Background
Phase III, open-label RCT (DeLLphi-304). 437 patients with ES-SCLC progressing after first-line platinum-etoposide ± anti-PD-(L)1. All had DLL3 ≥1% by IHC. Randomized 1:1; stratified by prior anti-PD-(L)1, 1L response, and ECOG PS.
Interventions and follow up
Arm A: Tarlatamab 10 mg IV every 2 weeks.
Arm B: Investigator's choice chemotherapy (topotecan, irinotecan, or paclitaxel).
Primary endpoint: OS
mFollow up: 13.2mo
Arm B: Investigator's choice chemotherapy (topotecan, irinotecan, or paclitaxel).
Primary endpoint: OS
mFollow up: 13.2mo
Results
mOS: 13.6 vs 8.9mo, HR 0.67, 95% CI 0.52–0.86, P=.002
mPFS: 4.2 vs 3.2mo, HR 0.72, 95% CI 0.57–0.90
ORR: 43% vs 17%
mPFS: 4.2 vs 3.2mo, HR 0.72, 95% CI 0.57–0.90
ORR: 43% vs 17%
Adverse events
Overall: Grade ≥3 events 57% vs 61%. Discontinuation 9% vs 11%. No treatment-related deaths in tarlatamab arm.
Immune effector / CRS: CRS any grade 54% (grade ≥3 2%); ICANS grade ≥3 3%.
Hematologic: Neutropenia grade ≥3 7% vs 40%.
Immune effector / CRS: CRS any grade 54% (grade ≥3 2%); ICANS grade ≥3 3%.
Hematologic: Neutropenia grade ≥3 7% vs 40%.
Conclusions
Tarlatamab significantly improved OS vs standard chemotherapy as second-line treatment for ES-SCLC, establishing a new standard of care in DLL3-expressing SCLC after platinum-etoposide failure.
Key Limitations
DLL3 ≥1% threshold enrolls nearly all SCLC, so biomarker selection is non-discriminatory. OS gain of 4.7mo (HR 0.67) statistically significant but modest. CRS adds logistical complexity. Crossover/subsequent-therapy data not reported. Comparator allowed 3 chemotherapy agents (heterogeneity).
Clinical Context
First randomized OS benefit for a novel agent in 2L SCLC in over a decade, converting tarlatamab's accelerated approval (DeLLphi-301) toward regular approval. Establishes tarlatamab as preferred 2L therapy in DLL3+ ES-SCLC after platinum-etoposide.