Background: The genomic determinants of response to PD-1/PD-L1 axis blockade in non-squamous NSCLC are incompletely understood. We previously identified STK11/LKB1 alterations as a major genomic driver of low tumor cell PD-L1 expression and primary resistance to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma. A critical unanswered question is whether STK11/LKB1 alterations predict for lack of response to PD-1/PD-L1 blockade independently of PD-L1 expression. Here, we report the impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors in PD-L1-positive non-squamous NSCLC. Methods: 66 patients with non-squamous NSCLC treated with PD-1/PD-L1 inhibitors at MDACC (61% pembrolizumab, 24% nivolumab, 8% atezolizumab, 5% durvalumab/tremelimumab) with available STK11/LKB1 NGS-based genomic profiling and positive tumor cell PD-L1 expression (≥1%, based on the FDA-approved 22C3 pharmDx assay) were identified retrospectively. Response assessment was based on RECIST1.1. Results: In this PD-L1-positive population of non-squamous NSCLC, STK11/LKB1 alterations were associated with significantly lower ORR to PD-1/PD-L1 blockade compared to tumors with intact STK11/LKB1 status (ORR 0% versus 34.5%, P = 0.026). STK11/LKB1-mutant tumors exhibited significantly shorter progression-free survival (mPFS 1.7 months versus 19.3 months, HR 4.76, 95% CI 2.0-11.1, P = 0.00012, log-rank test) and overall survival (mOS 11.1 months versus 26.5 months, HR 14.3, 95% CI 3.4-50.0, P < 0.0001, log-rank test) with PD-1/PD-L1 blockade. Although fewer STK11/LKB1-mutant tumors expressed high (≥50%) levels of PD-L1 (45.5% versus 61.8%), the difference did not reach statistical significance (P = 0.5). Conclusions:STK11/LKB1 genomic alterations are associated with de novo resistance to PD-1/PD-L1 inhibitors even among PD-L1-positive non-squamous NSCLC patients, suggesting that their effect is at least partially independent of PD-L1 expression. Evaluation of STK11/LKB1 genomic status may enhance the predictive utility of a composite PD-1/PD-L1-inhibitor predictive biomarker panel incorporating PD-L1 expression and TMB.