TARLATAMAB plus durvalumab significantly improved survival in patients with extensive-stage small-cell lung cancer following initial chemoimmunotherapy.
The Phase III DeLLphi-305 trial demonstrated substantial improvements in overall survival and progression-free survival compared with durvalumab maintenance alone, potentially establishing a new treatment approach for patients whose disease has not progressed after initial therapy.
Extensive-stage small-cell lung cancer remains an aggressive malignancy associated with poor outcomes, with median overall survival historically reaching approximately 12–13 months.
Tarlatamab is a bispecific T-cell engager targeting delta-like ligand 3 (DLL3) and CD3, designed to direct immune cells against cancer cells. Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor used in chemoimmunotherapy.
The international, randomized, open-label trial enrolled 563 patients without disease progression following initial chemoimmunotherapy. Participants received either tarlatamab plus durvalumab (282 patients) or durvalumab alone (281 patients) as first-line maintenance therapy.
At the prespecified interim analysis, median overall survival reached 21.1 months with tarlatamab plus durvalumab, compared with 12.7 months for durvalumab alone.
This represented an 8.4-month improvement in median overall survival and a 58% reduction in the hazard of death (hazard ratio [HR]: 0.42; 95% confidence interval [CI]: 0.32–0.54; P<0.001).
Median progression-free survival also improved substantially, reaching 7.4 months with combination maintenance therapy versus 1.9 months with durvalumab alone (HR: 0.34; 95% CI: 0.28–0.42; P<0.001).
These findings demonstrate significant improvements in both survival endpoints among patients entering the maintenance treatment phase.
Grade 3 or higher adverse events occurred in 46.8% of patients receiving tarlatamab plus durvalumab, compared with 40.6% receiving durvalumab alone.
Cytokine release syndrome was observed in nearly half of patients receiving combination therapy, although most cases were Grade 1 or 2.
The findings highlight the importance of monitoring treatment-related toxicity when considering combination immunotherapy.
Overall, DeLLphi-305 provides compelling evidence supporting tarlatamab plus durvalumab as a potential first-line maintenance strategy for extensive-stage small-cell lung cancer. Longer follow-up will help establish the durability of survival benefits and further characterize treatment safety.
Reference
Pérol M et al. Tarlatamab–Durvalumab Maintenance for Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2026. DOI: 10.1056/NEJMoa2609482.
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