Enhertu Versus Ramucirumab Plus Paclitaxel: Which Has the Upper Hand in Gastric Cancer?

Why Does It Matter?

Gastric cancerranks among the leading causes of cancer-related death worldwide, in fifth place. One in every 5-6 gastric cancers is HER2-positive , a subtype that is susceptible to targeted therapies. In the first line, trastuzumab plus chemotherapy is considered the standard approach, but the best second-line option after resistance develops has long been debated.

Presented at ASCO 2025 and simultaneously published in NEJM, the DESTINY-Gastric04 phase 3 study provides a strong answer to this question: The targeted antibody-drug conjugate containing trastuzumab deruxtecan (T-DXd), Enhertu , raises the following question:is it more effective than ramucirumab + paclitaxel in the second line?

DESTINY-Gastric04 Study Design

• Patient population: 494 patients with HER2-positive metastatic gastric or GEJ adenocarcinoma who had received trastuzumab-based treatment
• Treatment arms compared:
  • T-DXd: 6.4 mg/kg every 21 days
  • RAM + PTX: standard doses in a 28-day cycle
• Primary endpoint: Overall survival (OS)
• Secondary endpoints: Progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), safety

Efficacy Findings

Median Overall Survival (OS)

• T-DXd: 14.7 months (95% CI: 12.1–16.6)
• RAM+PTX: 11.4 months (95% CI: 9.9–15.5)
• Hazard ratio: 0.70 (P = 0.004)

➡ A 3.3-month survival gain, statistically significant and clinically meaningful.

Median Progression-Free Survival (PFS)

• T-DXd: 6.7 months
• RAM+PTX: 5.6 months
• Hazard ratio: 0.74 (P = 0.007)

Objective Response Rate (ORR)

• T-DXd: 44.3%
• RAM+PTX: 29.1%
• P value: <0.001

Duration of Response

• T-DXd: 7.4 months
• RAM+PTX: 5.3 months

Safety and Side Effects

Overall Adverse Events (Any Grade)

• T-DXd: 93.0%
• RAM+PTX: 91.4%

Severe Adverse Events (Grade ≥3)

• T-DXd: 50.0%
• RAM+PTX: 54.1%

Special Focus: Interstitial Lung Disease (ILD)

• With T-DXd: 13.9% (mostly Grade 1-2)
• With RAM+PTX: 1.3% (2 patients with Grade 3, 1 patient with Grade 5)

➡ ILDis a known risk with T-DXd and requires careful patient selection and close monitoring.

Can Quality of Life Be Maintained?

Patient-reported quality-of-life measures showed that both treatment arms maintained quality of life .

What Do These Results Mean?

The DESTINY-Gastric04 study showed that in HER2-positive metastatic gastric or GEJ cancer, second-line T-DXd was clearly superior .

• The OS and PFS gains are consistent with earlier phase 2 DESTINY-Gastric01/02/06 data.
• In patients with persistent HER2 expression, T-DXd is emerging as the most effective option after trastuzumab .
• However, the risk of ILD makes careful monitoring and patient selection essential.

Conclusion: A New Standard?

Yes. T-DXd is a candidate for a new standard of second-line treatment in HER2-positive patients. However, its toxicity profile, particularly pulmonary toxicity, must be carefully assessed.