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Trastuzumab Deruxtecan vs Chemotherapy for Previously Treated Patients With HER2-Positive Advanced Gastric Cancer


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Results of the phase II DESTINY-Gastric01 study—reported at the ASCO20 Virtual Scientific Program (Abstract 4513) and published in The New England Journal of Medicine, by Kohei Shitara, MD, of the National Cancer Center Hospital East, Kashiwa, and colleagues—found that the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) improved objective response rate and overall survival vs physician’s choice of chemotherapy in patients with HER2-positive advanced gastric or gastroesophageal carcinoma who had received at least two prior therapies, including trastuzumab.

Kohei Shitara, MD

Kohei Shitara, MD

Study Details

In the open-label trial, 187 patients from sites in Japan and South Korea were randomly assigned 2:1 between November 2017 and May 2019 to receive T-DXd at 6.4 mg/kg every 3 weeks (n = 125) or physician’s choice of chemotherapy (n = 62), consisting of irinotecan at 150 mg/m2 every 2 weeks (n = 55) or paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks (n = 7). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate on independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.

Response and Survival

Objective response was observed in 51% of patients in the T-DXd group vs 14% of the physician’s choice group (P < .001), including complete response in 9% vs 0%. An additional 35% vs 48% of patients had stable disease. Confirmed objective response—defined as complete or partial response confirmed on follow-up scan at least 4 weeks after initial response—was observed in 43% vs 12%. Median duration of confirmed objective response was 11.3 months vs 3.9 months.

KEY POINTS

  • Trastuzumab deruxtecan was associated with a significantly higher objective response rate vs physician’s choice of chemotherapy.
  • Median overall survival was 12.5 vs 8.4 months.

Median overall survival was 12.5 vs 8.4 months (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.39–0.88, P = .01, crossing the prespecified boundary of P =.0202 for significance), with 6- and 12-month rates of 80% vs 66% and 52% vs 29%. Median progression-free survival was 5.6 months vs 3.5 months (HR = 0.47, 95% CI= 0.31–0.71), with 6- and 12-month rates of 43% vs 21% and 30% vs 0%. Subsequent treatment after discontinuation of study treatment was received by 48% vs 74% of patients.

Adverse Events

The most common grade ≥ 3 adverse events reported in the T-DXd group were decreased neutrophil count (51% vs 24% of physician’s choice group), anemia (38% vs 23%), and decreased white blood cell count (21% vs 11%). Febrile neutropenia occurred in six patients (5%, all grade 3) vs two patients (3%, grade 3 in 1 patient and grade 4 in 1 patient).

Adverse events led to treatment interruption in 62% vs 37% of patients, and to discontinuation in 15% vs 6%. Interstitial lung disease/pneumonitis occurred in 12 patients (10%) in the T-DXd group (grade 1 or 2 in 9 patients and grade 3 or 4 in 3). One treatment-related death was observed, caused by pneumonia in a patient receiving T-DXd.

The investigators concluded, “Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects.”

Disclosure: The study was funded by Daiichi Sankyo. For full disclosures of the study authors, visit nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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