Background: Immune checkpoint inhibitors (nivolumab and pembrolizumab) have clear activity in EGC. However, benefit is modest in an unselected population. TMB may be of value as a quantitive marker to identify patients (pts) with durable benefit from immunotherapy (Cancer Discov 2018 Jan;8(1):49-58). We present updated data from an expanded cohort, including irAEs and abx use as determinants of pt outcomes. Methods: All pts treated with anti-CTLA-4, PD-1 or PD-L1 Abs were identified. Outcomes were correlated with TMB by MSK-IMPACT NGS panel of up to 468 genes and clinical variables, including irAEs and abx use. The third quartile of TMB was used as the cut-off. Progression-free (PFS) and overall survival (OS) were calculated from the start of immunotherapy. Results: Of 120 pts (110 adenoCs, 10 SCC), 90% had received ≥2 prior chemo regimens, 6 received ≥2 IO regimens. 66 (55%), 17 (14%) and 37 (31%) pts respectively received anti-PD-1, anti PD-L1 and anti-CTLA-4 plus anti-PD-1/PD-L1 Abs. The median PFS and OS were 1.8 and 5.9 mos; 2-yr OS 19%; objective response rate of 13% (n = 15, 7 PRs, 8 CRs). In IMPACT tested tumors, excluding low purity samples (n = 62), a TMB cut-off of ≥7.4 mut/Mb stratified TMB-low vs -high pts (46 vs 16), with a trend toward improved OS in the TMB-high group (27.1 vs 8.4 mos, p = 0.063). 7 of 7 dMMR pts were TMB-high. In 41 pts (34%) treated with abx during immunotherapy (and 1 month prior), there was a significant improvement in PFS (3.3 vs 1.6 mos, p = 0.04) vs those who were not; with no difference in OS (7.3 vs 4.7 mos, p = 0.23). irAEs occurred in 36 pts (30%) and were associated with improved OS (18.2 vs 3.7 mos, p < 0.0001), irrespective of AE grade. OS (12.7 vs 4.2 mos, p = 0.034) was improved even in pts where irAEs occurred ≤8 weeks from start of immunotherapy. The median PFS and OS in 36 pts (30%) who received chemo following progression were 4.3 and 7.7 mos. Conclusions: A TMB of 7.4 may serve as a cut-off to identify EGC pts more likely to benefit from immunotherapy. Abx use did not negatively impact outcomes and occurrence of irAEs was associated with improved OS. Outcomes for post-immunotherapy chemo appear promising in these heavily treated pts.