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.

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.

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