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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月13日

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  • Eric Y. Stutheit-Zhao,
  • Yongqi Zhong,
  • Collin A. Melton,
  • Elizabeth D. Lightbody,
  • Michael A. Hinterberg,
  • Yarong Wang,
  • Owen Hall,
  • Eduardo V. Sosa,
  • Jeremy B. Provance,
  • Junjun Zhang,
  • Abel Licon,
  • Zhihui Amy Liu,
  • Albiruni R. Abdul Razak,
  • Anna Spreafico,
  • Philippe L. Bedard,
  • Aaron R. Hansen,
  • Stephanie Lheureux,
  • Pamela S. Ohashi,
  • Alan Williams,
  • Scott V. Bratman,
  • Brian A. Allen,
  • Jing Zhang,
  • Daniel D. De Carvalho,
  • Anne-Renee Hartman,
  • Lillian L. Siu,
  • Enrique Sanz-Garcia

摘要

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.