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Core Predictive Biomarkers in Advanced NSCLC​

Current clinical practice guidelines converge on a defined group of predictive biomarkers that are routinely assessed in patients with advanced NSCLC to inform initial and subsequent treatment decisions:


Core Actionable Biomarkers in NSCLC

  • EGFR
    Activating mutations and resistance variants guiding tyrosine kinase inhibitor (TKI) therapy

  • ALK
    Gene fusions associated with sensitivity to ALK-targeted inhibitors

  • ROS1
    Gene fusions with established targeted treatment options

  • BRAF
    Activating mutations, most notably p.V600E

  • KRAS
    With specific therapeutic relevance for the p.G12C mutation

  • MET exon 14 skipping
    Splice alterations conferring sensitivity to MET-directed therapies

  • RET
    Gene fusions associated with targeted inhibitor response

  • NTRK1/2/3
    Rare gene fusions with tumour-agnostic therapeutic implications


Although the prevalence of several of these alterations is low, missing them can mean overlooking highly effective targeted treatments. For this reason, molecular testing in NSCLC should be designed to check broadly across many alterations, rather than focusing only on the most common ones.

Orthogonal biomarkers and non-NGS assays​

In parallel with genomic profiling, PD-L1 expression is routinely assessed by immunohistochemistry (IHC) to guide immunotherapy decisions.

PD-L1 testing is operationally inseparable from the NSCLC CDx workflow, as molecular and immunotherapy stratification are performed together during diagnosis.

Implications for CDx assay scope​

The diversity of genetic alterations that must be assessed in NSCLC directly shapes how diagnostic assays are designed:

  • Single-gene tests cannot efficiently capture the full range of actionable alterations
  • DNA only approaches may miss clinically relevant gene fusions and splice events
  • Comprehensive testing must balance coverage, sensitivity, tissue usage, and turnaround time

As a result, NSCLC requires more complex diagnostic workflows, and testing increasingly relies on integrated, multi-target sequencing strategies rather than isolated assays.