STK11/KEAP1 Advanced/Metastatic Non-Squamous NSCLC

Authored by Open Medicine, published on 2026-06-09 19:25:58.0

The algorithm is partially aligned with current metastatic Non-Squamous NSCLC practice in its emphasis on broad molecular testing and guideline-directed targeted therapy when actionable drivers are present, and on chemo-immunotherapy as the backbone for most patients. However, it elevates tremelimumab+durvalumab+platinum (POSEIDON) as a preferred approach specifically for STK11/KEAP1-altered disease, which is not a universally guideline-endorsed biomarker-directed standard and rests largely on subgroup/biomarker analyses rather than dedicated prospective biomarker-stratified trials. The ivonescimab-based intensification approach remains investigational/region-dependent and should generally be framed as clinical-trial or where approved/available.

  1. Patient with metastatic Non-Squamous NSCLC
    This is the top-level disease state; broad guideline references support the overall first-line systemic therapy framework (chemo-IO for most, maintenance concepts, and role of biomarkers/testing).
    • Comprehensive Next-Generation Sequencing (NGS)
      • STK11 and/or KEAP1 altered NSCLC
        Evidence supports STK11/KEAP1 alterations as adverse prognostic factors and as markers associated with reduced benefit from PD-(L)1 monotherapy in some datasets; whether they should dictate a specific first-line regimen remains evolving and not uniformly standardized in guidelines.
        • PD-L1 <50% (includes PD-L1 <1%)
          • Prefer tremelimumab + durvalumab + platinum-doublet chemotherapy (POSEIDON)
            Tremelimumab + durvalumab + platinum chemotherapy Followed by durvalumab maintenance Precautions: higher rates of colitis and dermatitis than single-agent IO + chemo. Alternative Nivolumab + Ipilimumab + platinum-doublet chemotherapy CheckMate 9LA evaluated a first-line regimen of: Nivolumab (Opdivo) — PD-1 inhibitor + Ipilimumab (Yervoy) — CTLA-4 inhibitor + Plus 2 cycles of platinum-doublet chemotherapy While durva/treme has stronger subgroup data in an STK11/KEAP1 specific population, there is no direct comparison between them, and both of the PD-(L)1+CTLA-4 regimens were included in the Di Frederico meta-analysis.
            • Induction (4 cycles platinum-doublet + IO)
              • Maintenance (durvalumab maintenance, tremelimumab limited-dose schedule completed)
        • PD-L1 ≥50%
          • Platinum Doublet with Pemetrexed and Pembrolizumab (KEYNOTE-189)
            This regimen is a guideline-endorsed first-line standard for metastatic squamous NSCLC and is supported by a pivotal randomized trial demonstrating improved overall survival and progression-free survival versus chemotherapy alone across PD-L1 strata.
            • Induction: 4 cycles pembrolizumab + pemetrexed + carboplatin/cisplatin
              Induction (Cycles 1-4) Pembrolizumab 200 mg q3w Pemetrexed 500 mg/m² q3w Cisplatin 75 mg/m² q3w or carboplatin AUC 5 q3w
              • Maintenance pembrolizumab + pemetrexed (per KEYNOTE-189)
                Maintenance (starting Cycle 5) Pembrolizumab q3w (up to 35 cycles total) Pemetrexed q3w until progression/toxicity
        • Contraindication to immunotherapy or combination therapy?
          Active autoimmune disease Prior severe ICI toxicity / irAE Uncontrolled comorbidities Organ transplant
          • Non-IO option (platinum-doublet chemotherapy)
            If PD‑1/VEGF inhibitors are contraindicated or not appropriate: Platinum‑doublet chemotherapy (e.g., carboplatin + paclitaxel or nab‑paclitaxel) Maintenance: Observation or continuation of chemotherapy per clinical judgment
      • 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.
  2. 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.
  3. 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.
tosprivacyCTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitorsDurvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON StudyLong-term overall survival with dual CTLA-4 and PD-L1 or PD-1 blockade and biomarker-based subgroup analyses in patients with advanced non-small-cell lung cancer: a systematic review and reconstructed individual patient data meta-analysisPembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer