SUMMARY: The American Cancer Society estimates that in the US, about 30,300 new cases of Gastric cancer will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for stomach cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.
The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced Gastric and GastroEsophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Upon progression, Paclitaxel plus Ramucirumab (CYRAMZA®), an anti-VEGFR-2 antibody is recommended as second-line therapy, regardless of HER2 expression, based on OS and Progression Free Survival (PFS) data for this combination regimen.
Trastuzumab Deruxtecan (T-DXd) (ENHERTU®) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike ado-Trastuzumab emtansine (KADCYLA®), T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure.
The DESTINY-Gastric04 study represents the first confirmatory Phase 3 trial evaluating T-DXd as second-line therapy against the current standard, Ramucirumab plus Paclitaxel, in patients with Trastuzumab-pretreated HER2-positive metastatic disease.
Study Design
DESTINY-Gastric04 is a global, randomized, open-label, Phase 3 trial in which 494 patients (N=494) with HER2-positive metastatic gastric or GEJ adenocarcinoma were randomly assigned in a 1:1 ratio to receive T-DXd 6.4 mg/kg IV every 3 weeks (N=246) or Ramucirumab 8 mg/kg IV days 1 and 15 every 28 days along with Paclitaxel 80 mg/m² IV days 1, 8, 15 every 28 days (N=248). Treatment continued until progression or unacceptable toxicity. No crossover was allowed during the trial. The median patient age was 64 yrs, randomized patients had an ECOG performance status of 0–1, documented HER2 positivity on post-trastuzumab tumor biopsy (IHC 3+ or IHC 2+/ISH+) and no prior history of interstitial lung disease (ILD) or pneumonitis. Approximately, two thirds of the patients had the primary tumor location in the stomach whereas one third had tumors at the GE junction. Patients were stratified based on HER2 status (IHC 3+ vs. 2+/ISH+), geographic region, and time to progression on prior therapy. The Primary end point was Overall Survival (OS). Secondary end points included Progression-Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), and safety.
Efficacy Outcomes
Overall Survival (OS):
The Overall Survival was significantly longer with T-DXd than with Ramucirumab plus Paclitaxel with a 30% reduction in the risk of death. The median OS was 14.7 months with T-DXd versus 11.4 months with Ramucirumab–Paclitaxel (HR=0.70; P=0.004). The 24-month OS rate was 29.0% with T-DXd versus 13.9% with Ramucirumab–Paclitaxel
Progression-Free Survival (PFS):
The median PFS was 6.7 months versus 5.6 months (HR=0.74; P=0.007) and 12-month PFS rate was 22.9% versus 13.6%, favoring T-DXd
Objective Response Rate (ORR):
The confirmed ORR was 44.3% with T-DXd versus 29.1% with Ramucirumab–Paclitaxel (P<0.001) and the median duration of response was 7.4 months versus 5.3 months and higher Disease Control Rate was observed in T-DXd group, reflecting both improved response and stable disease.
Safety Profile
Overall Safety:
Grade 3 or more drug-related Adverse Events were 50.0% in the T-DXd group versus 54.1% in the Ramucirumab–Paclitaxel group. Drug discontinuation due to AEs was 11.5% versus 13.3% respectively.
Interstitial Lung Disease (ILD)/Pneumonitis:
ILD occurred in 13.9% of T-DXd recipients (mostly grade 1–2) and 0.4% experienced grade 3 events versus 1.3% in the Ramucirumab–Paclitaxel group (one grade 5 event)
Clinical Interpretation
The DESTINY-Gastric04 trial reinforces the clinical value of Trastuzumab deruxtecan as a second-line option in HER2-positive gastric and GEJ cancers, demonstrating superior survival outcomes and deeper, more durable responses compared to Ramucirumab plus Paclitaxel. Notably, this benefit was achieved even in the absence of protocol-defined crossover, and despite access to post-trial HER2-targeted agents in some regions. ILD remains a recognized risk associated with T-DXd and mandates proactive monitoring and prompt intervention. Nonetheless, the overall safety profile was manageable and consistent with prior studies.
Key Takeaways for Practice
- Trastuzumab deruxtecan offers a statistically and clinically significant OS advantage over Ramucirumab plus Paclitaxel in the second-line setting for HER2-positive gastric/GEJ cancer.
- HER2 re-testing after progression on Trastuzumab is crucial, as HER2 loss is documented and impacts therapeutic eligibility.
- Safety profiles of both regimens are acceptable, though clinicians must remain vigilant for ILD with T-DXd.
- These results support the positioning of T-DXd as the preferred second-line therapy in eligible patients who retain HER2 positivity.
Future Directions
Given the survival gains observed in this trial, ongoing studies are evaluating T-DXd in earlier lines of therapy and in combination with immunotherapy. Longer follow-up and Real-World Data will further clarify optimal sequencing strategies and management of T-DXd–associated toxicities.
