What are the clinical implications of STK11 (Serine/Threonine Kinase 11) or KEAP1 (Kelch-like ECH-associated protein 1) mutations in patients with metastatic Non-Small Cell Lung Cancer (NSCLC), particularly those with a history of smoking and good performance status (0-1)?

Clinical Nuances of STK11 and KEAP1 Mutations in NSCLC

Critical Prognostic Impact

STK11 and KEAP1 mutations in metastatic NSCLC confer aggressive disease biology with significantly shortened overall survival and represent primary resistance markers to immune checkpoint inhibitors, regardless of PD-L1 expression. 1, 2

These mutations occur in approximately 20-30% of patients with metastatic NSCLC and are strongly associated with primary resistance to standard immunotherapy regimens, either alone or combined with chemotherapy 1. Patients with STK11 mutations demonstrate median overall survival of only 4.7-8.6 months compared to 15.9-17.3 months in STK11 wild-type patients when treated with first-line immunotherapy or chemo-immunotherapy 3, 4.

Molecular Context and Co-Mutation Patterns

STK11 Co-Occurring Mutations

• KRAS co-mutation (54% of STK11-mutated cases) creates a particularly aggressive phenotype with enrichment for wound-healing immune subtype and profound immunotherapy resistance 2
• TP53 co-mutation (44% of cases) paradoxically associates with improved immunotherapy benefit compared to STK11/KRAS co-mutation, showing enrichment for IFN-γ immune subtype 2
• CDKN2A co-mutation occurs in 37% of STK11-mutated cases 2
• KEAP1 co-mutation (27% of STK11-mutated cases) compounds treatment resistance across all therapeutic modalities 2

KEAP1 Mutations

• Concurrent STK11 and KEAP1 mutations confer resistance to radiotherapy, immunotherapy, and chemotherapy even in KRAS wild-type NSCLC 5
• KEAP1 mutations independently trend toward dismal median OS (8.9 vs 15.9 months) 4

Treatment Response Patterns

Immunotherapy Resistance

• STK11 mutations remain significantly associated with increased death risk (HR 1.66-2.01) after adjusting for age, sex, treatment type, and other genomic alterations including KRAS, KEAP1, TP53, and SMARCA4 4
• The negative prognostic impact of STK11 mutations appears unrelated to immunotherapy administration itself—these patients demonstrate poor outcomes with both immunotherapy alone and chemo-immunotherapy combinations 4
• Response to immunotherapy is poor across all STK11 co-occurring mutations, though TP53 co-mutation shows improved clinical benefit 2

Chemotherapy Resistance

• Patients with STK11 mutations demonstrate chemotherapy resistance with significantly shortened time to treatment failure 3
• First-line treatment failure occurs more rapidly regardless of chemotherapy or immunotherapy selection (RR = 1.87, p = 0.005) 3

Tumor Mutation Burden as Modifier

• Higher TMB associates with longer progression-free survival on immunotherapy even in STK11-mutated patients 2
• Patients with low TMB and STK11 mutation have particularly poor immunotherapy outcomes 2

Locoregional Treatment Considerations

• Patients with STK11-mutated NSCLC receiving locoregional therapy (surgery or radiation) achieve median OS of 8.6 years with no significant difference based on KRAS or TP53 co-mutations 2
• STK11-mutated tumors demonstrate similar outcomes with localized treatment compared to STK11 wild-type tumors 2
• This suggests aggressive surgical or radiation approaches for oligometastatic disease may overcome the systemic therapy resistance phenotype 2

Testing Methodology and Clinical Implementation

• Comprehensive next-generation sequencing panels should routinely include STK11 and KEAP1 mutation analysis in all metastatic NSCLC patients, particularly those with KRAS mutations 1, 2
• Testing is critical before initiating first-line therapy to identify patients unlikely to benefit from standard immunotherapy approaches 1
• Approximately 20-30% of patients with high PD-L1 expression still harbor STK11 or KEAP1 mutations and display primary immunotherapy resistance 1

Clinical Management Algorithm

For newly diagnosed metastatic NSCLC with STK11 or KEAP1 mutations:

1. Assess for oligometastatic disease (1-3 metastases)—prioritize definitive local therapy with stereotactic ablative radiotherapy or surgical resection as these patients achieve 8.6-year median OS with locoregional approaches 2

2. For disseminated disease, avoid PD-1/PD-L1 inhibitor monotherapy as it shows inferior efficacy regardless of PD-L1 expression 6

3. Evaluate tumor mutation burden—patients with high TMB may derive some benefit from chemo-immunotherapy combinations despite STK11 mutation 2

4. Assess TP53 co-mutation status—STK11/TP53 co-mutated patients show improved immunotherapy benefit compared to STK11/KRAS co-mutation 2

5. Consider platinum-based chemotherapy combinations as first-line therapy, recognizing that response rates remain poor but may provide modest disease control 3

6. Enroll patients in clinical trials targeting alternative pathways, as standard therapies provide minimal benefit 1

Critical Pitfalls to Avoid

• Do not rely on PD-L1 expression to predict immunotherapy benefit in STK11 or KEAP1-mutated patients—these mutations override PD-L1 status 1
• Do not assume chemo-immunotherapy combinations overcome STK11-mediated resistance—the negative prognostic impact persists regardless of treatment modality 4
• Do not overlook locoregional treatment options in oligometastatic STK11-mutated disease—surgical or radiation approaches provide dramatically superior outcomes compared to systemic therapy alone 2
• Do not miss the opportunity for aggressive local therapy consolidation, as median OS of 8.6 years with locoregional treatment vastly exceeds the 4.7-8.6 months achieved with systemic therapy 2, 3