Tarlatamab (Imdelltra, Amgen) demonstrated superior overall survival in small cell lung cancer

In the global, Phase 3 DeLLphi-304 clinical trial¹ evaluating Imdelltra^® (tarlatamab-dlle) treatment for patients with small cell lung cancer (SCLC) who progressed on or after a single line of platinum-based chemotherapy, the drug demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared to local standard-of-care (SOC) chemotherapy.

Small-cell lung cancer (SCLC) is characterized by aggressive behaviour and a dismal prognosis, with a 5-year survival rate below 5% for patients with extensive-stage disease. Despite initial responses to frontline platinum-based chemotherapy, etoposide, and PD-L1 inhibitors, the median overall survival remains limited, approximately 12 months. The prognosis is particularly poor for patients with platinum-resistant disease or those who develop brain metastases. Historically, second-line treatment options have been limited, with topotecan being the standard in many countries, and lurbinectedin and amrubicin approved in selected regions. These chemotherapy options have shown limited survival benefit (median OS 7.5 to 9.3 months) and are associated with significant hematologic toxic effects. The need for more effective therapies with better tolerability profiles in the second-line setting has been underscored by these poor outcomes and challenging side effects.

Tarlatamab is a novel bispecific T-cell engager immunotherapy that targets delta-like ligand 3 (DLL3), highly expressed on SCLC cells in the majority of patients (85% to 96%), and CD3 on T cells. This dual targeting aims to induce direct tumour-cell lysis. Based on promising earlier data, tarlatamab received accelerated approval from the FDA in May 2024 for extensive-stage SCLC that has progressed during or after platinum-based chemotherapy.

The multinational, phase 3, open-label DeLLphi-304 trial compared tarlatamab with standard chemotherapy as second-line treatment for patients with SCLC whose disease had progressed during or after initial platinum-based chemotherapy. Patients were randomized 1:1 to receive either tarlatamab or investigator’s choice of chemotherapy (topotecan, lurbinectedin, or amrubicin, depending on regional availability). Eligible patients were aged 18 or older with progressive SCLC after first-line platinum and had an ECOG performance status of 0 or 17. Patients with stable, asymptomatic brain metastases were included. DLL3 expression was not a prerequisite for trial participation. The trial enrolled 509 patients (254 to tarlatamab, 255 to chemotherapy) with baseline characteristics typical of this population, including a median age of 65 years, ~45% with brain metastases, ~44% with platinum-resistant disease, and ~71% having received prior PD-L1 or PD-1 inhibitors.

Tarlatamab was administered intravenously with a step-up dose followed by the target dose every two weeks in 28-day cycles. Initial post-infusion monitoring was 48 hours, later reduced to 6-8 hours in the outpatient setting. Chemotherapy was given in 21-day cycles.

The primary endpoint was OS; secondary endpoints included investigator-assessed progression-free survival (PFS) and patient-reported outcomes (PROs) for symptoms like dyspnoea and cough.

Results from the prespecified interim analysis demonstrated significantly longer overall survival with tarlatamab compared to chemotherapy. The median OS was 13.6 months (95% CI, 11.1 to not reached) for tarlatamab versus 8.3 months (95% CI, 7.0 to 10.2) for chemotherapy. This translated to a stratified hazard ratio for death of 0.60 (95% CI, 0.47 to 0.77; P<0.001), representing a 40% reduction in the risk of death. The 12-month OS rates were 53% for tarlatamab and 37% for chemotherapy.

The estimated restricted mean PFS at 12 months was 5.3 months for tarlatamab versus 4.3 months for chemotherapy (P = 0.002).

Objective response rates were higher in the tarlatamab group. The confirmed objective response rate was 35% with tarlatamab versus 20% with chemotherapy. The median duration of response was 6.9 months versus 5.5 months, respectively. Notably, 47% of tarlatamab responders remained on trial without progression or death at data cutoff, compared to 15% of chemotherapy responders.

Patient-reported outcomes

Treatment with tarlatamab resulted in significantly greater decreases in symptom scores than chemotherapy for dyspnoea and cough. Numerical improvements in physical functioning and global health status were also observed.

Safety

While treatment-related AEs were common overall, severe (Grade ≥3) treatment-related AEs were significantly lower with tarlatamab (27%) than with chemotherapy (62%). Common severe AEs with chemotherapy included significant haematologic toxicities (anaemia, neutropenia, leukopenia, febrile neutropenia, thrombocytopenia), which were less frequent or lower grade with tarlatamab.

Tarlatamab-specific AEs included cytokine release syndrome (CRS), reported in 56% of patients, primarily Grade 1 or 2 (1% Grade 3, no Grade 4/5). CRS events predominantly occurred after the first two doses and were generally manageable. Neurologic AEs occurred in 56% of tarlatamab patients. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 6%, mostly Grade 1 or 2, with one Grade 5 event.

Conclusion

The DeLLphi-304 trial shows that the bi-specific T-cell engager tarlatamab provides significantly longer overall survival and progression-free survival, alongside improved symptom control for dyspnoea and cough, compared to standard chemotherapy in previously treated SCLC. The safety profile is characterized by mainly low-grade toxic effects, with manageable CRS and infrequent ICANS, and overall fewer severe AEs and discontinuations than chemotherapy. These results support tarlatamab as an important new treatment option for SCLC patients progressing after platinum-based chemotherapy.

MHRA approval

Tarlatamab (Imdylltra) was granted approval in December 2024 by The Medicines and Healthcare products Regulatory Agency (MHRA) to treat adult patients with small cell lung cancer (SCLC) that has spread throughout the lungs and/or to other parts of the body.

In February 2025 the MHRA granted a conditional marketing authorisation to Imdylltra for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after at least two prior lines of therapy, including platinum-based chemotherapy.

Reference

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. Mountzios G et al. for the DeLLphi-304 Investigators. New Engl. J Med. June 2025 DOI: 10.1056/NEJMoa2502099