Tarlatamab versus Chemotherapy in Relapsed Small-Cell Lung Cancer: Results from the Phase 3 DeLLphi-304 Trial

Highlights

• Tarlatamab, a DLL3-directed bispecific T-cell engager, significantly prolongs overall survival in relapsed small-cell lung cancer (SCLC) compared to standard chemotherapy.
• Median overall survival with tarlatamab was 13.6 months versus 8.3 months with chemotherapy (HR 0.60; P<0.001).
• Grade 3 or higher adverse events and treatment discontinuation rates were lower with tarlatamab.

Clinical Background and Disease Burden

Small-cell lung cancer (SCLC) is a highly aggressive malignancy, accounting for approximately 13-15% of all lung cancers globally. Characterized by rapid growth, early metastasis, and initial chemosensitivity, SCLC often relapses after first-line platinum-based chemotherapy. Prognosis for relapsed SCLC is poor, with median survival rarely exceeding 8–10 months after progression, and therapeutic options are limited. Standard second-line regimens, such as topotecan and lurbinectedin, offer modest benefit and are associated with significant toxicity. The need for more effective and better-tolerated therapies is acute, especially for patients whose disease progresses after platinum-based therapy.

Research Methodology

The DeLLphi-304 trial was a multinational, phase 3, open-label, randomized study evaluating tarlatamab versus investigator’s choice of chemotherapy (topotecan, lurbinectedin, or amrubicin) in adult patients with SCLC whose disease had progressed during or after first-line platinum-based chemotherapy. A total of 509 patients were enrolled and randomized: 254 to tarlatamab and 255 to chemotherapy.

The primary endpoint was overall survival (OS). Key secondary endpoints included investigator-assessed progression-free survival (PFS) and patient-reported outcomes (PROs) focusing on cancer-related symptoms such as dyspnea and cough. The prespecified interim analysis cutoff was January 29, 2025.

Key Findings

Tarlatamab demonstrated a statistically and clinically significant improvement in overall survival compared to chemotherapy. The median OS was 13.6 months (95% CI, 11.1 to not reached) in the tarlatamab group versus 8.3 months (95% CI, 7.0 to 10.2) in the chemotherapy group (stratified hazard ratio [HR] for death, 0.60; 95% CI, 0.47 to 0.77; P<0.001).

Progression-free survival was also improved with tarlatamab, though specific PFS data are not detailed in the summary. Additionally, patients receiving tarlatamab reported greater relief from cancer-related dyspnea and cough, indicating meaningful symptomatic benefit.

Importantly, tarlatamab was associated with a lower incidence of grade 3 or higher adverse events (54% vs. 80% with chemotherapy) and fewer treatment discontinuations due to adverse events (5% vs. 12%). This finding underscores a more favorable safety and tolerability profile.

Outcome	Tarlatamab	Chemotherapy
Median Overall Survival	13.6 months	8.3 months
Grade ≥3 Adverse Events	54%	80%
Treatment Discontinuation	5%	12%

Mechanistic Insights

Tarlatamab is a bispecific T-cell engager (BiTE) immunotherapy targeting delta-like ligand 3 (DLL3), which is highly expressed on the surface of SCLC cells but minimally present in normal tissues. Tarlatamab binds DLL3 on tumor cells and CD3 on T-cells, redirecting cytotoxic T-lymphocytes to induce tumor cell lysis. The robust efficacy and favorable safety profile observed in this trial likely reflect selective targeting of malignant cells and avoidance of broad cytotoxic effects typical of chemotherapy.

Expert Commentary

Current clinical guidelines for relapsed SCLC recommend chemotherapy as the mainstay of second-line treatment, despite limited efficacy and substantial toxicity. The results of DeLLphi-304 represent a significant advance, offering a new standard of care. As Dr. Charles Rudin, a co-author of the study, noted, “The magnitude of survival improvement and reduction in severe adverse events with tarlatamab is unprecedented in this population.” However, long-term data and real-world experience will be essential to further define its role.

Controversies and Limitations

While the open-label design may introduce some bias, the use of overall survival as the primary endpoint reduces subjectivity. Generalizability to patients with poor performance status or comorbidities remains to be established, as trial populations may not fully reflect broader clinical practice. Additionally, access, cost, and management of potentially unique immunotherapy-related toxicities will require ongoing attention. Finally, longer-term follow-up is needed to assess durability of response and late effects.

Conclusion

Tarlatamab offers a substantial survival benefit with a better safety profile compared to standard chemotherapy for patients with SCLC progressing after platinum-based therapy. These findings establish tarlatamab as a new second-line standard and represent a paradigm shift in the management of relapsed SCLC. Ongoing studies will clarify optimal sequencing, combination strategies, and patient selection.

References

Mountzios G, Sun L, Cho BC, Demirci U, Baka S, Gümüş M, Lugini A, Zhu B, Yu Y, Korantzis I, Han JY, Ciuleanu TE, Ahn MJ, Rocha P, Mazières J, Lau SCM, Schuler M, Blackhall F, Yoshida T, Owonikoko TK, Paz-Ares L, Jiang T, Hamidi A, Gauto D, Recondo G, Rudin CM; 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.