Metastatic Non-Small Cell Lung Cancer (NSCLC) Biomarker-Guided Treatment

Authored by Chinmay Jani, published on 2026-09-04 10:11:19.0

The algorithm is broadly aligned with current metastatic NSCLC practice: upfront comprehensive molecular testing, targeted therapy for actionable alterations, and chemo-immunotherapy for biomarker-negative disease. The first-line chemo-IO backbones shown for squamous and non-squamous disease are consistent with major guideline-endorsed regimens. Several later-line or investigational items (e.g., telisotuzumab vedotin for “CMS1”, zongertinib for HER2, zenocotuzumab for “VRG1”) are evolving and not uniformly guideline-standard across settings.

  1. Stage IV NSCLC
    • Obtain broad molecular profiling (NGS) + PD-L1 before systemic therapy
      Guidelines recommend broad, upfront molecular profiling in metastatic NSCLC (including tissue and/or plasma ctDNA) to identify actionable alterations that determine first-line therapy selection.
      • No actionable driver identified (Squamous / Non-squamous → PD-L1-guided treatment)
        • Squamous
          • Carbo/Taxol + Pembro/Cemipilimab
            Platinum-doublet chemotherapy plus PD-1 inhibitor is a standard first-line option for metastatic squamous NSCLC without actionable drivers; pembrolizumab has pivotal phase 3 evidence and is guideline-endorsed. Cemiplimab plus chemotherapy is also supported by phase 3 evidence, though specific chemo partners vary by trial and guidelines.
          • Nivo + Ipi (especially STK11 / KEAP1)
            Nivolumab+ipilimumab (often with limited chemotherapy) is an accepted first-line option in metastatic NSCLC, but selecting it specifically because of STK11/KEAP1 alterations is not firmly guideline-standard; evidence for these biomarkers as predictive for ICI combinations is evolving and inconsistent.
            • Disease progression? → repeat molecular profiling + assess MET/HER2 expression
              Re-biopsy and/or plasma ctDNA testing at progression is recommended to detect resistance mechanisms and new actionable alterations (e.g., MET amplification, EGFR secondary mutations), informing subsequent-line therapy or trial selection.
              • None
                • Docetaxel ± ramucirumab / other subsequent therapy
              • HER2 amplification/overexpression
                HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
                • Trastuzumab Deruxtecan
                  Trastuzumab deruxtecan for patients with HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
              • High c-MET protein overexpression
                Met protein-overexpression in NSCLC defined as MET IHC 31 in ≥50% of tumor cells.
                • Teliso-V
              • KRAS G12C
                • Adagrasib
                • Sotorasib
              • NRG1 Fusion
                • Zenocotuzumab
          • Single-agent immunotherapy
            Single-agent PD-1/PD-L1 therapy is standard first-line treatment for metastatic NSCLC without actionable drivers when PD-L1 TPS is high (classically ≥50%) and there are no contraindications; the algorithm does not specify PD-L1 criteria, so applicability is conditional.
            • Disease progression? → repeat molecular profiling + assess MET/HER2 expression
              Re-biopsy and/or plasma ctDNA testing at progression is recommended to detect resistance mechanisms and new actionable alterations (e.g., MET amplification, EGFR secondary mutations), informing subsequent-line therapy or trial selection.
              • None
                • Docetaxel ± ramucirumab / other subsequent therapy
              • HER2 amplification/overexpression
                HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
                • Trastuzumab Deruxtecan
                  Trastuzumab deruxtecan for patients with HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
              • High c-MET protein overexpression
                Met protein-overexpression in NSCLC defined as MET IHC 31 in ≥50% of tumor cells.
                • Teliso-V
              • KRAS G12C
                • Adagrasib
                • Sotorasib
              • NRG1 Fusion
                • Zenocotuzumab
        • Non-Squamous
          • Carbo + Pemetrexed + Pembro / Cemiplimab
            • Disease progression? → repeat molecular profiling + assess MET/HER2 expression
              Re-biopsy and/or plasma ctDNA testing at progression is recommended to detect resistance mechanisms and new actionable alterations (e.g., MET amplification, EGFR secondary mutations), informing subsequent-line therapy or trial selection.
              • None
                • Docetaxel ± ramucirumab / other subsequent therapy
              • HER2 amplification/overexpression
                HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
                • Trastuzumab Deruxtecan
                  Trastuzumab deruxtecan for patients with HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
              • High c-MET protein overexpression
                Met protein-overexpression in NSCLC defined as MET IHC 31 in ≥50% of tumor cells.
                • Teliso-V
              • KRAS G12C
                • Adagrasib
                • Sotorasib
              • NRG1 Fusion
                • Zenocotuzumab
          • Nivo + Ipi (especially STK11 / KEAP1)
            • Disease progression? → repeat molecular profiling + assess MET/HER2 expression
              Re-biopsy and/or plasma ctDNA testing at progression is recommended to detect resistance mechanisms and new actionable alterations (e.g., MET amplification, EGFR secondary mutations), informing subsequent-line therapy or trial selection.
              • None
                • Docetaxel ± ramucirumab / other subsequent therapy
              • HER2 amplification/overexpression
                HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
