Tarlatamab Significantly Improves Survival in Patients With Small Cell Lung Cancer Post-Progression

Tarlatamab (Imdelltra; Amgen, Inc), a bispecific T-cell engager (BiTE) immunotherapy, meaningfully improved overall survival (OS), progression-free survival (PFS), and patient-reported outcomes (PROs) compared with chemotherapy (CTx) in patients with small cell lung cancer (SCLC) that progressed on or after initial platinum-based CTx. These observations are according to results from the phase 3 DeLLphi-304 clinical trial (NCT05740566), published by investigators in Journal of Clinical Oncology and presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.^1,2

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In previous phase 1 and 2 trials, tarlatamab demonstrated promising safety and efficacy in the SCLC population. In 2024, the FDA granted accelerated approval to the treatment for patients with extensive-stage SCLC based on results of the phase 2 DeLLphi-301 study, which found a 40% overall response rate and a median duration of response (DOR) of 9.7 months in this population. Additionally, PROs from the DeLLphi-301 trial [NCT05060016]—for which 100 patients were eligible for analysis—found that patients with tarlatamab experienced reduced symptom burden and exceeded the median time to deterioration of 6 months for cough and dyspnea.^3-6

Tarlatamab Remains Effective in Patients Who Progressed or Were Treated With Chemotherapy

Until now, tarlatamab had not been investigated in a phase 3 setting and compared directly with CTx, which is a standard of care option for these patients. Therefore, the current investigators sought to report results from a primary analysis of the randomized controlled phase 3 DeLLphi-304 study, which evaluated tarlatamab versus CTx in patients with SCLC, following disease progression either on or after platinum-based CTx. Patients were randomized 1:1 to either tarlatamab or topotecan, lurbinectedin, or amrubicin. They were further stratified by prior treatment, including with a programmed death ligand 1 (PD[L]-1) inhibitor, chemotherapy-free interval, brain metastases, and intended CTx.¹

A series of end points were evaluated in the study, including the previously mentioned OS, PFS, and PROs, along with objective response rate, duration of response, and safety. In total, 509 patients were randomized (tarlatamab, n = 254; CTx, n = 255), and the median follow-up was 11.2 months for tarlatamab and 11.7 months for CTx, according to the investigators.¹

At the respective cohort follow-up points, patients in the tarlatamab arm had significantly higher OS (median: 13.6 vs 8.3 months; hazard ratio [HR]: 0.60 [95% CI, 0.47—0.77]; P < .001) and PFS (median: 4.2 vs 3.2 months; HR: 0.72 [95% CI, 0.59—0.88]; P < .001) compared with patients in the CTx arm. Importantly, tarlatamab was found to improve cancer-related symptoms of cough and dyspnea compared with CTx patients. Furthermore, there were lower rates of grade 3 or more treatment-related adverse events (TRAEs) that occurred with tarlatamab treatment (27%) compared with CTx, and treatment discontinuations because of TRAEs were lower in tarlatamab-treated patients (3% vs 6%).¹

Mechanism of Action and Management of Tarlatamab

Tarlatamab is designed to recognize and facilitate T-cell-driven destruction of delta-like ligand 3 (DLL3)-positive tumor cells, which are highly expressed in many SCLC cases. DLL3 inhibits Notch signaling, which becomes abnormally expressed on the surface of SCLC cells and is expressed in 85% to 94% of patients with SCLC. Tarlatamab is one of a series of novel treatment options targeting DLL3, including antibody-drug conjugates, trispecific antibodies, and chimeric antigen receptor T-cell therapy.^1,7

Pharmacists and health care professionals in oncology settings will be critical in the proper administration and management of patients with SCLC treated with tarlatamab. Monitoring possible AEs, including fatigue, decreased appetite, constipation, and anemia, will be of utmost importance, while following a step-up dosing schedule of 1 mg on day 1 and 10 mg on day 8 will be essential for preventing cytokine release syndrome or other AEs. In addition, pharmacists can observe patients and gauge their need for early supportive care or complementary treatment with corticosteroids.⁷

REFERENCES

1. 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(17). doi:10.1200/JCO.2025.43.17_suppl.LBA8008. Presented at: 2025 American Society of Clinical Oncology Annual Meeting; May 30 to June 3, 2025; Chicago, Illinois.

2. Study Comparing Tarlatamab With Standard of Care Chemotherapy in Relapsed Small Cell Lung Cancer (DeLLphi-304). National Library of Medicine. ClinicalTrials.gov identifier: NCT05740566. Last Updated May 18, 2025. Accessed June 5, 2025. https://www.clinicaltrials.gov/study/NCT05740566

3. FDA. FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer. News Release. Released May 16, 2024. Accessed June 5, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tarlatamab-dlle-extensive-stage-small-cell-lung-cancer

4. Ahn M, Cho BC, Felip E, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389(22):2063-2075. doi:10.1056/NEJMoa2307980

5. A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301). National Library of Medicine. ClinicalTrials.gov identifier: NCT05060016. Last Updated May 2, 2025. Accessed June 5, 2025. https://clinicaltrials.gov/study/NCT05060016

6. Gerlach A. Patient-reported outcomes reinforce clinical benefits of tarlatamab in small cell lung cancer. Pharmacy Times. Published March 14, 2025. Accessed June 5, 2025. https://www.pharmacytimes.com/view/patient-reported-outcomes-reinforce-clinical-benefits-of-tarlatamab-in-small-cell-lung-cancer

7. Lasko AR, Meador CB. Targeting DLL3 in small cell lung cancer and other neuroendocrine carcinomas. Pharmacy Practice in Focus: Oncology. 2025;7(2). Published online February 16, 2025. Accessed June 5, 2025. https://www.pharmacytimes.com/view/targeting-dll3-in-small-cell-lung-cancer-and-other-neuroendocrine-carcinomas