Clinical trialPhase 3Stomach cancer

Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer

N Engl J Med · 2025494 patients

Shitara K, Van Cutsem E, Gümüş M, et al. N Engl J Med. 2025. 393:336-348

Study type: Clinical trial
Study name: DESTINY-Gastric04
Phase: Phase 3
Design: International, randomised, open-label trial
Sample size: 494 patients
Source: N Engl J Med · 2025
Trial registration: NCT04704934

In plain words

When HER2-positive stomach cancer progresses after first treatment (including trastuzumab), the usual second-line treatment was the combination of ramucirumab and paclitaxel. In this study, the "antibody-drug" medicine trastuzumab deruxtecan (which carries chemotherapy attached to an anti-HER2 antibody and goes straight to HER2-positive cells) helped patients live about 3 months longer on average and shrank the tumour in a larger share of patients. Before starting this drug, it is best to take a new sample from the tumour to confirm that it is still HER2-positive. The most important side effect to note is lung inflammation, which was mostly mild; if you have a new cough, shortness of breath or fever, tell your doctor straight away.

Key results

14.7 vs 11.4 months

Median overall survival

HR for death 0.70 (95% CI 0.55–0.90); P=0.004

HR 0.74

Progression-free survival

95% CI 0.59–0.92

44.3% vs 29.1%

Confirmed objective response

Trastuzumab deruxtecan vs ramucirumab–paclitaxel

50.0% vs 54.1%

Grade 3 or higher drug-related adverse events

Any grade: 93.0% vs 91.4%

13.9% vs 1.3%

Interstitial lung disease / pneumonitis

In the T-DXd group, 33 patients grade 1 or 2 and 1 patient grade 3

Drugs in this study:Paclitaxel (Taxol)Trastuzumab (Herceptin)Trastuzumab deruxtecan (Enhertu)

Dose and schedule cards

Trastuzumab deruxtecan (DESTINY-Gastric04 trial)

Advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, HER2-positive (IHC 3+ or IHC 2+ with positive ISH), after a trastuzumab-containing regimen; in the trial, HER2 positivity was confirmed on a biopsy taken after progressionCycle length: Every 21 daysOn the page “Stomach cancer” · After disease progression: second line and beyond

Drug	Dose	Route	Schedule
Trastuzumab deruxtecan	6.4 mg/kg	IV (not as a bolus; do not dilute with sodium chloride solution)	Day 1

Cycle length: Every 21 days
Duration: Until disease progression or unacceptable toxicity

Dose from the FDA label and the DESTINY-Gastric04 trial. Not interchangeable with trastuzumab or T-DM1. Premedication to prevent nausea and vomiting is required. The label reports interstitial lung disease (ILD) in 10% of patients with gastric cancer: for asymptomatic ILD (grade 1), withhold the drug until resolution; for symptomatic ILD (grade 2 or higher), discontinue permanently and start corticosteroids promptly. Monitor the CBC before each dose and LVEF before starting and periodically. Dose reduction: 5.4 mg/kg, then 4.4 mg/kg.

On the page “Stomach cancer” · After disease progression: second line and beyond

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

1Trastuzumab deruxtecan

Trastuzumab deruxtecan (T-DXd) 6.4 mg/kg body weight, IV infusion on day 1 of each 21-day cycle (every 3 weeks), until disease progression or unacceptable toxicity.

2Ramucirumab + paclitaxel (control)

Ramucirumab 8 mg/kg IV on days 1 and 15 with paclitaxel 80 mg/m² IV on days 1, 8 and 15 of each 28-day cycle.

Source of the regimen details: Abstract of the paper (NEJM 2025: T-DXd 6.4 mg/kg), ClinicalTrials.gov NCT04704934 (T-DXd schedule and ramucirumab and paclitaxel doses) and the FDA label for Enhertu

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

Adults with HER2-positive (IHC ‎3+‎ or IHC ‎2+‎ with positive ISH) metastatic gastric or gastro-oesophageal junction adenocarcinoma, with HER2 positivity confirmed on a tumour biopsy taken after disease progression during or after first-line trastuzumab-based therapy, and ECOG performance status 0 or 1.

Endpoints

Primary endpoint: overall survival (OS).

Secondary endpoints: progression-free survival, confirmed objective response (complete or partial response lasting 4 weeks or more), disease control, duration of response and safety.

Safety and side effects

Drug-related adverse events of any grade occurred in 93.0% of the trastuzumab deruxtecan group and 91.4% of the ramucirumab–paclitaxel group, and grade 3 or higher events in 50.0% and 54.1%, respectively. Drug-related interstitial lung disease or pneumonitis (adjudicated) occurred in 13.9% of the T-DXd group (grade 1 or 2 in 33 patients and grade 3 in 1 patient) and 1.3% of the comparator group (grade 3 in 2 patients and grade 5 in 1 patient). Monitoring of respiratory symptoms (cough, dyspnoea, fever) during T-DXd treatment is essential.

Clinical significance and place in guidelines

Trastuzumab deruxtecan had already (2021) been approved by the FDA, based on phase 2 studies, for locally advanced or metastatic HER2-positive gastric and gastro-oesophageal junction adenocarcinoma after a trastuzumab-based regimen (label dose: 6.4 mg/kg every 3 weeks). DESTINY-Gastric04 was the first randomised phase 3 trial to show its overall survival superiority in the second line versus ramucirumab–paclitaxel. The NCCN guideline (version 2.2025, published before this paper) lists T-DXd as a preferred category 2A option in the second or later line after a trastuzumab-based regimen.

Limitations

The trial was open-label. The requirement for re-biopsy and HER2 confirmation after progression restricted the study population to patients who remained HER2-positive; the results cannot be extrapolated to patients without re-biopsy. The risk of interstitial lung disease was considerably higher with T-DXd.

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.