An immune checkpoint inhibitor (ICI), pembrolizumab, is approved for third-line treatment of microsatellite stable GEA tumors with PD-L1 expression by combined positivity score (CPS) ≥ 1, although response rate is only 13.3%. Recently, the strategy of ICIs in combination with anti-HER2 antibodies for HER2-amplified tumors has demonstrated efficacy. For GEA tumors harboring other RTK amplifications, such as EGFR, this strategy of dual-target inhibition toward the RTK in combination with ICIs to harness both the innate and adaptive immune systems to potentially overcome resistance mechanisms toward either agent alone may represent an important novel therapeutic strategy. Herein, we report the first case, to our knowledge, of an exceptional response to combination anti-EGFR and anti–PD-1 dual antibody therapy in a patient with chemorefractory GEA harboring EGFR amplification and low-level PD-L1 expression.