ASCO 2025: DESTINY-Gastric04 Shows that Trastuzumab Deruxtecan Reduces the Risk of Death in Patients with HER2 Positive Unresectable or Metastatic Gastric Cancer

The international phase 3 DESTINY-Gastric04 clinical trial (NCT04704934), sponsored  by Daiichi Sankyo, found that second-line treatment with trastuzumab deruxtecan (Enhertu®; also known as T-DXd; DS-8201; Daiichi Sankyo and AstraZeneca, See ADC Drugmap) can help people with advanced human epidermal growth factor receptor 2 (HER2-) positive (IHC 3+ or IHC 2+/ISH+) unresectable and/or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJA) that have grown during first-line treatment live about 3 months longer. The study outcomes demonstrated a statistically significant and clinically
meaningful improvement in overall survival (OS) compared to ramucirumab (Cyramza®; Eli Lilly and Company) plus paclitaxel (Taxol®; Bristol-Myers Squibb).

These findings further support the use of trastuzumab deruxtecan in the second-line setting for these patients.

The outcomes from this research were presented at the annual meeting of the American Society of Clinical Oncology (ASCO; LBA4002) , held May 30-June 3, 2025 in Chicago, Illinois. The study results were and simultaneously published in The New England Journal of Medicine.[1][2]

Gastric cancer is the fifth most common cancer worldwide and the fifth leading cause of cancer-related death.[3] Approximately one million cases of gastric cancer were diagnosed in 2022.[3] Gastric cancer is generally associated with a poor prognosis, particularly in advanced stages of the disease where the five-year survival rate is 5% to 10%.[4]

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including gastric cancer.3 Approximately one in five gastric cancers are considered HER2 positive.[5][6] Prior to the results of the DESTINY-Gastric04 trial of trastuzumab deruxtecan, no other HER2 directed medicine has demonstrated a survival benefit in the second-line metastatic setting in a randomized clinical trial.[7]

Extending survival
“If disease progression occurs in the first-line metastatic setting of HER2-positive gastric cancer, there historically have been no HER2-directed medicines that have demonstrated a survival benefit in a phase 3 clinical trial in the second-line setting,” noted the lead study author Kohei Shitara, MD, National Cancer Center Hospital East, Kashiwa, Japan.

The results of DESTINY-Gastric04 show that second-line treatment with HER2-directed trastuzumab deruxtecan can extend survival compared to a chemotherapy-based regimen,” Shitara added.

Poor prognosis
Patients diagnosed with metastatic gastric cancer often have a poor prognosis, with a 5-year survival rate ranging from 5% to 10%. About 5% to17% of these cancers are HER2-positive. For people with metastatic HER2-positive gastric cancer or GEJA that has progressed during first-line treatment, a standard second-line treatment option is paclitaxel with ramucirumab. Historically, there have not been any treatments that directly target the HER2 protein for people with metastatic HER2-positive gastric cancer in the second-line setting.

Trastuzumab deruxtecan is a targeted therapy drug that directly targets the HER2 protein on cancer cells. Based on results from previous phase 2 clinical trials, trastuzumab deruxtecan has been approved for patients diagnosed with advanced HER2-positive gastric cancer or GEJA who have previously received treatment with a trastuzumab-based regimen.

The DESTINY-Gastric04 clinical trial is the first phase 3 clinical trial to directly compare trastuzumab deruxtecan against paclitaxel with ramucirumab in the second-line setting for these patients.

Key Findings
DESTINY-Gastric04 included 494 patients with metastatic or unresectable HER2-positive gastric cancer or GEJA that had progressed during or after treatment with a trastuzumab-based regimen. The median age of the patients was about 64 years old, and most of the patients were from Western Europe or Asia. The patients were randomly assigned to receive either trastuzumab deruxtecan (n = 246 patients) or paclitaxel with ramucirumab (n= 248 patients).

About 60% of the patients in each treatment group had gastric cancer, and about 40% in each group had GEJA.

After a median follow-up of 16.8 months for the trastuzumab deruxtecan group and 14.4 months for the standard treatment group, researchers found that:

• Trastuzumab deruxtecan helped patients live 3.3 months longer. The median overall survival was 14.7 months for patients who received trastuzumab deruxtecan vs. 11.4 months for patients who received paclitaxel with ramucirumab.
• Trastuzumab deruxtecan reduced the risk of death by 30% for patients.
• The median progression-free survival for the trastuzumab deruxtecan group was 6.7 months vs. 5.6 months in the standard treatment group.
• For the patients in the trastuzumab deruxtecan group, their risk of disease progression was reduced by 26%.
• The objective response rate (ORR), or percentage of patients whose cancer shrank following treatment, was 44.3% In the trastuzumab deruxtecan group vs. 29.1% in the standard treatment group.
• The disease control rate (DCR), or percentage of patients whose cancer either shrank or stabilized following treatment, was 91.9% in the trastuzumab deruxtecan group vs. 75.9% for the standard treatment group.

