FDA Grants Traditional Approval to Tarlatamab-dlle for ES-SCLC After Phase 3 Survival Benefit

The FDA approved Tarlatamab-dlle (Imdelltra) as a second-line therapy for patients with extensive-stage small-cell lung cancer (ES-SCLC) whose disease has progressed after platinum-based chemotherapy. In the confirmatory Phase 3 DeLLphi-304 trial, tarlatamab extended median overall survival (OS) and improved progression-free survival, establishing it as a new standard of care (SOC) option in this setting.

Tarlatamab-dlle Profile & Mechanism

• Profile: first-in-class bispecific T-cell engager (BiTE) that binds DLL3 on tumor cells and CD3 on T lymphocytes to increase proximity
• Mechanism: Recruits and activates T cells at DLL3-expressing tumor sites, triggering cell death via cytolytic synapse formation.
  • Tumor Specific Immunotherapy: DLL3 = highly expressed on tumor cell surface, but minimally expressed on healthy cells
• Target Population: Adult ES-SCLC patients with disease progression following platinum-based chemotherapy
• Delivery System: intravenous (IV)
• Treatment Schedule: Step-up dosing (1 cycle = 28 days)
  • Cycle 1
    • 1 mg of tarlatamab IV on day 1
    • 10 mg IV on day 8
    • 10 mg IV on day 15
  • Cycle 2, 3, 4, 5, and beyond
    • 10 mg IV on days 1 and 15 until disease progression or unacceptable toxicity

DeLLphi-304 Study Design (NCT05740566)

• Study Objective: Compare the efficacy of tarlatamab with the SOC (chemotherapy) on prolonging OS
• Participants: 509 adult ES-SCLC patients
  • 254 – tarlatamab
  • 255 – chemotherapy [topotecan, lurbinectedin, or amrubicin]
• Method: Randomized, multinational, open-label, controlled study

Study Outcomes

• Median OS: 13.6 months (95% CI, 11.1-not evaluable) versus 8.3 months (95% CI, 7.0-10.2) with SOC chemotherapy
• Risk of Death: Reduced by 40% (HR, 0.60; 95% CI, 0.47-0.77; p < 0.001)
• Risk of Disease Progression/Death: 28% reduction versus SOC
• Median Progression-Free Survival: 4.2 months versus 3.2 months for SOC

Regulatory Milestones

• Approval Date: November 19, 2025
• Regulatory Pathway: Traditional (full) approval
• Approval Review: Project Orbis (facilitates concurrent oncology-drug reviews across multiple international regulatory agencies)

Safety

• Overall Adverse Effects (AE) Burden:
  • Any-grade treatment-emergent AE (TEAEs): 99% tarlatamab versus 100% chemotherapy
  • Any-grade treatment-related AEs (TRAEs): 93% versus 91%
• Severity of Toxicity:
  • Grade 3 TRAEs: 27% tarlatamab versus 62% chemotherapy
  • Serious TRAEs: 28% versus 31%
  • Grade 5 TRAEs: 0.4% versus 2%
• Treatment Modifications:
  • Dose interruption/reduction: 19% tarlatamab versus 55% chemotherapy
  • Treatment discontinuation due to TRAEs: 3% versus 6%
• Cytokine Response Syndrome (CRS) with Tarlatamab:
  • With 48-hour monitoring (n = 209): CRS in 60%; Serious CRS 19%
  • With 6-8 hour monitoring (n = 43): CRS in 37%; Serious CRS 7%
• Patterns of AEs:
  • Tarlatamab: more CRS, dysgeusia, fever, and decreased appetite
  • Chemotherapy: higher rates of anemia, neutropenia, thrombocytopenia, leukopenia, febrile neutropenia, and other cytopenias
  • Grade ≥3 hematologic toxicities were more frequent with chemotherapy than with tarlatamab

Development Status

• Current Status: Fully approved as the only Category 1 preferred treatment for adult patients with ES-SCLC after platinum-based chemotherapy.
• Prescribing information: Available at Drugs@FDA
• Side Effect Reporting: Healthcare professionals are encouraged to report negative side effects to the FDA

Sources:

Bolte, Fabian J., et al. “Real-World Outcomes of Tarlatamab in Small Cell Lung Cancer, Including Patients with Untreated Brain Metastases.” Clinical Lung Cancer, 26 Mar. 2025, www.sciencedirect.com/science/article/pii/S152573042500052X, https://doi.org/10.1016/j.cllc.2025.03.006. Accessed 1 Dec. 2025.

Giannis Mountzios, et al. “Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy.” New England Journal of Medicine, 2 June 2025, https://doi.org/10.1056/nejmoa2502099.

Rosa, Kristi. “FDA Grants Full Approval to Tarlatamab for Extensive-Stage Small Cell Lung Cancer.” OncLive, MJH Life Sciences, 19 Nov. 2025, www.onclive.com/view/fda-grants-full-approval-to-tarlatamab-for-extensive-stage-small-cell-lung-cancer. Accessed 1 Dec. 2025.

“Study Comparing Tarlatamab with Standard of Care Chemotherapy in Relapsed Small Cell Lung Cancer (DeLLphi-304).” Clinicaltrials.gov, 3 Oct. 2025, www.clinicaltrials.gov/study/NCT05740566#study-plan. Accessed 1 Dec. 2025.