Improved Survival with Trastuzumab Deruxtecan in Patients with HER2-Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: DESTINY-Gastric01

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The open-label, multicenter, randomized, phase 2 DESTINY-Gastric01 trial demonstrated overall survival (OS) benefit with the novel antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in patients with HER2-positive advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). Updated efficacy and safety results including final OS analysis were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The study enrolled adult patients with locally advanced or metastatic, centrally confirmed HER2-positive (immunohistochemistry [IHC]3-positive or IHC2-positive/in situ hybridization-positive on archival tissue) GC or GEJC that had progressed after ≥2 previous lines of therapy that must have included fluoropyrimidine and a platinum agent. Eligible patients were randomized (2:1) to receive T-DXd (6.4 mg/kg every 3 weeks) or chemotherapy (physician’s choice [PC] of irinotecan or paclitaxel). Stratification was by country, Eastern Cooperative Oncology Group performance status (0 or 1), and HER2 status. The primary end point was overall response rate (ORR) by independent central review; key secondary end points were OS, duration of response (DOR), progression-free survival, disease control rate (DCR), confirmed ORR, and safety. Data cutoff date was June 3, 2020.

A total of 187 patients were enrolled in the study; of these, 125 patients received T-DXd and 62 received chemotherapy (irinotecan, n = 55; paclitaxel, n = 7). Demographics and clinical characteristics were well-balanced; in the T-DXd cohort, 79.7% of patients were Japanese and 20.3% were Korean. In both groups, the majority of patients were male; the primary site was gastric; patients had had a median of 2 prior lines of therapy (all had received trastuzumab); and 8% of T-DXd and 0% of PC chemotherapy patients remained on treatment.

At a median follow-up of 18.5 months (133 OS events, 71.1% maturity), OS was significantly improved with T-DXd therapy compared with PC chemotherapy (median OS, 12.5 vs 8.9 months; hazard ratio, 0.60; 95% confidence interval, 0.42-0.86), with a 12-month OS of 52.2% versus 29.7%, respectively. Patients treated with T-DXd therapy achieved a significantly higher ORR compared with patients treated with PC chemotherapy (51.3% vs 14.3%; P <.0001); 11 complete responses and 50 partial responses were achieved in the T-DXd group compared with 8 partial responses in the PC chemotherapy group. Compared with the patients treated with chemotherapy, those treated with T-DXd achieved a significantly higher confirmed ORR (42.0% vs 12.5%; P = .0001), DCR (85.7% vs 62.5%; P = .0005), and confirmed median DOR (12.5 vs 3.9 months).

Grade ≥3 adverse events (AEs) were higher in the T-DXd group compared with the PC chemotherapy group (85.6% vs 56.5%); the most common grade ≥3 AEs in the T-DXd group compared with the chemotherapy group were a decrease in neutrophil count (51.2% vs 24.2%), anemia (38.4% vs 22.6%), and a decrease in white blood cell count (20.8% vs 11.3%). T-DXd–related interstitial lung disease/pneumonitis occurred in 16 (12.8%) patients, most of which were grade 1/2; there were 2 grade 3 and 1 grade 4 cases of interstitial lung disease reported.

These results indicate that with additional follow-up, T-DXd therapy continued to demonstrate OS benefit and clinically relevant improvement in ORR versus chemotherapy accompanied by a manageable safety profile, in previously treated HER2-positive advanced GC or GEJC.

Source

Yamaguchi K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2–positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01). Presented at: 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 20-22, 2022. Abstract 242.

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