158P A phase II study of trastuzumab with S-1 plus oxaliplatin for HER2-positive advanced gastric cancer (HIGHSOX study): Final report

We previously reported that trastuzumab (Tmab) combined with S-1 plus oxaliplatin (SOX) exhibited promising activity with well-tolerated toxicities in patients (pts) with human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) (Gastric Cancer 2019). Here, we report the results of a follow-up extension, including exploratory analyses performed to investigate predictive factors for treatment effects. We conducted an open-label, phase II trial in pts with chemo-naïve, HER2-positive AGC. Pts received S-1 (40 mg/m2) BID orally on days 1–14, oxaliplatin (130 mg/m2) intravenously on day 1, and Tmab (course 1, 8 mg/kg; course 2, 6 mg/kg) intravenously on day 1 of a 21-day cycle. The primary endpoint was objective response rate (ORR); secondary end points included overall survival (OS), progression-free survival (PFS), and adverse events. A sample of 75 provided the study with 90% power to test a hypothesis of threshold RR of 50% and an expected RR of 65% at a one-sided significance level of 0.05 using the binomial test. Seventy-five patients were enrolled from June 2015 to January 2018. Pts characteristics were previously reported. In the full analysis set of 75 pts with a median follow up of 20.6 months, ORR was 70.7% (95% confidence interval (CI): 59.0–80.6) and the disease control rate was 93.3% (95% CI: 85.1–97.8). OS and PFS (median) were 20.6 (95% CI: 15.9–29.2) and 8.8 (95% CI: 7.3–11.8) months, respectively. In the exploratory analyses, both OS and PFS were longer in pts with HER2 3+ (n=55) than in pts with 2+ (n=20) [OS, 25.9 vs.16.3 months; hazard ratio (HR), 0.59; 95% CI: 0.329–1.053; P=0.07; PFS, 9.8 vs. 7.0 months; HR, 0.72; 95% CI: 0.421–1.229; P=0.23]. Pts who underwent conversion surgery (n=8) exhibited dramatically prolonged survival [OS, not reached; 3-year survival rate, 85.7% (95% CI: 33.4–97.9), PFS, 34.5 months (95% CI: 6.9–not reached)]. Tmab in combination with SOX exhibited promising therapeutic effects in pts with HER2-positive AGC. Efficacy was enhanced in pts with HER2 3+ and in those who underwent conversion surgery.