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Introduction <p>Tumors with <i>STK11</i> mutations and those co-occurring with <i>KEAP1</i> and <i>KRAS</i> 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 <i>STK11</i> (co)-mutations.</p> Methods <p>Adults (≥ 18&#xa0;years old) diagnosed with de novo stage&#xa0;IV mNSCLC in the USA were identified from the Flatiron Clinico-Genomic Database. The frequencies of <i>STK11</i> mutation and <i>KEAP1</i> and <i>KRAS</i> 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 <i>STK11</i> (co)-mutations and rwOS.</p> Results <p>Among 4392 patients with de novo mNSCLC, the frequencies of <i>STK11</i> mutation and co-mutations in <i>KEAP1</i>, <i>KRAS</i>, and both <i>KEAP1</i> and <i>KRAS</i> were 16.1%, 6.4%, 8.5%, and 3.7%, respectively. Compared with patients without these mutations, median rwOS was shorter in patients with <i>STK11</i> mutation (8.6 vs. 12.8&#xa0;months) and with co-mutations in <i>KEAP1</i> (6.6 vs. 12.5&#xa0;months), <i>KRAS</i> (10.1 vs. 12.5&#xa0;months), and both <i>KEAP1</i> and <i>KRAS</i> (5.2 vs. 12.5&#xa0;months). The adjusted risk of mortality was higher in patients with <i>STK11</i> co-mutations in <i>KEAP1</i> (hazard ratio [HR] 1.68; 95%&#xa0;CI 1.29, 2.18), KRAS (HR 1.44; 95%&#xa0;CI 1.17, 1.76), and both <i>KEAP1</i> and <i>KRAS</i> (HR 2.33; 95%&#xa0;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.</p> Conclusion <p><i>STK11</i> mutations with <i>KEAP1</i> or <i>KRAS</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Firas Dabbous,
  • Mehmet Berktas,
  • Rajrupa Ghosh,
  • Samuel Huse,
  • Ching-Yu Wang,
  • Ashish Gautam,
  • Kazeem Idowu,
  • Daniel Simmons,
  • Puneeth Iyengar

摘要

Introduction

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.

Methods

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.

Results

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.

Conclusion

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.