Clinical trialPhase 3Lung cancer

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy

N Engl J Med · 2025509 patients

Mountzios G, Sun L, Cho BC, Demirci U, Baka S, Gümüş M, et al. N Engl J Med. 2025. 393:349-361

Study type: Clinical trial
Study name: DeLLphi-304
Phase: Phase 3
Design: Multinational, randomised, open-label trial
Sample size: 509 patients
Source: N Engl J Med · 2025
Trial registration: NCT05740566

In plain words

Tarlatamab is a drug given by drip that acts like a "bridge", linking immune cells (T cells) to cancer cells that carry the DLL3 protein. In small-cell lung cancer that has come back after first chemotherapy, this drug helped people live longer than second-line chemotherapy (median about 14 versus 8 months) and caused fewer severe side effects. During the first doses, monitoring in hospital is needed because of possible immune reactions (fever, low blood pressure, confusion).

Key results

13.6 vs 8.3 months

Median overall survival

Stratified HR 0.60; 95% CI 0.47–0.77; P<0.001

4.2 vs 3.2 months

Median progression-free survival (investigator assessment)

HR 0.72; 95% CI 0.59–0.88; P<0.001 (FDA label)

HR 0.60 (<90 days) and 0.65 (≥90 days)

Overall survival by chemotherapy-free interval (exploratory)

95% CI 0.43–0.84 and 0.45–0.93 (FDA label)

54% vs 80%

Grade 3 or higher adverse events

5% vs 12%

Discontinuation due to adverse events

Dose and schedule cards

Tarlatamab (DeLLphi-304)

Extensive-stage SCLC progressing on or after platinum-based chemotherapyOn the page “Lung cancer” · Small cell lung cancer: after progression

Extensive-stage SCLC progressing on or after platinum-based chemotherapy

Drug	Dose	Route	Schedule
Cycle 1
Tarlatamab	1 mg (step-up dose)	IV (1 h)	Cycle 1, day 1
Tarlatamab	10 mg	IV (1 h)	Cycle 1, days 8 and 15
Cycle 2 onward
Tarlatamab	10 mg	IV (1 h)	Days 1 and 15 of each cycle

Cycle length: Every 28 days (i.e., every 2 weeks)
Duration: Until disease progression or intolerable toxicity

Source: FDA label; trial. Boxed warning: cytokine release syndrome (CRS) and neurologic toxicity/ICANS. Premedication on cycle 1, days 1 and 8: dexamethasone 8 mg IV within 1 hour before the infusion, and 1 liter of normal saline IV over 2 to 4 hours immediately after the infusion; the patient should be well hydrated before the infusion. Monitoring: for 6 to 8 hours after the start of the infusion on cycle 1, days 1 and 8 (and cycle 1, day 15 and cycle 2), 3 to 4 hours in cycles 3 and 4, and 2 hours from cycle 5 onward; after the day 1 and day 8 doses, the patient should stay with a caregiver and within 1 hour of a treatment centre for 48 hours. CBC and liver tests before each dose until cycle 5, day 15.

On the page “Lung cancer” · Small cell lung cancer: after progression

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Tarlatamab

Tarlatamab IV (1-hour infusion): step-up dose of 1 mg on day 1 of cycle 1, then 10 mg on days 8 and 15 of cycle 1, and thereafter 10 mg every 2 weeks until disease progression or unacceptable toxicity (254 patients).

Per the FDA label: before the day 1 and day 8 infusions of cycle 1, dexamethasone 8 mg IV (or equivalent) within 1 hour before, and immediately after the end of the infusion 1 litre of normal saline IV over 2 to 4 hours. Monitoring for 6 to 8 hours in a healthcare facility after the day 1 and day 8 doses of cycle 1 (and the patient staying with a caregiver within 1 hour of the facility for 48 hours), 6 to 8 hours after day 15 of cycle 1 and in cycle 2, 3 to 4 hours in cycles 3 and 4, and 2 hours from cycle 5 onwards; after a dose delay, restart with step-up dosing per the label table.

2Standard chemotherapy

Investigator's choice of chemotherapy per local standard until progression or unacceptable toxicity: topotecan (73%), lurbinectedin (18%) or amrubicin (9%) (255 patients). The doses of these drugs are not stated in ClinicalTrials.gov or the FDA label and were not verified in these sources.

Source of the regimen details: FDA label for Imdelltra (DailyMed, sections 2.2, 2.3 and 14.1, September 2026 version; tarlatamab dosing schedule in DeLLphi-304); ClinicalTrials.gov NCT05740566 for the control group ("per local standard") — control drug doses not verified

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with small-cell lung cancer that had progressed during or after platinum-based chemotherapy (with or without an anti-PD-1/PD-L1 antibody) (second-line treatment), with ECOG 0 or 1 and at least one measurable lesion (RECIST 1.1); symptomatic brain metastases and active immunodeficiency were exclusion criteria (asymptomatic/treated brain metastases allowed; 45% had brain metastases at baseline). 71% had received prior anti-PD-‎(L)1 immunotherapy and 44% had a chemotherapy-free interval of <90 days. Stratification by prior anti-PD-‎(L)1 exposure, platinum sensitivity (chemotherapy-free interval ≥180, 90 to <180 or <90 days), brain metastases and the control chemotherapy chosen.

Endpoints

Primary endpoint: overall survival. Key secondary: investigator-assessed progression-free survival and patient-reported outcomes (dyspnoea and cough). This paper is a prespecified interim analysis (data cut-off 29 January 2025).

Safety and side effects

Grade 3 or higher adverse events were less frequent with tarlatamab than with chemotherapy (54% versus 80%), and so was discontinuation due to adverse events (5% versus 12%). According to the FDA label (252 tarlatamab patients): cytokine release syndrome (CRS) 56% (grade 3–4: 1.2%); ICANS and other neurological toxicities in fewer than 15%; serious adverse events 52% (CRS 17%, pyrexia 6%, pneumonia 5%, ICANS 3.6%); fatal adverse events 8% (including one ICANS case); permanent discontinuation 6% and dose interruption 38%. Grade 3–4 cytopenias were far less frequent with tarlatamab than with chemotherapy (decreased neutrophils 10% versus 36%, decreased platelets 0.4% versus 20%, decreased haemoglobin 4.5% versus 29%). CRS mostly occurs after cycle 1 doses, and monitoring per the label is required.

Clinical significance and place in guidelines

DeLLphi-304 was the first phase 3 trial to show an overall survival advantage of a bispecific T-cell engager over chemotherapy in small-cell lung cancer. Tarlatamab had already received FDA accelerated approval (May 2024) based on the phase 2 DeLLphi-301 study, and this trial strengthened its position as the preferred second-line treatment.

Limitations

Interim and open-label analysis; the control group included several different chemotherapy regimens; patients with poor performance status or untreated brain metastases were largely not enrolled; the need for hospital admission and monitoring during the first doses limits access.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.