Trastuzumab Deruxtecan Shows Survival Benefit in HER2-Positive Advanced Gastric Cancers

Trastuzumab deruxtecan (Enhertu; T-DXd) continues to show superior antitumor activity and improved survival compared with standard chemotherapy in patients with advanced HER2-expressing gastric or gastroesophageal junction (GEJ) cancer, according to updated results from the phase 2 DESTINY-Gastric01 trial. T-DXd is an antibody–drug conjugate comprising an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor.

With a median follow-up of 18.5 months (71.1% data maturity), median overall survival (OS) was 12.5 months in the T-DXd arm versus 8.9 months in the standard chemotherapy arm (hazard ratio, 0.60; 95% confidence interval, 0.42-0.86), reported lead investigator Kensei Yamaguchi, MD, Department Director, Gastroenterological Chemotherapy, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

“T-DXd demonstrated clinically meaningful OS benefit and clinically relevant improvement in objective response rate [ORR] compared with physician’s choice of standard chemotherapy with continued follow-up,” he said. “This additional follow-up provides further evidence that T-DXd is an effective treatment option for patients with HER2-positive advanced gastric or GEJ adenocarcinoma who have progressed after 2 or more previous lines of therapy, including trastuzumab [Herceptin], a fluoropyrimidine, and a platinum.”

The overall safety profile of T-DXd was manageable, with the most common adverse events being gastrointestinal or hematologic in nature. Sixteen patients had T-DXd–related interstitial lung disease as determined by an independent adjudication committee, most of which were grade 1 or 2. T-DXd is approved with boxed warnings for interstitial lung disease in the United States and Japan.

Study Details

In the open-label, multicenter DESTINY-Gastric01 trial, 187 patients with locally advanced or metastatic, centrally confirmed HER2-positive gastric or GEJ cancer that had progressed after ≥2 previous lines of therapy were randomly assigned in a 2:1 ratio 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 end point was ORR on independent central review using RECIST version 1.1.

Median age was 65.0 years in the T-DXd arm and 66.0 years in the physician’s choice arm. Approximately three-fourths of patients in each arm had HER2 expression by immunohistochemistry. The primary site of cancer was gastric in 86.4% and 88.7% of the 2 arms, respectively, and the primary site was GEJ in 13.6% and 11.3%, respectively. All patients had received previous trastuzumab-containing therapy. Some 20.0% of patients in the T-DXd arm and 9.7% in the physician’s choice arm had received ≥4 previous systemic therapies for advanced or metastatic disease. Overall, approximately one-third of patients had received previous immune checkpoint inhibitor therapy.

In the primary analysis, with a median survival follow-up of 12.3 months (54.0% data maturity), T-DXd showed statistically significant benefit versus standard chemotherapy in terms of ORR and OS.

In the updated analysis, the estimated 6-month OS in the T-DXd arm was 80.1% compared with 65.0% in the physician’s choice arm, and the estimated 12-month OS was 52.2% versus 29.7%, respectively.

An ORR (complete response [CR] or partial response [PR]) by independent central review was achieved by 61% in the T-DXd arm versus 14.3% in the physician’s choice arm (P = .0001). The rate of CR was 9.2% among patients randomized to T-DXd and 0% among those randomized to physician’s choice, and the PR rates were 42.0% and 14.3%, respectively. The rates of confirmed ORR were 42.0 with T-DXd versus 12.5% with physician’s choice (P = .0001), with a confirmed CR rate of 8.4% and 0%, respectively, and a confirmed PR rate of 33.6% and 12.5%, respectively.

The median progression-free survival was 5.6 months with T-DXd versus 3.5 months with physician’s choice (hazard ratio, 0.47; 95% confidence interval, 0.31-0.71).

Grade ≥3 adverse events occurred in 85.6% of T-DXd patients versus 56.5% of physician’s choice patients. The most common grade ≥3 adverse events were a decrease in neutrophil count (51.2% in the T-DXd arm vs 24.2% in the physician’s choice arm), anemia (38.4% vs 22.6%, respectively), and a decrease in white blood cell count (20.8% vs 11.3%, respectively). As reported in the primary analysis, there was 1 T-DXd–related death from pneumonia (non-interstitial lung disease).

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