JCO.23.01435. Epub 2023 Oct 11. PMID: 37820295.
- Desai RK, Zhou EJ, Chan KKW. Systematic review and network meta-analysis: evaluation of systemic therapies for platinum refractory or resistant small cell lung cancer. Lung Cancer. 2025 Dec;210:108812. doi: 10.1016/j.lungcan.2025.108812. Epub 2025 Nov 3. PMID: 41197381.
- Moghanaki D, Taylor J, Bryant AK, Vitzthum LK, Sebastian N, et al. Lung Cancer Survival Trends in the Veterans Health Administration. Clin Lung Cancer. 2024 May;25(3):225-232. doi: 10.1016/j.cllc.2024.02.009. Epub 2024 Mar 2.
- Ahn M-J, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med 2023;389:2063-2075
- Sands J, Cho BC, Ahn MJ, et al. Tarlatamab sustained clinical benefit and safety in previously treated SCLC: DeLLphi-301 phase 2 extended follow-up. J Thorac Oncol 2024;19:Suppl:S30-S31. abstract.
- Dowlati A, Hummel HD, Champiat S, Olmedo ME, Boyer M, He K, 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 Oct 10;42(29):3392-3399. doi: 10.1200/JCO.24.00553. Epub 2024 Aug 29. PMID: 39208379; PMCID: PMC11458107.
- Mountzios G, Sun L, Cho BC, Demirci U, Baka S, Gümüş M, et al; DeLLphi-304 Investigators. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. N Engl J Med. 2025 Jul 24;393(4):349-361. doi: 10.1056/NEJMoa2502099. Epub 2025 Jun 2. PMID: 40454646.
- Rocha P, Sun L, Cho BC, et al. Tarlatamab as second-line (2L) treatment for small cell lung cancer (SCLC): Outcomes by chemotherapy-free interval (CFI) and prior PD-(L)1 inhibitor use in the phase 3 DeLLphi-304 trial. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. LBA101.