Researchers used NFE2L2 and KEAP1 mutation status to evaluate real-world survival outcomes and treatment patterns in patients with advanced squamous cell NSCLC. A retrospective analysis utilized a de-identified US-based clinico-genomic database from January 2011 to December 2018. Adults with advanced squamous cell NSCLC with greater than or equal to 2 in-network visits and thorough genetic profiling were included in the study. Investigators looked at real-world progression-free survival (rwPFS) by therapeutic line and overall survival (OS). Anti-PD-1/PD-L1 first-line therapy was also tested in patients with NFE2L2 and KEAP1 mutations in the real world. NFE2L2 and KEAP1 mutations were found in 31.6% of the 703 individuals (median age: 70.0 years). Platinum-based chemotherapies and anti-PD-1/PD-L1 therapies were the most common first- and second-line treatments, independent of mutation status. In individuals with an NFE2L2 and KEAP1 mutation, anti-PD-1/PD-L1 therapy was the most common third-line treatment, followed by single-agent chemotherapy in patients with wild-type illness. Patients with an NFE2L2 and KEAP1 mutation had a substantially shorter rwPFS (4.54 vs. 6.25 months; P=.003) and a considerably shorter median OS (13.59 vs. 17.37 months; P=.4105) than patients with wild-type illness. Patients with an NFE2L2 and KEAP1 mutation who received first-line anti-PD-1/PD-L1 medicines outlived those who received other therapy. Real-world survival was poor in patients with advanced squamous cell NSCLC who had an NFE2L2 and KEAP1 mutation, underscoring the necessity for a genotype-directed therapy strategy in the population. NFE2L2 and KEAP1 mutations were linked to a poor prognosis in non-small cell lung cancer (NSCLC). The study group used a clinico-genomic database to conduct a retrospective analysis to investigate real-world survival outcomes and treatment trends among patients with NFE2L2/KEAP1+ advanced squamous cell NSCLC. The results showed poor real-world survival in this population, indicating the necessity for a genotype-directed therapy strategy.