# Clinical validation of a tissue-agnostic genome-wide methylome enrichment assay to monitor response to pembrolizumab

## TL;DR

A blood test using methylation analysis can predict how well cancer patients respond to pembrolizumab, helping guide treatment decisions.

## Contribution

A commercial-grade, tissue-agnostic methylation assay is validated for monitoring immunotherapy response using plasma DNA.

## Key findings

- Decreased ctDNA methylation levels correlated with better treatment response and survival outcomes.
- The methylation assay remained significant in multivariable models for progression-free survival.
- The assay enables tissue-agnostic response monitoring for pembrolizumab across multiple tumor types.

## Abstract

Immunotherapy has significantly improved the treatment of metastatic solid tumors; however, detecting early signs of response to enable timely intervention for resistant tumors remains challenging. A blood-only circulating tumor DNA (ctDNA) test may provide a rapid assessment of tumor response without reliance on matched tumor tissue. We applied a tissue-agnostic, genome-wide methylation enrichment assay, based on cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq), to plasma samples from patients in a phase 2 trial evaluating pembrolizumab across multiple solid tumors (NCT02644369). A decrease in ctDNA from baseline to pre-cycle 3 was significantly associated with higher objective response and clinical benefit rates and longer progression-free and overall survival in univariate analyses, with these associations remaining significant in multivariable models except for overall survival. These results validate a commercial-grade, tissue-agnostic plasma cfDNA methylation platform for immunotherapy response monitoring, which may facilitate earlier, more informed treatment decisions and improve patient outcomes.