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 ASCO 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.
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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