Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive malignancy for which effective second-line therapies remain an urgent unmet need. The bispecific antibody tarlatamab (Imdelltra®; Amgen) is a first-in-class delta-like ligand 3 (DLL3)-directed T-cell engager immunotherapy. In March 2026, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending the approval of tarlatamab as monotherapy for adults with ES-SCLC who have relapsed following platinum-based chemotherapy.
Small cell lung cancer (SCLC) accounts for 13–15% of all lung cancer diagnoses and is characterized by rapid growth, early dissemination, and a dismal prognosis. While platinum-based chemotherapy remains the standard first-line treatment, relapse is common and outcomes in the relapsed setting are poor, with limited efficacy for available second-line cytotoxic agents. There is a critical need for new, effective, and well-tolerated therapies in this population [2–4].
Mechanism of Action: Tarlatamab
Tarlatamab is a bispecific antibody that functions as a T-cell engager. It simultaneously binds to DLL3, a protein aberrantly expressed on the surface of SCLC tumor cells, and CD3 on T cells [1].
By bringing T-cells into close proximity to DLL3-expressing cancer cells, tarlatamab facilitates T-cell activation, leading to targeted tumor cell lysis via the release of cytotoxic proteins and inflammatory cytokines. DLL3’s selective expression on malignant cells, with minimal presence in normal tissues, makes it an attractive target for immunotherapy.
Regular pathway
On March 27, 2026, the CHMP recommended granting marketing authorization for tarlatamab as monotherapy for adult patients with ES-SCLC whose disease has relapsed during or after first-line platinum-based chemotherapy. The European Commission (EC) will now review this recommendation. If approved, tarlatamab will provide a new targeted immunotherapy option in the European Union (EU) for this hard-to-treat population.
The CHMP opinion is based on the results of the global, randomized, open-label Phase 3 DeLLphi-304 trial (NCT05740566), which compared tarlatamab to the investigator’s choice of standard-of-care chemotherapy (topotecan, lurbinectedin, or amrubicin) in 509 adults with ES-SCLC relapsed after platinum-based chemotherapy [1].
Study Results
- Overall Survival (OS): Tarlatamab significantly improved median OS to 13.6 months (95% CI, 11.1 to not reached) versus 8.3 months (95% CI, 7.0 to 10.2) in the chemotherapy arm (hazard ratio [HR] for death, 0.60; 95% CI, 0.47 to 0.77; P<0.001), reflecting a 40% reduction in the risk of death.
Progression-Free Survival (PFS): Median PFS was 4.2 months with tarlatamab compared with 3.2 months for chemotherapy. - Patient-Reported Outcomes: Tarlatamab recipients reported significant improvements in cancer-related dyspnea and cough compared with chemotherapy.
- Adverse Events: Grade 3 or higher adverse events occurred in 54% of patients on tarlatamab versus 80% in the chemotherapy group. Treatment discontinuation due to adverse events was also lower with tarlatamab (5% vs. 12%).
Safety and Tolerability
The safety profile of tarlatamab in DeLLphi-304 was consistent with previous studies. The most frequently observed grade 3 or greater treatment-related adverse events (TRAEs) with tarlatamab were neutropenia (4%) and lymphopenia (4%), compared with anemia (28%) and neutropenia (22%) observed with standard chemotherapy.
- Cytokine Release Syndrome (CRS): CRS was the most common and serious immune-related adverse event, manifesting as fever, hypotension, and respiratory distress. CRS can be life-threatening and requires prompt recognition and management.
- Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Another serious potential adverse event is ICANS, characterized by neurological symptoms such as confusion, speech difficulty, and gait disturbances.
- Other Common Adverse Events: Decreased appetite, fever, dysgeusia, constipation, anemia, fatigue, nausea, asthenia, hyponatremia, headache, and lymphopenia.
To mitigate risks, all patients will receive education on CRS and ICANS via a patient card, and healthcare providers will receive management guidelines as part of the product information.
Clinical Significance
SCLC is a rare and aggressive cancer with a high relapse rate following standard therapy and poor long-term survival [2–4]. The approval of tarlatamab would address a critical gap by providing a novel, effective, and relatively well-tolerated option for patients with relapsed ES-SCLC.
If approved by the EC, tarlatamab would mark a significant advance for European patients and clinicians, reflecting ongoing progress in immuno-oncology and the development of targeted therapies tailored to tumor-specific molecular features.
Access and Next Steps
The CHMP’s positive opinion is a crucial intermediate step toward patient access. Following EC approval, pricing and reimbursement decisions will be determined at the national level within each EU member state, taking into account the role of tarlatamab in the context of local healthcare systems.
Tarlatamab represents a new era in the management of relapsed ES-SCLC, offering meaningful improvements in survival and quality of life compared with existing chemotherapy options. The robust efficacy and manageable safety profile demonstrated in the DeLLphi-304 trial support its adoption as a new standard of care pending EC approval.
As a first-in-class DLL3-directed T-cell engager, tarlatamab exemplifies the promise of precision immunotherapy for aggressive solid tumors.
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Clinical trials
Study Comparing Tarlatamab With Standard of Care Chemotherapy in Relapsed Small Cell Lung Cancer (DeLLphi-304) – ClinicalTrials.gov ID NCT05740566
Highlights of prescribing information
Tarlatamab (Imdelltra®; Amgen)[Prescribing Information]
References
[1] Mountzios G, Sun L, Cho BC, et al. Tarlatamab in small-cell lung cancer after platinum-based chemotherapy. N Engl J Med. 2025;393(4):349-361.
[2] Oronsky B, Abrouk N, Caroen S, et al. A 2022 update on extensive stage small-cell lung cancer (SCLC). J Cancer. 2022;13(9):2945-2953.
[3] International Agency for Research on Cancer. GLOBOCAN 2022: Trachea, bronchus and lung fact sheet. Online. Last accessed in March 2026.
[4] Sabari JK, Lok BH, Laird JH, et al. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14(9):549-561.
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