                • Trastuzumab Deruxtecan
                  Trastuzumab deruxtecan for patients with HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
              • High c-MET protein overexpression
                Met protein-overexpression in NSCLC defined as MET IHC 31 in ≥50% of tumor cells.
                • Teliso-V
              • KRAS G12C
                • Adagrasib
                • Sotorasib
              • NRG1 Fusion
                • Zenocotuzumab
          • Single-agent immunotherapy
            • Disease progression? → repeat molecular profiling + assess MET/HER2 expression
              Re-biopsy and/or plasma ctDNA testing at progression is recommended to detect resistance mechanisms and new actionable alterations (e.g., MET amplification, EGFR secondary mutations), informing subsequent-line therapy or trial selection.
              • None
                • Docetaxel ± ramucirumab / other subsequent therapy
              • HER2 amplification/overexpression
                HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
                • Trastuzumab Deruxtecan
                  Trastuzumab deruxtecan for patients with HER2-overexpressing in NSCLC defined as HER2 IHC 31 (by gastric scoring).
              • High c-MET protein overexpression
                Met protein-overexpression in NSCLC defined as MET IHC 31 in ≥50% of tumor cells.
                • Teliso-V
              • KRAS G12C
                • Adagrasib
                • Sotorasib
              • NRG1 Fusion
                • Zenocotuzumab
      • Actionable driver identified (EGFR | ALK | ROS1 | BRAF V600E | RET | METex14 | NTRK | HER2 | KRAS G12C)
        • EGFR
          • Osimertinib + Chemotherapy (FLAURA2)
            For EGFR exon 20 insertion–positive metastatic NSCLC, amivantamab combined with platinum-based chemotherapy has phase 3 evidence and has become a guideline-supported option (subject to regulatory status) in the first-line setting.
            • Second line progression options
              • Amivantamab Combinations
                • Third line progression options
                  • Docetaxel
                  • Single agent Chemotherapy
              • Docetaxel
                • Third line progression options
                  • Docetaxel
                  • Single agent Chemotherapy
              • Dato-DxD
                • Third line progression options
                  • Docetaxel
                  • Single agent Chemotherapy
              • New alteration -> targeted Rx
                • Third line progression options
                  • Docetaxel
                  • Single agent Chemotherapy
          • Amivantamab + Lazertinib (MARIPOSA)
            Osimertinib is the established preferred first-line EGFR TKI for common EGFR mutations in metastatic NSCLC based on superior PFS and OS versus earlier-generation EGFR TKIs. The optional addition of chemotherapy is supported by emerging/positive randomized data but is not universally adopted for all patients.
            • Second line progression options
              • Platinum Doublet +/- EGFR TKI
                • Third line progression options
                  • Docetaxel
                  • Platinum Doublet
                  • Dato-DxD
              • Ivonescimab + Platinum doublet?
                • Third line progression options
                  • Docetaxel
                  • Platinum Doublet
                  • Dato-DxD
              • New alteration -> targeted Rx
                • Third line progression options
                  • Docetaxel
                  • Platinum Doublet
                  • Dato-DxD
          • Osimertinib (FLAURA)
            • Second line progression options
              • Ivonescimab + Platinum Doublet ?
                • 3rd line progression options
                  • Docetaxel
                  • Amivantamab + Lazertinib
                  • Dato-DxD
              • Osimertinib +/- Chemotherapy (COMPELL)
                • 3rd line progression options
                  • Docetaxel
                  • Amivantamab + Lazertinib
                  • Dato-DxD
              • Amivantamab + Platinum Doublet (MARIPOSA-2)
                • 3rd line progression options
                  • Docetaxel
                  • Amivantamab + Lazertinib
                  • Dato-DxD
              • New alteration -> targeted Rx
                • 3rd line progression options
                  • Docetaxel
                  • Amivantamab + Lazertinib
                  • Dato-DxD
        • ALK fusion
          • Lorlatinib (Crown)
            • Alectinib / Brigatinib
        • ROS1 fusion
          • Repotrectinib / Taletrectinib
            • Crizotinib
            • Entrectinib
        • BRAF V600E
          • Dabrafenib + Trametinib
          • Encorafenib + Binimetinib
        • MET exon 14 skipping
          Bubble note: 'MET exon14'
          • Capmatinib
          • Tepotinib
        • RET fusion
          • Selpercatinib
        • HER2 (ERBB2) TKD activating mutation
          • Zongertinib
            • 2nd line progression options
              • Transtuzumab deruxtecan
              • Sevabertinib
        • NTRK fusion
          • Entrectinib
          • Larotrectininb and Repotrectinib
        • KRAS G12C
          • Systemic Chemo + ICI combination (depending on squamous/non-squamous)
            • Second line progression?
              • Adagrasib
              • Sotorasib
                Sotorasib is a standard targeted therapy option after prior systemic therapy for KRAS G12C–mutant metastatic NSCLC, supported by pivotal trial data and guideline recommendations; comparative data versus docetaxel support its use in previously treated disease.
        • NRG1 Fusion
          • Systemic Chemo + ICI combination
            • Second line progression?
              • Zenocotuzumab
tosprivacyMolecular Profiling Across 80,000 Patients With Lung Cancer