Trastuzumab Deruxtecan in Anti–Human Epidermal Growth Factor Receptor 2 Treatment–Naive Patients With Human Epidermal Growth Factor Receptor 2–Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial

Author(s): Kensei Yamaguchi, MD1;Yung-Jue Bang, MD, PhD2;Satoru Iwasa, MD3;Naotoshi Sugimoto, MD4;Min-Hee Ryu, MD, PhD5;Daisuke Sakai, MD6;Hyun Cheol Chung, MD, PhD7;Hisato Kawakami, MD, PhD8;Hiroshi Yabusaki, MD9;Jeeyun Lee, MD10;Tatsu Shimoyama, MD11;Keun-Wook Lee, MD, PhD12;Kaku Saito, MSc, MBA13;Yoshinori Kawaguchi, MSc, MBA13;Takahiro Kamio, MD13;Akihito Kojima, MSc14;Masahiro Sugihara, PhD14;and Kohei Shitara, MD15
Source: DOI: 10.1200/JCO.22.00575 Journal of Clinical Oncology
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

Her2-low is here to stay. Expect further studies on Enhertu and Trodelvy for gastroesophageal Her-2 low patients. Response rates were modest however, so temper expectations as single agent therapy. I look forward to trials on future combination therapy.


To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)–low gastric or gastroesophageal junction (GEJ) adenocarcinoma.


Patients with locally advanced or metastatic HER2-low (cohort 1, immunohistochemistry 2+/in situ hybridization–negative; cohort 2, immunohistochemistry 1+) gastric/GEJ adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 therapy naive, received T-DXd 6.4 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate by independent central review.


Among 21 patients enrolled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received T-DXd, and had measurable tumors at baseline. The confirmed objective response rate was 26.3% (95% CI, 9.1 to 51.2) from five partial responses in cohort 1 and 9.5% (95% CI, 1.2 to 30.4) from two partial responses in cohort 2. Thirteen patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumor size. The median overall survival was 7.8 months (95% CI, 4.7 to nonevaluable) in cohort 1 and 8.5 months (95% CI, 4.3 to 10.9) in cohort 2; the median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively. The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient in each cohort (grade 1 or 2). No drug-related deaths occurred.


This study provides preliminary evidence that T-DXd has clinical activity in patients with heavily pretreated HER2-low gastric/GEJ adenocarcinoma.

Author Affiliations

1Gastroenterological Chemotherapy Department, The Cancer Institute Hospital of JFCR, Tokyo, Japan;2Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea;3Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan;4Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan;5Department of Oncology, Asan Medical Center, Seoul, South Korea;6Department of Frontier Science for Cancer and Chemotherapy, Osaka University Hospital, Osaka, Japan;7Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea;8Department of Medical Oncology, Kindai University Hospital, Osaka, Japan;9Department of Medical Oncology, Niigata Cancer Center Hospital, Niigata, Japan;10Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, South Korea;11Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan;12Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea;13Daiichi Sankyo, Inc, Basking Ridge, NJ;14Daiichi Sankyo, Tokyo, Japan;15Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

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