DeLLphi-304 Trial

Design - Phase 3 tarlatamab (DLL3 bispecific T-cell engager) vs chemotherapy, second-line SCLC after platinum-based therapy (NCT05740566).

OS (primary, met) - Median 13.6 vs 8.3 mo, HR 0.60 (95% CI 0.47-0.77; p<0.001).

PFS / response - PFS 4.2 vs 3.2 mo (HR 0.72); objective response rate 27% vs 9%.

CNS (ASCO 2026 post hoc, Abstract 8006) - First CNS-efficacy data for a T-cell engager in SCLC: ITT CNS PFS HR 0.54; among baseline brain-mets patients CNS PFS HR 0.40.

Safety - Grade >=3 AEs 54% vs 80% (chemo); cytokine release syndrome 56% (Grade >=3 only 1.2%), concentrated around step-up dosing.

Regulatory / drug - FDA approved (relapsed SCLC); Amgen; tarlatamab (Imdelltra).

Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated July 21, 2026.

CNS Post Hoc — Intracranial Efficacy (#ASCO26, Abstract 8006)

In this post hoc analysis — the first CNS-efficacy data for a T-cell engager in SCLC — tarlatamab delayed time to CNS progression/death versus chemotherapy across the overall (ITT) population — median CNS PFS not reached vs 7.2 months (HR 0.54; 95% CI 0.39–0.75). Among patients with baseline brain metastases (39% of each arm), the intracranial benefit was more pronounced: median CNS PFS 6.5 vs 4.2 months (HR 0.40; 95% CI 0.24–0.66); intracranial complete response 15% vs 5%; CNS tumor shrinkage (≥30%) 56% vs 38%; CNS duration of disease control 8.2 vs 5.2 months; and overall survival 13.9 vs 6.8 months (HR 0.51; 95% CI 0.34–0.74) favoring tarlatamab.

Overall Survival (Primary Endpoint — MET, ASCO 2025 / NEJM)

In the pivotal analysis presented at ASCO 2025 and published in NEJM, tarlatamab produced a statistically significant overall-survival benefit versus chemotherapy in 2L SCLC: median OS 13.6 vs 8.3 months (HR 0.60; 95% CI 0.47–0.77; p<0.001). The benefit was consistent regardless of platinum-free interval (OS HR 0.60 for CFI <90 days, 0.65 for ≥90 days).

Progression-Free Survival & Response (ASCO 2025 / NEJM)

Tarlatamab also improved progression-free survival — median PFS 4.2 vs 3.2 months (HR 0.72; 95% CI 0.59–0.88; p<0.001) — and roughly tripled the objective response rate (ORR 27% vs 9%) versus chemotherapy, with more durable responses. Patient-reported dyspnea also improved significantly at week 18 with tarlatamab.

Safety & Tolerability

Tarlatamab was associated with fewer severe (Grade ≥3) adverse events than chemotherapy (54% vs 80%), largely reflecting reduced hematologic toxicity. The characteristic tarlatamab toxicities are cytokine release syndrome (CRS, 56% — predominantly Grade 1–2; Grade ≥3 only 1.2%), concentrated around the step-up dosing period, and immune effector cell–associated neurotoxicity syndrome (ICANS) — both carry boxed warnings and are managed with monitoring and supportive care. Serious adverse reactions occurred in 52% of patients; 6% discontinued tarlatamab due to an adverse reaction.

Clinical Implications

DeLLphi-304 establishes tarlatamab as a standard second-line option in relapsed SCLC, an area with historically poor outcomes. The ASCO 2026 CNS data are especially meaningful because brain metastases are common in SCLC and have been difficult to control with chemotherapy — multiple KOLs called the intracranial signal one of the most clinically relevant SCLC updates of the meeting. The findings support tarlatamab use in patients with CNS involvement and reinforce the confirmatory Phase 3 basis for its regulatory standing.

What is the DeLLphi-304 trial?

DeLLphi-304 is a Phase 3 randomized trial (NCT05740566) comparing tarlatamab (Imdelltra), a DLL3-targeting bispecific T-cell engager, with standard chemotherapy in patients with relapsed small cell lung cancer after platinum-based therapy. Overall survival was the primary endpoint.

What overall survival benefit did DeLLphi-304 show?

Tarlatamab produced a statistically significant overall-survival benefit: median OS was 13.6 versus 8.3 months (HR 0.60; 95% CI 0.47-0.77; p<0.001). It also improved progression-free survival (4.2 vs 3.2 months; HR 0.72) and roughly tripled the objective response rate (27% vs 9%) versus chemotherapy.

What did the ASCO 2026 CNS analysis of DeLLphi-304 find?

At ASCO 2026 (Abstract 8006), a post hoc analysis - the first CNS-efficacy data for a T-cell engager in SCLC - showed tarlatamab delayed intracranial progression versus chemotherapy across the overall population (CNS PFS HR 0.54) and, among patients with baseline brain metastases, an even larger benefit (CNS PFS HR 0.40). Brain metastases are common in SCLC, which is why KOLs highlighted this signal.

Is tarlatamab FDA approved for small cell lung cancer?

Yes. Tarlatamab (Imdelltra) is FDA approved for extensive-stage small cell lung cancer that has progressed on or after platinum-based chemotherapy. It initially received accelerated approval in May 2024, and on November 19, 2025 the FDA converted it to traditional approval in the relapsed setting, based on the DeLLphi-304 overall-survival benefit.

What is the safety profile of tarlatamab in DeLLphi-304?

Tarlatamab caused fewer severe (Grade >=3) adverse events than chemotherapy (54% vs 80%), largely reflecting less hematologic toxicity. Its characteristic toxicity is cytokine release syndrome, which occurred in 56% of patients but was predominantly Grade 1-2 (Grade >=3 only 1.2%) and concentrated around the step-up dosing period; immune effector cell-associated neurotoxicity syndrome (ICANS) can also occur, so monitoring during initiation is required.