Medical Disclaimer
genoCDS is a clinical reference tool for qualified healthcare professionals only. Content is derived from published guidelines and regulatory sources and may contain errors or outdated information. It is not a substitute for professional medical judgment, institutional protocols, or individual patient assessment. Always verify recommendations against current primary sources before making clinical decisions. Full disclaimer →
Stage Stage IVA
Single extrathoracic metastatic lesion or contralateral lung nodule or pleural/pericardial involvement. Metastatic but potentially oligometastatic.
6 test recommendations across 2 clinical indications
Stage IVA adenocarcinoma. NCCN Category 1: comprehensive molecular profiling (EGFR/ALK/ROS1/BRAF/KRAS/MET/RET/NTRK/HER2) and PD-L1 required for all patients prior to first-line systemic therapy. Testing should not delay treatment if urgent — liquid biopsy can provide faster results while tissue NGS is pending.
Required — 2 tests
Comprehensive Solid Tumor NGS Panel
Comprehensive NGS
Next-generation sequencing panel covering ≥300 cancer-relevant genes, including all major NSCLC drivers (EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, NTRK, HER2, FGFR), plus tumor mutational burden (TMB) and microsatellite instability (MSI). Examples include FoundationOne CDx, Tempus xT, Caris MI Transcriptome, and equivalent institutional panels. Preferred over single-gene sequential testing for efficiency and cost-effectiveness.
Ordering Note
NCCN Category 1. Required before first-line therapy. Tests for EGFR, ALK, ROS1, BRAF V600E, KRAS G12C, MET ex14, RET, NTRK, HER2, TMB, MSI simultaneously. If tissue inadequate, liquid biopsy can bridge — positive liquid biopsy result is actionable; negative requires tissue confirmation.
Specimen
Evidence
NCCN Category 1: broad molecular profiling required for all metastatic NSCLC adenocarcinoma prior to first-line systemic therapy.
ASCO/CAP/AMP/IASLC strong recommendation: broad molecular testing for all metastatic NSCLC.
ESMO: broad molecular profiling recommended as standard for metastatic NSCLC.
Reflex Testing
At disease progression on first- or second-generation EGFR TKI, perform T790M testing (liquid biopsy preferred).
At disease progression on first- or second-generation EGFR TKI, perform T790M testing (liquid biopsy preferred).
PD-L1 Expression by Immunohistochemistry (IHC)
PD-L1 IHC
Measurement of PD-L1 (programmed death-ligand 1; CD274) protein expression on tumor cells by IHC. Reported as Tumor Proportion Score (TPS) for NSCLC. Key thresholds: TPS <1% (PD-L1 negative), TPS 1–49% (low expression), TPS ≥50% (high expression). FDA-approved companion diagnostics: 22C3 pharmDx (pembrolizumab), 28-8 pharmDx (nivolumab), SP142 (atezolizumab), SP263 (durvalumab). PD-L1 ≥50% qualifies for pembrolizumab monotherapy first-line; all TPS levels are relevant for combination chemo-immunotherapy selection.
Ordering Note
NCCN Category 1. PD-L1 ≥50%: pembrolizumab monotherapy preferred if no contraindications and no actionable driver. PD-L1 1–49%: combination chemo-immunotherapy. PD-L1 <1%: combination chemo-immunotherapy. PD-L1 is relevant even if driver mutation identified — used to risk-stratify post-progression immunotherapy.
Specimen
Evidence
FDA approval: pembrolizumab monotherapy for PD-L1 ≥50% NSCLC first-line. Combination with chemo for PD-L1 1–49% and <1%.
Recommended — 2 tests
Tumor Mutational Burden (TMB)
TMB
Quantitative measurement of the number of somatic mutations per megabase (mut/Mb) of tumor genome. High TMB (TMB-H, ≥10 mut/Mb per FoundationOne CDx) is an FDA-approved pan-tumor biomarker for pembrolizumab (Keytruda). In NSCLC, TMB-H correlates with improved response to immune checkpoint inhibitors independently of PD-L1 expression. TMB is typically calculated from comprehensive NGS panels (FoundationOne CDx FDA-approved for TMB). Note: TMB thresholds and clinical utility vary by assay platform — direct comparison between assays requires caution.
Ordering Note
TMB-H (≥10 mut/Mb): pembrolizumab approved pan-tumor (FDA 2020). In NSCLC, TMB-H is an independent predictor of immunotherapy benefit, particularly useful when PD-L1 is low. Typically reported from comprehensive NGS panel.
Specimen
Evidence
FDA pan-tumor approval: pembrolizumab for TMB-H (≥10 mut/Mb) solid tumors. NCCN 2B for NSCLC specifically.
