Safety and early efficacy results of a phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2-positive advanced gastric cancer (Ni-HIGH study).
Authors: Takahari Daisuke , Shoji Hirokazu , Minashi Keiko , Hara Hiroki , Chin Keisho , Oki Akira , Ogura Mariko , Nakayama Izuma , Kato Ken , Iwasa Satoru , Hirano Hidekazu , Amanuma Yusuke , Ishizuka Naoki , Boku Narikazu , Yamaguchi Kensei 
Published: January 2022

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Background: Addition of an anti-PD-1 antibody to trastuzumab reportedly enhances ADCC activity of trastuzumab, leading to an additive antitumor effect. In the KEYNOTE-811 study, pembrolizumab in combination with trastuzumab plus chemotherapy resulted in a durable response. We investigated the safety and tolerability of nivolumab plus trastuzumab combined with S-1 or capecitabine (Cape) and oxaliplatin (Ox) for patients (pts) with HER2-positive advanced gastric cancer (AGC). The safety parts of this study have already shown that there are no safety concerns (Takahari, et al. ASCO-GI 2021). Methods: This study is an open-label, non-randomized phase 1b study conducted at four centers in Japan to confirm the tolerability of addition of nivolumab to chemotherapies with trastuzumab in safety part (n = 12) followed by assessing their efficacy in expansion part (n = 30). Chemotherapy-naïve adult pts with histologically confirmed HER2-positive AGC who had measurable lesions were eligible. Pts received nivolumab (360 mg/body, day 1) and trastuzumab (cycle 1: 8 mg/kg; cycle 2–: 6 mg/kg, day 1), Ox (130 mg/m2, day 1) in combination with 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. Initial eligible 12 pts for safety part were enrolled alternatively to cohort 1 or 2, and patients for expansion part were allocated to either cohort by investigators’ choice up to 21 patients in each cohort. Safety and short-term efficacy data during 8 cycles (6 months) were assessed for this presentation. Results: Between November 2018 and January 2021, a total of 42 pts with HER2-positive AGC were enrolled (21 pts in each cohort). As of July 31, 2021, 29 pts discontinued protocol treatment and the rest 13 pts are still on treatment. Of the 29 pts, only 3 pts (10.3%)discontinued the treatment due to adverse event (AE). AE (≥ G3) occurred in 25 pts (59.5%) including neutropenia in 8 pts (19.0%) and diarrhea in 4 pts (9.5%). Immune-related AEs (≥ G3) occurred in 7 pts (16.6%) including diarrhea/colitis in 4 pts (9.5%). Median relative dose intensity was 100%, 78%, 73%, 75%, and 75% for nivolumab, trastuzumab, Ox, S-1, and Cape, and the percentage of dose reduction or discontinuation within initial 8 cycles were 33%, 33%, 79%, 81%, and 81%, respectively. The ORR was 76.2% (95% CI 60.6-86.9, CR 4.8%, PR 71.4%), and the DCR was 97.6%. Conversion surgery was performed in 2 pts (4.8%). 6-month PFS rate was 68.7% (95% CI 51.7-81.3). Subset results by the cohorts will be presented at the conference. Conclusions: Nivolumab, trastuzumab and either S-1 or Cape plus Ox was tolerable and showed acceptable safety and promising early efficacy results in pts with HER2-positive AGC. Clinical trial information: UMIN000034222.