Hiroshi Yabusaki

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer. METHODS: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety. RESULTS: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group. CONCLUSIONS: 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. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Purpose Intraperitoneal paclitaxel plus systemic chemotherapy demonstrated promising clinical effects in patients with gastric cancer with peritoneal metastasis. We aimed to verify its superiority over standard systemic chemotherapy in overall survival. Patients and Methods This randomized phase III trial enrolled patients with gastric cancer with peritoneal metastasis who had received no or short-term (&lt; 2 months) chemotherapy. Patients were randomly assigned at a two-to-one ratio to receive intraperitoneal and intravenous paclitaxel plus S-1 (IP; intraperitoneal paclitaxel 20 mg/m 2 and intravenous paclitaxel 50 mg/m 2 on days 1 and 8 plus S-1 80 mg/m 2 per day on days 1 to 14 for a 3-week cycle) or S-1 plus cisplatin (SP; S-1 80 mg/m 2 per day on days 1 to 21 plus cisplatin 60 mg/m 2 on day 8 for a 5-week cycle), stratified by center, previous chemotherapy, and extent of peritoneal metastasis. The primary end point was overall survival. Secondary end points were response rate, 3-year overall survival rate, and safety. Results We enrolled 183 patients and performed efficacy analyses in 164 eligible patients. Baseline characteristics were balanced between the arms, except that patients in the IP arm had significantly more ascites. The median survival times for the IP and SP arms were 17.7 and 15.2 months, respectively (hazard ratio, 0.72; 95% CI, 0.49 to 1.04; stratified log-rank P = .080). In the sensitivity analysis adjusted for baseline ascites, the hazard ratio was 0.59 (95% CI, 0.39 to 0.87; P = .008). The 3-year overall survival rate was 21.9% (95% CI, 14.9% to 29.9%) in the IP arm and 6.0% (95% CI, 1.6% to 14.9%) in the SP arm. Both regimens were well tolerated. Conclusion This trial failed to show statistical superiority of intraperitoneal paclitaxel plus systemic chemotherapy. However, the exploratory analyses suggested possible clinical benefits of intraperitoneal paclitaxel for gastric cancer.