DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer
A bispecific antibody that pulls T cells onto small-cell lung cancer cells produced responses in 40% of patients whose cancer had come back after chemotherapy, lasting far longer than any previous drug in this setting.
Open-label phase 2 trial of 220 patients with small-cell lung cancer that had progressed after platinum-based chemotherapy (and usually immunotherapy), testing tarlatamab, a DLL3 x CD3 bispecific T-cell engager, at 10 mg or 100 mg every two weeks. Primary endpoint was objective response rate.
At 10 mg the response rate was 40%, median PFS 4.9 months and median OS 14.3 months, with cytokine release syndrome in about half of patients, mostly grade 1-2 and mainly during the first cycle. It led to accelerated FDA approval in 2024 and was confirmed by the phase 3 DeLLphi-304 trial, which showed a survival benefit over chemotherapy (median OS 13.6 vs 8.3 months, HR 0.60).
- Objective response 40% at 10 mg and 32% at 100 mg; median duration of response over 9 months.
- At 10 mg: median PFS 4.9 months; median overall survival 14.3 months in a population with a historical OS of 6-8 months.
- Cytokine release syndrome 51% (10 mg) and 61% (100 mg), mostly grade 1-2 in cycle 1; ICANS or associated neurological events in about 8% (10 mg).
- Discontinuation for treatment-related adverse events 3% at the 10 mg dose, which was selected for further development.
- DeLLphi-304 phase 3 (2025): OS 13.6 vs 8.3 months versus chemotherapy, HR 0.60.
Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.
- Single-arm phase 2 with a randomised dose comparison, not a randomised comparison against chemotherapy (that came with DeLLphi-304).
- Cytokine release syndrome and neurotoxicity require hospital-based step-up dosing and limit use in frail patients or centres without experience.
- Every-two-week intravenous dosing is burdensome for patients with a short life expectancy.
- DLL3 expression was not required for entry and was not predictive, so there is no selection biomarker.
Pages like this
not linked directly; found by shared links- TermStep-up dosing (T-cell engagers)
Shares Tarlatamab, ICANS (neurotoxicity), Bispecific antibodies, Cytokine release syndrome (CRS).
- Key paperMagnetisMM-3: elranatamab, a second BCMA bispecific, with a switch to fortnightly dosing after response
Shares CD3, Bispecific antibodies, Objective response rate (ORR), Cytokine release syndrome (CRS).
- Key paperMajesTEC-1: teclistamab, an off-the-shelf BCMA bispecific antibody, in heavily pretreated myeloma
Shares CD3, Bispecific antibodies, Objective response rate (ORR), Cytokine release syndrome (CRS).
- Key paperEPCORE NHL-1: epcoritamab, a subcutaneous CD20 x CD3 bispecific, in relapsed large B-cell lymphoma including after CAR-T
Shares ICANS (neurotoxicity), CD3, Bispecific antibodies, Objective response rate (ORR).
- Key paperCodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug
Shares Amgen, Objective response rate (ORR), Accelerated approval, Wrong doses.
- ProductXaluritamig
Shares Amgen, CD3, Cytokine release syndrome (CRS), T-cell engagers (bispecific).
- InstitutionHospital Universitario 12 de Octubre
Shares DLL3, Tarlatamab, T-cell engagers (bispecific), Small-cell lung cancer.
- TrialDeLLphi-305
Shares DLL3, Tarlatamab, Small-cell lung cancer.