Microsatellite Instability / Mismatch Repair Status (MSI/MMR)
MSI/MMR
Testing for microsatellite instability (MSI) and/or mismatch repair (MMR) deficiency. Methods: PCR-based MSI testing, IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2), or NGS-based MSI calculation. MSI-H (high instability) / dMMR (deficient MMR) is an FDA-approved pan-tumor biomarker for pembrolizumab and dostarlimab. MSI-H/dMMR is rare in NSCLC (<1%) but justifies routine testing given pan-tumor approval. IHC for MMR proteins can be performed on most tissue specimens.
Ordering Note
MSI-H/dMMR rare in NSCLC (<1%) but pan-tumor pembrolizumab/dostarlimab approvals make routine testing appropriate. Usually included in comprehensive NGS panel.
Specimen
Evidence
Rare in NSCLC (<1%) but pan-tumor pembrolizumab/dostarlimab approval warrants testing.
Disease progression after EGFR TKI therapy. T790M mutation testing required for patients who progress on first- or second-generation EGFR TKI (erlotinib, gefitinib, afatinib, dacomitinib). T790M positive (~50–60%): osimertinib. T790M negative: tissue re-biopsy required; consider comprehensive re-profiling for emerging resistance mechanisms (MET amplification, HER2 amplification, SCLC transformation, C797S).
Required — 1 test
EGFR T790M Resistance Mutation (Reflex)
EGFR T790M
Detection of EGFR T790M (p.Thr790Met) mutation — the most common mechanism of acquired resistance to first- and second-generation EGFR TKIs (erlotinib, gefitinib, afatinib, dacomitinib). Present in ~50–60% of EGFR-mutant NSCLC patients at progression on first/second-gen TKIs. Osimertinib (Tagrisso) is FDA-approved for T790M-positive NSCLC. Liquid biopsy (plasma ctDNA) is preferred at progression to avoid invasive re-biopsy. T790M testing is performed as a REFLEX test — only after disease progression on an EGFR-directed TKI.
Ordering Note
Liquid biopsy (plasma ctDNA) preferred — non-invasive and provides rapid results. cobas EGFR v2 or similar FDA-approved assay. T790M detected: osimertinib is standard second-line. T790M not detected in plasma: proceed to tissue re-biopsy (false negative rate 20–30%). Tissue re-biopsy also evaluates for SCLC transformation, MET amplification, and other resistance mechanisms.
Specimen
Evidence
FDA approval: osimertinib for T790M+ NSCLC after progression on first/second-gen EGFR TKI. cobas EGFR v2 companion diagnostic for plasma T790M testing.
Reflex Testing
Plasma T790M negative (false negative rate 20–30%): proceed to tissue re-biopsy with comprehensive NGS panel to evaluate all resistance mechanisms.
Plasma T790M negative (false negative rate 20–30%): proceed to tissue re-biopsy with comprehensive NGS panel to evaluate all resistance mechanisms.
Conditional — 1 test
Comprehensive Solid Tumor NGS Panel
Comprehensive NGS
Next-generation sequencing panel covering ≥300 cancer-relevant genes, including all major NSCLC drivers (EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, NTRK, HER2, FGFR), plus tumor mutational burden (TMB) and microsatellite instability (MSI). Examples include FoundationOne CDx, Tempus xT, Caris MI Transcriptome, and equivalent institutional panels. Preferred over single-gene sequential testing for efficiency and cost-effectiveness.
Ordering Note
Comprehensive re-profiling of tissue re-biopsy to identify mechanism of EGFR TKI resistance: SCLC transformation (10%), MET amplification (5–10%), HER2 amplification (<5%), BRAF mutation (<3%), EGFR amplification, C797S mutation, PIK3CA. Results guide clinical trial enrollment or combination therapy strategies.
Specimen
Payer Coverage
Payer Coverage Summary
Coverage status as of last policy review. Prior authorization requirements and coverage criteria may change. Verify directly with each payer before ordering.
| Test | Medicare (CMS) | UnitedHealth | Anthem BCBS | Humana | Cigna | Aetna |
|---|---|---|---|---|---|---|
| Comprehensive NGS | Covered | Covered | Covered | Prior Auth | Covered | Covered |
| PD-L1 IHC | Covered | Covered | Covered | Covered | Covered | Covered |
| TMB | Covered | Prior Auth | Covered | Prior Auth | Covered | Covered |
| MSI/MMR | Covered | Unknown | Unknown | Unknown | Unknown | Unknown |
| EGFR T790M | Covered | Covered | Unknown | Unknown | Unknown | Unknown |
Coverage data last verified via automated policy research. Always confirm current policies with each payer.
Recommendations on this page are derived from publicly available guidelines (NCCN, ASCO, ESMO, FDA, OncoKB) and are paraphrased for reference. They do not constitute medical advice. Evidence levels reflect the grading systems of each respective organization and should be interpreted in clinical context. This reference is updated periodically but may not reflect the most recent guideline revisions.