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

4525 Background: Addition of an anti-PD-1 antibody to trastuzumab (Tmab) reportedly enhances ADCC activity of Tmab, leading to an additive antitumor effect. We investigated the safety and tolerability of nivolumab (Nivo) plus Tmab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for pts with HER2-positive (+) advanced gastric cancer (AGC). Here, we report the safety evaluation results. Methods: This open-label, phase 1b study was conducted at four centers in Japan. The study consisted of safety (n = 12) and expansion (n = 24–30) parts. Chemotherapy-naïve pts aged ≥ 20 years with histopathologically confirmed HER2+ AGC and measurable lesions were eligible. In the safety evaluation, pts were assigned to cohort 1 or 2 in sequence. Pts received Nivo (360 mg, day 1), Tmab (course 1: 8 mg/kg; course 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) and either S-1 (40 mg/m2 bid, days 1–14; cohort 1) or Cape (1000 mg/m2 bid, days 1–14; cohort 2) every 3 weeks until disease progression or unacceptable toxicity. The primary purpose of the safety evaluation was to determine the toxicity and tolerability of this combination therapy. An independent data and safety monitoring committee assessed the tolerability of the study treatments before starting the second treatment course. A preliminary evaluation of tumor response on the cut-off date (December 16, 2019) was also performed. Results: From November 2018 to August 2019, 12 pts with HER2+ AGC were enrolled in the safety part (six pts each in cohorts 1 and 2). During the 1st course, all 12 pts experienced at least one adverse event (AE). The most common AEs were peripheral sensory neuropathy (PSN) (n = 4) and leukocytopenia (n = 3) in cohort 1 and PSN (n = 5) and anorexia (n = 4) in cohort 2. AEs of grade ≥ 3 were observed in only one pt in cohort 1 (grade 3 neutropenia). No pt suspended or discontinued study treatments due to AEs. One pt in cohort 1 reduced dose of S-1 due to grade 2 erythema and continued the subsequent courses with the dose. After a median follow-up of 6.1 (range, 3.1–13.3) months, one pt from cohort 1 achieved a complete response, eight pts (four in each cohort) achieved a partial response, and three pts (one in cohort 1 and two in cohort 2) showed stable disease. No progressive disease was observed. Conclusions: Both Nivo plus Tmab and either S-1 or Cape plus Ox are tolerable in pts with HER2+ AGC. Both cohorts 1 and 2 have progressed to the expansion part of the study. Clinical trial information: 000034222 .