Overall survival benefit with trastuzumab deruxtecan in previously treated HER2-positive gastric cancer
In the final overall survival analysis from the phase II DESTINY-Gastric01 trial, trastuzumab deruxtecan continued to demonstrate an overall survival benefit and a clinically relevant improvement in objective response rate as compared to standard chemotherapy, in patients with previously treated HER2-positive, advanced gastric or gastro-oesophageal junction adenocarcinoma.
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of a humanised, monoclonal, anti-HER2 antibody bound to a cytotoxic topoisomerase I inhibitor (drug payload) by means of a cleavable, tetrapeptide-based linker. Previous results of the DESTINY-Gastric01 trial demonstrated that therapy with T-DXd led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. At ASCO GI 2022, the final OS analysis as well as updated efficacy and safety results of the DESTINY-Gastric01 study were presented.
DESTINY-Gastric01 study design
DESTINY-Gastric 01 is a randomised, phase II trial involving patients with HER2-expressing, locally advanced or metastatic gastric or gastroesophageal junction cancer that had progressed after the patient had received at least two previous regimens, which included a fluoropyrimidine, a platinum agent, and trastuzumab. Patients were excluded if they had, or were suspected of having, interstitial lung disease (ILD) or pneumonitis, or if they had a history of non-infectious ILD or pneumonitis that had been treated with steroids. Patients were randomly assigned in a 2:1 ratio to receive either trastuzumab deruxtecan (6.4 mg/kg Q3W) or the treating physician’s choice (PC) of irinotecan (150 mg/m2 Q2W) or paclitaxel (80 mg/m2 administered on days 1, 8 and 15 Q4W). Patients were stratified by country, ECOG performance status (0, 1), and HER2 status. Treatment continued until disease progression, withdrawal of patient consent, or the occurrence of unacceptable adverse events.
Results
In total, 187 patients were included in the trial, 125 of them received T-DXd, 62 were treated with PC. Median age of study participants was 65 years and all patients were of Japanese (79.7%) or Korean (20.3%) origin. Patients had received a median of two prior lines of systemic therapies for advanced or metastatic disease, 44.4% of patients had received at least three prior lines of treatment. All patients received prior trastuzumab treatment. The objective response rate (ORR) was 51.3% in the T-DXd arm versus 14.3% in the PC arm (p< 0.0001), corresponding rates of complete response were 9.2% and 0% respectively. Confirmed ORR (responses were confirmed by a follow-up scan at least four weeks after initial complete or partial response) were 42.0% vs. 12.5% for the T-DXd and PC arms, respectively. Confirmed disease control rate was 85.7% in the T-DXd arm and 62.5% in the PC arm. The confirmed median duration of response was also longer in the T-DXd arm as compared to the control arm (12.5 vs. 3.9 months). Median time to response was 1.5 months for patients receiving T-DXd and 1.6 months for patients receiving PC. As in the primary analysis, in this updated analysis with a median survival follow-up of 18.5 months, T-DXd demonstrated superior antitumour activity compared to PC. Overall survival was improved with T-DXd as compared to PC, with a median OS of 12.5 vs. 8.9 months (HR[95%
CI]: 0.60[0.42-0.86]). Twelve-month OS rates were respectively 52.2% and 29.7%.
Grade ≥3 adverse events occurred in 85.6% of T-DXd patients vs. 56.5% of patients treated with PC. The most common AEs were decreased neutrophil count (51.2% vs. 24.2%), anaemia (38.4% vs. 22.6%) and decreased white blood cell count (20.8% vs. 11.3%). In total, 16 patients (12.8%) had T-DXd–related ILD or pneumonitis, as determined by an independent adjudication committee. There were two events of grade 3, one of grade 4 and no grade 5 events. Among the 16 total ILD/pneumonitis events, the median time to first onset was 102.5 days. There were no ILD/pneumonitis events in the PC arm. As reported in the primary analysis, there was one T-DXd–related death from pneumonia (non-ILD).
Conclusion
With continued follow-up after the primary analysis, T-DXd demonstrated a clinically meaningful OS benefit and a clinically relevant improvement in ORR as compared with physician’s choice of standard chemotherapy in HER2-positive advanced gastric or GEJ cancer. In addition, the overall safety profile of T-DXd was manageable and consistent with that of the primary analysis. Additional follow-up thus provided evidence that T-DXd is an effective treatment option for patients with HER2+ advanced gastric or GEJ adenocarcinoma who have progressed after at least two previous lines of therapy, including trastuzumab, fluoropyrimidine and a platinum agent.
Reference
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 ASCO GI 2022; Abstract 242.
