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

Abstract

Background: Trastuzumab with cisplatin and fluoropyrimidines(FUs) improved the overall survival of patients with human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC). S-1 plus oxaliplatin (SOX) is a one of the standard regimen for HER2-negative AGC especially in Japan. However, to date, few studies have evaluated the efficacy and safety of trastuzumab combined with SOX in patients with HER2-positive AGC. Methods: This is the multi-central, phase II study that is conducted in 10 Japanese institutions. Patients with HER2-positive AGC received S-1 (80mg/m2) twice a day orally on days 1-14, oxaliplatin (130mg/m2) intravenously on day 1, and trastuzumab (course 1, 8mg /kg; course 2-, 6mg/kg) intravenously on day 1 of a 21-day cycle. The primary end point was confirmed response rate (cRR); secondary end points included overall survival (OS), progression-free survival(PFS), and adverse events.The sample size was determined to be 75cases based on a hypothesis of threshold RR of 50% and an expected RR of 65%, 90% power, with an alpha value of 0.1 (one-sided) using the binomial test. Results: From June 2015 to January 2018, a total of 78 patients were screened, of whom 75 were enrolled and eligible. The median age was 64 years. ECOG PS(0/1);57/18, unresectable/ recurrence; 66/9, Gastric/EGJ; 64/11, pathology(tub1/tub2/por/sig); 13/33/24/ 5, metastatic sites(LNs/liver/peritoneum/lung/bone/others); 40/35/20/9/3/8. The proportion of IHC 3+ was 73.3%. In the full analysis set of 75 patients as of March 2018, cRR was 65.2% (95% confidence interval (CI).52.4-76.5); n=66: excluding unconfirmed 9 cases; and the disease control rate was 89.4% (95% CI.79.4-95.6). Median OS, PFS, were estimated as 20.6 (95% CI.14.8-30.6) and 9.4(95% CI.7.4-14.7) months, respectively. Major grade 3 or 4 adverse events included sensory neuropathy (14.7%), neutropenia (9.3%), diarrhea (6.7%), and anemia (6.7%). There were no treatmentrelated deaths. Conclusions: Trastuzumab in combination with SOX showed promising activity with well-tolerated toxicities in patients with HER2-positive AGC as well as other platinum and FUs. Final analysis based on confirmed response will be reported at the conference.