Clinical Outcomes Associated with Single STK11 Mutations and Those Co-occurring with KEAP1 and KRAS Mutations in Metastatic Non-Small Cell Lung Cancer

Tumors with STK11 mutations and those co-occurring with KEAP1 and KRAS mutations commonly occur in patients with metastatic non-small cell lung cancer (mNSCLC). However, real-world evidence on the associated clinical outcomes is limited. This study assessed real-world progression-free survival (rwPFS) and overall survival (rwOS) among patients with mNSCLC and STK11 (co)-mutations. Adults (≥ 18 years old) diagnosed with de novo stage IV mNSCLC in the USA were identified from the Flatiron Clinico-Genomic Database. The frequencies of STK11 mutation and KEAP1 and KRAS co-mutations were reported. Time-to-event outcomes from mNSCLC diagnosis, including rwPFS and rwOS, were analyzed using Kaplan–Meier estimates and 95% confidence intervals (CIs). Multivariable Cox proportional hazards models assessed associations between STK11 (co)-mutations and rwOS. Among 4392 patients with de novo mNSCLC, the frequencies of STK11 mutation and co-mutations in KEAP1, KRAS, and both KEAP1 and KRAS were 16.1%, 6.4%, 8.5%, and 3.7%, respectively. Compared with patients without these mutations, median rwOS was shorter in patients with STK11 mutation (8.6 vs. 12.8 months) and with co-mutations in KEAP1 (6.6 vs. 12.5 months), KRAS (10.1 vs. 12.5 months), and both KEAP1 and KRAS (5.2 vs. 12.5 months). The adjusted risk of mortality was higher in patients with STK11 co-mutations in KEAP1 (hazard ratio [HR] 1.68; 95% CI 1.29, 2.18), KRAS (HR 1.44; 95% CI 1.17, 1.76), and both KEAP1 and KRAS (HR 2.33; 95% CI 1.87, 2.90), compared with those without these mutations. Similar increased mortality risks associated with STK11 co-mutations occurred in patients with PD-L1 tumor proportion score ≥ 1% and non-squamous histology. STK11 mutations with KEAP1 or KRAS co-mutations are associated with significantly worse survival outcomes in mNSCLC compared with patients without these co-mutations. These findings underscore the urgent need for targeted therapies to improve prognosis in this high-risk population. This study examines the effect of STK11 mutation and its co-occurrence with KEAP1 and KRAS mutations on the survival of patients with metastatic non-small cell lung cancer (mNSCLC). We used data from the Flatiron Clinico-Genomic Database to identify adults in the USA who were newly diagnosed with mNSCLC. We evaluated the frequencies of STK11 mutation and co-occurring KEAP1 and KRAS mutations in patients with mNSCLC. To understand the impact of these mutations on patient outcomes, we assessed time to death and disease progression from the time of mNSCLC diagnosis. We also explored the relationship between these mutations and overall survival. We included 4392 patients who were newly diagnosed with mNSCLC, and 16.1% of them had STK11 mutations. Co-occurrence of STK11 with KEAP1, KRAS, and both KEAP1 and KRAS mutations was observed in 6.4%, 8.5%, and 3.7% of the patients, respectively. The results showed that patients with STK11 mutations, either alone or in combination with the other mutations, had shorter survival times compared with those without these mutations. This trend remained consistent among patients with specific tumor characteristics, such as programmed death-ligand 1 tumor proportion score ≥ 1% and non-squamous mNSCLC histology. STK11 gene mutations and co-mutations are linked to poorer survival outcomes.