A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2 positive advanced gastric cancer (Ni-HIGH study).

Abstract

TPS177 Background: Trastuzumab (Tmab) with cisplatin and fluoropyrimidines improved the overall survival (OS) of patients (pts) with HER2 (+) advanced gastric cancer (AGC). Nivolumab (Nivo) is an anti-programmed cell death-1 (PD-1) antibody that demonstrated a survival benefit as third line or later of AGC. To date, most trials investigating anti-PD-1 antibody for 1st line treatment focus on HER2 (-) AGC. In HER2(+) breast cancer mouse model, combining Tmab with anti-PD-1 antibody was reported to enhance ADCC activity of Tmab, and show greater tumor regression. In our data, the PD-L1 expression was observed in 44% of tumor cells and 70% of immune cells in human HER2(+) AGC. Based on these data, we have plannedthis phase Ib investigator-initiated trial to investigate the safety and tolerabirity of Nivo plus Tmab and either S-1 or capecitabine (Cape) plus Oxaliplatin (Ox) for pts with HER2(+) AGC. Methods: Histopathologically confirmed HER2(+) AGC with mesurable lesions, aged > 20 years, chemo-naïve pts are enrolled in this study. Pts receive Nivo (360 mg/body; day 1) plus Tmab (course1, 8 mg/kg; course 2 onward, 6 mg/kg; day 1) and either S-1 (40 mg/m2 bid d1-14; cohort 1) or Cape (1000 mg/m2 bid d1-14; cohort 2) plus Ox (130 mg/m2; day 1) every three weeks until desease progression or unacceptable toxicity. In the primary part, six pts for each cohort will be assessed for tolerability.To estimate the objective response rate (ORR) in the analysis-set, on our hypothesis that a true response rate is 80%, 20 pts are required for the 90% C.I. to be ± 20%. Therefore the expansion part for each cohort will be 12-15 pts. Primary endpoint is safety. Secondary endpoint is tolerability and exploratory endpoints include ORR, disease control rate, progression free survival and OS. Collaborative biomarker analysis includes whole exome sequences, RNA sequences, gut microbiome, and IHC using biopsy specimens. In addition, T-cell repartry, circulating tumor DNA and exomes will be also analyzed using blood obtained during treatment. This study just has been initiated at four sites in Japan. Clinical trial information: UMIN000034222.