The ESMO Scale for Clinical Actionability of Molecular Targets, version 2 (ESCAT v2): an evidence-based framework for ranking alterations as actionability and resistance biomarkers in precision oncology

BACKGROUND: Since the publication of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) in 2018, precision oncology has evolved substantially. Tumour-agnostic therapy approvals, expanding real-world evidence datasets, and the clinical recognition of genomic resistance biomarkers have created the need to revise the original framework. METHODS: The ESMO Precision Oncology and Taxonomy Committee convened an international expert panel to revise the ESCAT classification. Through iterative review of the evolving evidence-base, structured feedback rounds, and consensus discussions, the panel developed an updated actionability scale and a novel resistance scale. The revision followed three principles: explicit grading of uncertainty within actionable tiers, formal inclusion of tumour-agnostic eligibility criteria, and systematic classification of resistance biomarkers to complement sensitivity designations. RESULTS: ESCAT version 2 (ESCAT v2) introduces several substantive changes. Tier I is restructured into three categories, proven, inferred, and extrapolated, that carry the same clinical directive but differ in the level of certainty within the supporting evidence. The guideline introduces formal tumour-agnostic gating criteria, the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S). Tier II is refined into three sub-tiers graded by prospective interventional evidence, high-quality real-world or non-prospective evidence, and replicated case-level evidence. Tier X is subdivided into alterations that are tested and found not to be predictive (X-A) and biomarker-therapy matches in which the therapy lacks meaningful activity in the biomarker-defined population (X-B). A parallel four-level resistance scale ranges from clinically validated resistance (contraindication) to preclinical or computational evidence (research use only). CONCLUSIONS: ESCAT v2 provides a comprehensive, evidence-graded framework for interpreting actionability and resistance biomarkers in cancer, enabling more nuanced communication among clinicians, patients, regulators, and researchers while preserving a clear directive to act when evidence supports patient benefit.