Tarlatamab Plus Durvalumab Improves Survival in Extensive-Stage Small Cell Lung Cancer: DeLLphi-305 Trial
The combination of tarlatamab and durvalumab significantly improved overall and progression-free survival compared with durvalumab maintenance alone in patients with extensive-stage small cell lung cancer (ES-SCLC), according to findings from the Phase 3 DeLLphi-305 trial presented at ESMO 2026.
The addition of tarlatamab, a DLL3-targeted bispecific T-cell engager, to durvalumab maintenance immunotherapy was associated with a substantial reduction in the risk of death and disease progression among patients whose cancer had not progressed following initial chemo-immunotherapy.
Small cell lung cancer is an aggressive malignancy characterised by rapid progression and frequent relapse after initial treatment. The DeLLphi-305 findings suggest that incorporating a targeted T-cell engager into first-line maintenance therapy could offer a new treatment approach for patients with ES-SCLC.
Significant Improvement in Overall Survival
The combination of tarlatamab and durvalumab reduced the risk of death by 58% compared with durvalumab maintenance alone (hazard ratio [HR], 0.42; P < 0.001).
Median overall survival (OS) was 21.1 months in patients receiving the combination, compared with 12.7 months in those receiving durvalumab alone. At 12 months, the estimated OS rate was 79.4% in the combination arm versus 53.3% in the control arm.
The findings indicate a substantial survival benefit with the addition of tarlatamab to maintenance immunotherapy in this patient population.
Progression-Free Survival and Response Rates Improve
The combination also significantly improved progression-free survival (PFS), reducing the risk of disease progression or death by 66% compared with durvalumab alone (HR, 0.34).
Median PFS was 7.4 months with tarlatamab plus durvalumab, compared with 1.9 months with durvalumab maintenance alone. The 12-month PFS rate was 38.4% in the combination group versus 9.5% in the control group.
Objective response rates were also higher with the combination. An objective response was observed in 26.4% of patients receiving tarlatamab plus durvalumab, compared with 4.1% of those receiving durvalumab alone (P < 0.001).
The survival benefit was reported across patient subgroups, including those with treated or untreated brain metastases at baseline and those with liver metastases.
Safety Profile and Tolerability
Cytokine release syndrome (CRS) was reported in 49.6% of patients receiving the combination, with most events being Grade 1 or 2. Grade 3 CRS occurred in 0.4% of patients, with no Grade 4 or 5 events reported.
Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon, occurring in 1.1% of patients, with no Grade 3 or higher events reported.
Treatment discontinuation due to adverse events occurred in 5.7% of patients receiving tarlatamab. No treatment-related deaths were attributed to the combination, according to the reported findings.
The safety results highlight the importance of monitoring for CRS and neurological complications when administering T-cell-engaging therapies.
Clinical Implications
DeLLphi-305 represents a Phase 3 evaluation of a DLL3-targeted T-cell engager added to first-line maintenance immunotherapy in ES-SCLC. The significant improvements in overall and progression-free survival suggest that this approach could expand maintenance treatment options for patients whose disease has not progressed after initial chemo-immunotherapy.
Further consideration of the findings will depend on the complete trial report, longer-term follow-up, regulatory assessment and integration into clinical practice. The results also underscore the growing role of immunotherapeutic strategies designed to direct T cells against tumour-associated targets in aggressive cancers such as small cell lung cancer.
