STK11/KEAP1 Advanced/Metastatic Squamous NSCLC

Authored by Open Medicine, published on 2026-05-28 23:00:26.0

Patient with metastatic squamous NSCLC
- Comprehensive Next-Generation Sequencing (NGS)
  - STK11 and/or KEAP1 altered NSCLC
    - PD-L1 <50% (includes PD-L1 <1%)
      - Prefer tremelimumab + durvalumab + platinum-doublet chemotherapy (POSEIDON)
        
        Tremelimumab + durvalumab + platinum chemotherapy Followed by durvalumab maintenance
        
        Induction (4 cycles platinum-doublet + IO)
        
        Maintenance (durvalumab maintenance, tremelimumab limited-dose schedule completed)
    - PD-L1 ≥50%
      - Consider intensified IO-based therapy (e.g., ivonescimab + platinum-doublet chemotherapy)
        
        (Aligned with POSEIDON approach)
        
        Continue Ivonescimab + Platinum-Doublet Chemotherapy for 4–6 cycles
        
        Maintenance IO-based therapy until progression/toxicity
  - If other actionable oncogenic driver identified, prioritize guideline-directed targeted therapy
    
    Use guideline-directed targeted therapy. EGFR mutations; ALK rearrangements; ROS1 rearrangements; BRAF V600E; METex14 skipping; RET rearrangements; NTRK fusions, etc. Follow NCCN Guidelines.
POSEIDON Regimen

Based on the POSEIDON (Phase 3) trial in STK11/KEAP1-altered mNSCLC. Limits CTLA-4 exposure by incorporating 5 doses of tremelimumab. Incorporates maintenance durvalumab following induction therapy. POSEIDON subgroup analyses demonstrated encouraging PFS and OS outcomes in STK11/KEAP1-altered mNSCLC compared with historical pembrolizumab + chemotherapy outcomes.
General Principles

Reassess at progression and consider clinical trials or subsequent-line therapies. Supportive care and risk factor modification (e.g., smoking cessation) are essential. Management should be individualized based on patient factors, comorbidities, and preferences.

tos privacy CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors