ESCAT v2 adds graded certainty tiers and a resistance scale for molecular targets

Background

The ESMO Scale for Clinical Actionability of Molecular Targets, abbreviated ESCAT, was published in 2018¹. Since then, the approval of tumour‑agnostic therapies, the expansion of real‑world evidence datasets, and the growing recognition of genomic resistance biomarkers have necessitated a revision of the original framework.¹.

Methods

The ESMO Precision Oncology and Taxonomy Committee convened an international expert panel to revise the classification¹. The panel used iterative review of the evolving evidence base, structured feedback rounds and consensus discussions¹. The revision followed three principles¹:

• explicit grading of uncertainty within actionable tiers
• formal inclusion of tumour-agnostic eligibility criteria
• systematic classification of resistance biomarkers to complement sensitivity designations

Key changes in ESCAT v2

• Tier I is restructured into three categories: proven, inferred and extrapolated. These carry the same clinical directive but differ in the level of certainty within the supporting evidence¹.
• Tumour-agnostic gating criteria are formalised as the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S)¹.
• 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 evidence¹.
• Tier X is subdivided into alterations 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)¹.
• A parallel four-level resistance scale ranges from clinically validated resistance (contraindication) to preclinical or computational evidence (research use only)¹.

Conclusions

ESCAT v2 provides a comprehensive, evidence-graded framework for interpreting actionability and resistance biomarkers in cancer¹. According to the authors, it enables more nuanced communication among clinicians, patients, regulators and researchers while preserving a clear directive to act when evidence supports patient benefit¹.