In the phase III DESTINY-Gastric04 trial, use of the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) was compared head to head with the monoclonal antibody ramucirumab and paclitaxel in patients with previously treated, HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Lead study author Kohei Shitara, MD, Director of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East in Kashiwa, Japan, reported that T-DXd showed statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and objective response over ramucirumab and paclitaxel in this patient population. These findings from a primary analysis were presented at the 2025 ASCO Annual Meeting1 and published simultaneously in The New England Journal of Medicine.2
“These results support trastuzumab deruxtecan as a global second-line standard of care for patients with HER2-positive gastric or GEJ cancer and justify further development in the earlier setting,” said Dr. Shitara during a press briefing on May 27, 2025, ahead of the ASCO Annual Meeting.
Kohei Shitara, MD
Pamela Kunz, MD, FASCO
“This study is practice-validating in the United States, given its existing inclusion in guidelines and current use in the second-line setting,” said ASCO expert in gastrointestinal cancers Pamela Kunz, MD, FASCO, Director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center. “It will be practice-changing in many countries outside the United States and will position trastuzumab deruxtecan as a preferred second-line treatment.”
Approximately 5% to 17% of patients with gastric cancer demonstrate HER2 expression in their tumors.3 HER2-targeted therapies have demonstrated significant benefits across tumor types for patients with HER2 positivity, even across expression levels. In the first-line setting, chemotherapy with trastuzumab plus pembrolizumab is recommended for patients with HER2-positive metastatic gastric or gastroesophageal junction cancer if the tumor is PD-L1–positive.4
T-DXd was approved in 2021 as treatment for patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma after prior trastuzumab-based therapy. Benefit for the HER2-directed antibody-drug conjugate in the second-line setting and beyond was proven in the phase II DESTINY-Gastric01 and DESTINY-Gastric02 trials.5,6
Study Design and Key Results
A total of 494 patients from Asia, Europe, and South America who had HER2-positive gastric or gastroesophageal junction adenocarcinoma were enrolled in the study. Patients had to have confirmed HER2 status locally or centrally based on a rebiopsy from after disease progression on prior trastuzumab treatment, and no clinically active central nervous system metastases were permitted. “This may have implications on timing of rebiopsy, as we implement this in the real-world setting,” commented Dr. Kunz, as she pointed out that HER2 expression can be lost after treatment with trastuzumab.
The patients were randomly assigned equally to receive either 6.4 mg/kg of T-DXd every 3 weeks or 8 mg/kg of ramucirumab every 2 weeks and weekly paclitaxel at 80 mg/m2. Patients were stratified by HER2 status of 3+ on immunohistochemistry (IHC) or IHC 2+/in situ hybridization–positive.
The median overall survival with T-DXd was 14.7 months compared with 11.4 months with ramucirumab plus paclitaxel (hazard ratio [HR] = 0.70; 95% confidence interval [CI] = 0.55–0.90; P = .0044). At 12 months, the overall survival rates were 57.6% with T-DXd and 48.9% with ramucirumab plus paclitaxel; at 24 months, the rates were 29.0% and 13.9%, respectively.
Median progression-free survival was 6.7 months in the T-DXd arm compared with 5.6 months in the ramucirumab and paclitaxel arm (HR = 0.74; 95% CI = 0.59–0.92; P = .0074). The 1-year progression-free survival rate was 22.9% in the T-DXd arm vs 13.6% in the ramucirumab plus paclitaxel arm.
A difference of 15% was seen in terms of response rate with the antibody-drug conjugate, with a confirmed objective response rate of 44.3% (95% CI = 37.8%–50.9%) compared with 29.1% (95% CI = 23.4%–35.3%) with ramucirumab and paclitaxel (P = .0006). The median duration of response was 7.4 months (95% CI = 5.7–10.1 months) with T-DXd vs 5.3 months (95% CI = 4.1–5.7 months) with ramucirumab and paclitaxel.
The overall disease control rate was 91.9% (95% CI = 87.7%–95.1%) in the T-DXd arm vs 75.9% (95% CI = 70.0%–81.2%) in the ramucirumab and paclitaxel arm. Best overall responses in the T-DXd arm included 7 complete responses and 97 partial responses; 112 patients had stable disease, and 13 had progressive disease. In the ramucirumab and paclitaxel arm, there were 3 complete responses and 66 partial responses; 111 patients had stable disease, and 22 had progressive disease.
Similar rates of drug-related grade 3 or higher treatment-emergent adverse events, serious events, treatment discontinuations, and deaths were observed between the two treatment arms. In the ramucirumab and paclitaxel arm, common adverse events included fatigue, myelosuppression, peripheral neuropathy, and hypertension. Interstitial lung disease or pneumonitis was reported in 13.9% of patients in the T-DXd arm compared with 1.3% in the ramucirumab and paclitaxel arm, but most events were reported to be low grade, and no events reached grade 4 or 5.
Going forward, Dr. Shitara and colleagues are investigating the front-line use of T-DXd with pembrolizumab and chemotherapy compared with trastuzumab and pembrolizumab with chemotherapy in metastatic HER2-positive gastric or gastroesophageal junction cancer in the ongoing phase III DESTINY-Gastric05 trial.7
DISCLOSURE: Funding for this study was provided by Daiichi Sankyo, which has an ongoing collaboration agreement with AstraZeneca for T-DXd. Dr. Shitara reported financial relationships with AbbVie, Amgen, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda, and Janssen. Dr. Kunz has received institutional research funding from RayzeBio and Novartis.
REFERENCES
1. Shitara K, et al: 2025 ASCO Annual Meeting. Abstract LBA4002. Presented May 31, 2025.
2. Shitara K, et al: N Engl J Med. May 31, 2025 (early release online).
3. Van Cutsem E, et al: Gastric Cancer 18:476-484, 2015.
4. ESMO: First-line for HER2-positive. ESMO Living Guideline: Gastric Cancer. Posted September 2024. Available at https://www.esmo.org/guidelines/living-guidelines/esmo-living-guideline-gastric-cancer/metastatic-disease/first-line-for-her2-positive. Accessed May 27, 2025.
5. Shitara K, et al: N Engl J Med 382:2419-2430, 2020.
6. Van Cutsem E, et al: Lancet Oncol 24:744-756, 2023.
7. Shitara K, et al: 2025 ASCO Annual Meeting. Abstract TPS4207.
