Several studies have shown that STK11 and TP53 mutations have different effects on the susceptibility to immune checkpoint blockade in KRAS-mutant non-small cell lung cancer (NSCLC). However, the impact of STK11/TP53 co-mutations on treatment outcomes in the same clinical setting has never been reported. We recently encountered a case of a 70-year-old man who was diagnosed with advanced lung adenocarcinoma with high-programmed death-ligand 1 (PD-L1) expression. He received pembrolizumab monotherapy as a frontline treatment; however, the tumor did not respond to this therapy and showed deleterious outcome. Next-generation sequencing revealed that the tumor harbored a rare STK11/TP53/KRAS triple mutation. Our case suggests that these compound mutations may constitute a distinct, aggressive subset that is resistant to immunotherapy even when the tumor strongly expresses PD-L1. In addition, this report highlights the importance of using molecular profiling to detect co-mutations that can be associated with primary resistance or disease progression to improve survival even in the immunotherapy setting.