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.