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Efficacy and Safety of Trastuzumab Deruxtecan in Exploratory Cohorts of Patients with HER2-Low Gastric or Gastroesophageal Junction Adenocarcinoma

Exploratory cohort results from a phase II study in patients who had not received previously anti-HER2 treatment
23 Nov 2022
Targeted Therapy
Gastric Cancer;  Gastro-Oesophageal Junction Cancer

In a phase II study, an antibody-drug conjugate, trastuzumab deruxtecan demonstrated clinical activity in patients with locally advanced or metastatic HER2–low gastric or gastroesophageal junction adenocarcinoma after progression on at least two previous fluoropyrimidine and platinum-containing regimens. Safety was consistent with the manageable safety profile of trastuzumab deruxtecan. Drug-related interstitial lung disease/pneumonitis is an important risk that requires careful monitoring and management in patients treated with trastuzumab deruxtecan. Efficacy and safety results with trastuzumab deruxtecan in exploratory cohorts of patients with HER2-low gastric or gastroesophageal junction adenocarcinoma who had not received anti-HER2 treatment in DESTINY-Gastric01 were reported by Dr. Kensei Yamaguchi of the Cancer Institute Hospital of Japanese Foundation for Cancer Research in Tokyo, Japan and colleagues on 15 November 2022 in the Journal of Clinical Oncology.

The authors wrote in the background that overexpression or amplification of HER2 occurs in approximately one-fifth of gastric or gastroesophageal junction cancers. HER2 expression levels are heterogeneous within and between tumours and can change after anti-HER2 treatment. The proportion of patients with HER2-low gastric cancer defined as immunohistochemistry (IHC) 2+/ in situ hybridization (ISH)–negative or IHC 1+ is not well documented but estimated at 5.4% or 18.6%. There is an unmet medical need for treatments of HER2-low gastric or gastroesophageal junction cancer.

Trastuzumab deruxtecan improved overall response rate (ORR) and overall survival (OS) versus physician's choice of chemotherapy in patients with HER2-positive gastric or gastroesophageal junction adenocarcinoma who had progressed on a trastuzumab-containing regimen in primary analysis of the DESTINY-Gastric01 study.

Trastuzumab deruxtecan has a drug-to-antibody ratio of approximately 8, and the topoisomerase I inhibitor payload is highly membrane permeable, suggesting it can penetrate neighbouring tumour cells that do not necessarily express HER2 or have low expression. These properties make trastuzumab deruxtecan a potential treatment for patients with HER2-low tumours. Trastuzumab deruxtecan demonstrated antitumour activity in HER2-low cells and mouse xenografts, in a phase I study that included patients with HER2-low breast cancer and one patient with HER2-low gastric cancer, and in phase I and III studies in HER2-low breast cancer.

In the latest article published in the JCO, the authors reported the efficacy and safety of trastuzumab deruxtecan in exploratory cohorts of patients with HER2-low (defined as IHC 2+/ISH– or IHC 1+) gastric or gastroesophageal junction adenocarcinoma who had not received anti-HER2 treatment in DESTINY-Gastric01. Patients with locally advanced or metastatic HER2-low (cohort 1, IHC 2+/ISH–; cohort 2, IHC 1+) gastric or gastrooesophageal junction adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 treatment naive, received trastuzumab deruxtecan 6.4 mg/kg intravenously once every 3 weeks. The primary endpoint was confirmed ORR by independent central review.

Among 21 patients enroled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received trastuzumab deruxtecan, and had measurable tumours at baseline. The confirmed ORR was 26.3% (95% confidence interval [CI] 9.1 to 51.2) from 5 partial responses in cohort 1 and 9.5% (95% CI 1.2 to 30.4) from 2 partial responses in cohort 2. In total, 13 patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumour size.

The median OS was 7.8 months (95% CI 4.7 to non-evaluable) 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).

The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anaemia (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.

The authors concluded that their study provides preliminary evidence that trastuzumab deruxtecan has clinical activity in patients with heavily pretreated HER2-low gastric or gastrooesophageal junction adenocarcinoma. Additional randomised controlled studies in larger cohorts are required to determine the efficacy and safety of trastuzumab deruxtecan in HER2-low gastric or gastrooesophageal junction adenocarcinoma.

The study was in part previously presented at the ESMO 2020 Virtual Congress.

The study was supported by Daiichi Sankyo Co, Ltd and AstraZeneca.


Yamaguchi K, Bang Y-J, Iwasa S, et al. 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. JCO; Published online 15 November 2022. DOI: 10.1200/JCO.22.00575

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