All of the patients in the trastuzumab deruxtecan group experienced side effects, as did nearly all of the patients in the standard treatment group (97.9%). For most patients in both groups, these side effects were grade 3 or higher (68% in the trastuzumab deruxtecan group vs. 73.8% in the standard treatment group). Overall, the side effects experienced by the patients in the trastuzumab deruxtecan group were consistent with the previously known side effects of the drug. The most common side effects of trastuzumab deruxtecan included fatigue (48% of patients), neutropenia (48%), nausea (44.3%) and anemia (31.1%).

Next Steps  
Researchers are expected to continue to study the safety and efficacy of trastuzumab deruxtecan for people with HER2-positive gastric cancer in the first-line setting in three separate clinical trials, including DESTINY-Gastric05, DESTINY-Gastric03, and ARTEMIDE-Gastric01.
__

Clinical trials
Trastuzumab Deruxtecan for Subjects With HER2-Positive Gastric Cancer or Gastro-Esophageal Junction Adenocarcinoma After Progression on or After a Trastuzumab-Containing Regimen (DESTINY-Gastric04) – ClinicalTrials.gov ID NCT04704934
Study of TDXd, Chemotherapy, Pembrolizumab, and Trastuzumab in First-Line Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer – ClinicalTrials.gov ID NCT06731478
Ph1b/​2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03) (DG-03) – ClinicalTrials.gov ID NCT04379596
A Phase Ⅲ Study of Rilvegostomig in Combination With Fluoropyrimidine and Trastuzumab Deruxtecan as the First-line Treatment for HER2-positive Gastric Cancer – ClinicalTrials.gov ID NCT06764875

Highlights of prescribing information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Ramucirumab (Cyramza®; Eli Lilly and Company)[Prescribing Information]
Paclitaxel (Taxol®; Bristol-Myers Squibb)[Prescribing Information]

Reference
[1] Shitara K, Van Cutsem E, Gümüş M, Lonardi S, de la Fouchardière C, Coutzac C, Dekervel J, Hochhauser D, Shen L, Mansoor W, Liu B, Fornaro L, Ryu MH, Lee J, Faustino C, Metges JP, Tabernero J, Franke F, Janjigian YY, Souza F, Jukofsky L, Zhao Y, Kamio T, Zaanan A, Pietrantonio F; DESTINY-Gastric04 Trial Investigators. Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer. N Engl J Med. 2025 May 31. doi: 10.1056/NEJMoa2503119. Epub ahead of print. PMID: 40454632.
[2] Shitara K, Gumus M, Pietrantonio F, Lonardi S, De La Fouchardiere C, Coutzac C, Dekervel J, Hochhauser D, Shen L, Mansoor W, Liu B, Fornaro L, Ryu MH, Lee J, Souza F, Jukofsky L, Zhao Y, Kamio T, Zaanan A, Van Cutsem E. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study. J Clin Oncol 43, 2025 (suppl 17; abstr LBA4002)
[3] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4. PMID: 38572751.
[4] Casamayor M, Morlock R, Maeda H, Ajani J. Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience. 2018 Nov 26;12:883. doi: 10.3332/ecancer.2018.883. PMID: 30679950; PMCID: PMC6345079.
[5] Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: An update. World J Gastroenterol. 2016 May 21;22(19):4619-25. doi: 10.3748/wjg.v22.i19.4619. PMID: 27217694; PMCID: PMC4870069.
[6] Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi: 10.1155/2014/852748. Epub 2014 Sep 7. PMID: 25276427; PMCID: PMC4170925.
[7] Mitani S, Kawakami H. Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance. Cancers (Basel). 2020 Feb 10;12(2):400. doi: 10.3390/cancers12020400. PMID: 32050652; PMCID: PMC7072407.

This article was first published in ADC Review | J. Antibody-drug Conjugates on June 1, 2025.

Featured image: ASCO Annual Meeting. Photo courtesy: © 2017 – 2025 ASCO/David Eulitt Morgan. Used with permission.

DOI