Background: Trastuzumab (T) + chemotherapy (ctx) is standard for 1st line advanced HER2+ GEA, yet subsequent targeted options are lacking. M is an anti-Her 2 monoclonal antibody with an optimized Fc domain to increase affinity for activating CD16A Fc-receptors (FcR) on NK cells. Outcomes for T-treated patients (pts) carrying the low-affinity CD16A-F allele are generally worse than pts homozygous for the high-affinity V allele. M is designed to be FcR genotype independent. Evidence of clinical activity of M alone has been seen in HER2+ GEA pts post T, while P has demonstrated durable activity. Loss of HER2 amplification may occur after T failure in a subset of initially HER2+ GEA pts. Preclinical studies suggest that engagement of innate and adaptive immunity with the combination of anti-HER-2 antibodies and T-cell checkpoint inhibition could achieve greater antitumor activity than either agent alone. Methods: Advanced HER2+, PD-L1-unselected GEA pts post T failure were eligible. Dose escalation evaluated 10 and 15 mg/kg M and 200 mg P for 2^nd line or higher pts. Cohort expansion evaluates safety and objective response rate (ORR) by RECIST v1.1 in 2^nd line pts. M + P is given every 21 days; response assessed every 6 weeks. HER2 amplification status was assessed in a subset of pts by plasma circulating tumor (ct) DNA analysis prior to Cycle 1 of M+P. Results: Dose escalation enrolled 9 pts; cohort expansion 48 pts at 15 mg/kg M: 30 in North America (NA) and 18 in Asia (A). Treatment was well tolerated, with 1 drug-related serious adverse event. Of 38 evaluable pts to date in expansion (24 NA and 14 A), the best overall responses include 7 pts (18.4%) with PR (4 confirmed and 3 unconfirmed) and 11 (28.9%) with SD. Higher ORR trends were observed in A vs NA (35.7% vs 8.3%) and G vs GEJ (31.6% vs 5.3%). Of 25 pts with ctDNA results, HER2 amplification detection was higher in GC than GEJ (80% vs 53%). Responses were independent of FcR genotype; CD16A genotype for evaluable pts with PR: 1 V/V, 2 V/F, 2 F/F with similar allelic distribution among non-responders. Conclusions: M+P is a well-tolerated ctx-free regimen that has shown preliminary antitumor activity in 2^nd line pts with advanced/metastatic GEA. Clinical trial information: NCT02689284