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

Background

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.

Methods

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.

Results

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)].

Conclusions

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.

Clinical trial identification

UMIN000017602.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Japanese Foundation for Multidisciplinary Treatment of Cancer.

Disclosure

A. Takashima: Honoraria (self), Research grant/Funding (self): Taiho; Honoraria (self), Research grant/Funding (self): Takeda; Honoraria (self): Eli Lilly; Honoraria (self): Ono; Honoraria (self): Yakult; Honoraria (self): Chugai; Research grant/Funding (self): Sumitomo Dainippon; Research grant/Funding (institution): LSK BioPartners. K. Minashi: Research grant/Funding (institution): MSD; Research grant/Funding (institution): Ono. S. Kadowaki: Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Ono; Research grant/Funding (institution): BMS; Honoraria (self): Yakult; Honoraria (self): Chugai; Honoraria (self): Bayer; Honoraria (self): Merck. T. Nishina: Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Eli Lilly; Honoraria (self), Research grant/Funding (institution): Ono; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self), Research grant/Funding (institution): Chugai; Honoraria (self), Research grant/Funding (institution): Yakult; Honoraria (self): Daiichi Sankyo; Honoraria (self): Dainippon Sumitomo; Honoraria (self): Boehringer Ingelheim; Honoraria (self): MSD. K. Amagai: Honoraria (self), Research grant/Funding (institution): Taiho; Research grant/Funding (institution): MSD; Honoraria (self): Eli Lilly; Honoraria (self): BMS; Honoraria (self): Yakult; Honoraria (self): Chugai; Honoraria (self): Daiichi Sankyo; Honoraria (self): Hisamitsu. N. Machida: Honoraria (self), Research grant/Funding (self): Taiho; Honoraria (self): Eli Lilly ; Honoraria (self): Ono; Honoraria (self): BMS; Honoraria (self): Yakult; Honoraria (self): Chugai; Honoraria (self): Nippon Kayaku; Honoraria (self): Daiichi Sankyo; Honoraria (self): MSD. M. Goto: Honoraria (self): Taiho; Honoraria (self): Yakult; Honoraria (self): Chugai; Honoraria (self): Ono; Honoraria (self): Takeda; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Novartis; Honoraria (self): Bayer; Honoraria (self): Mochida. N. Ishizuka: Honoraria (self): BMS; Honoraria (self): Novartis; Honoraria (self): MSD. D. Takahari: Honoraria (self), Research grant/Funding (institution): Taiho; Honoraria (self), Research grant/Funding (institution): Ono; Honoraria (self): Eli Lilly; Honoraria (self): BMS. All other authors have declared no conflicts of interest.