Background
Phase I/II single-arm trial (DeLLphi-301). 225 patients with relapsed/refractory SCLC after ≥2 prior lines. DLL3 expression ≥1% (IHC) required. Prior platinum-etoposide and anti-PD-(L)1 therapy permitted.
Interventions and follow up
Treatment: Tarlatamab 10 mg IV every 2 weeks (recommended Phase II dose from dose-escalation); single-arm, no comparator.
Primary endpoint: ORR (IRC, RECIST 1.1) at recommended Phase II dose
mFollow up: 10.6mo
Primary endpoint: ORR (IRC, RECIST 1.1) at recommended Phase II dose
mFollow up: 10.6mo
Results
ORR: 40%, 95% CI 29–52
DOR: 9.7mo
DCR: 68%
mPFS: 3.7mo
mOS: 13.2mo
DOR: 9.7mo
DCR: 68%
mPFS: 3.7mo
mOS: 13.2mo
Adverse events
Overall: Grade ≥3 events 52%. No treatment-related deaths.
Immune effector / CRS: CRS any grade 51% (grade ≥3 1%), mostly cycle 1 day 1; hospitalization for CRS in 23% during cycle 1. ICANS grade ≥3 3%.
Constitutional: Fatigue grade ≥3 7%.
Immune effector / CRS: CRS any grade 51% (grade ≥3 1%), mostly cycle 1 day 1; hospitalization for CRS in 23% during cycle 1. ICANS grade ≥3 3%.
Constitutional: Fatigue grade ≥3 7%.
Conclusions
Tarlatamab produced durable responses in heavily pretreated R/R SCLC with DLL3 expression, the first bispecific T-cell engager approval in SCLC and a novel mechanism in this disease.
Key Limitations
Single-arm, no randomized comparator; OS 13.2mo promising but needs confirmation. DLL3 ≥1% cutoff is broad (>95% of SCLC), limiting biomarker selection. CRS requires step-up dosing and hospitalization protocols, limiting access. Resistance mechanisms uncharacterized.
Clinical Context
FDA accelerated approval of tarlatamab for R/R SCLC after ≥2 prior lines (May 2024), the first DLL3-targeting bispecific approved in oncology. DeLLphi-304 subsequently confirmed benefit in the 2L setting, supporting earlier sequencing.