NPJ precision oncology · 2026
Clinical validation of a tissue-agnostic genome-wide methylome enrichment assay to monitor response to pembrolizumab.
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Stutheit-Zhao Eric Y, Zhong Yongqi, Melton Collin A, Lightbody Elizabeth D, Hinterberg Michael A, Wang Yarong, Hall Owen, Sosa Eduardo V, Provance Jeremy B, Zhang Junjun, Licon Abel, Liu Zhihui Amy, Abdul Razak Albiruni R, Spreafico Anna, Bedard Philippe L, Hansen Aaron R, Lheureux Stephanie, Ohashi Pamela S, Williams Alan, Bratman Scott V, Allen Brian A, Zhang Jing, De Carvalho Daniel D, Hartman Anne-Renee, Siu Lillian L, Sanz-Garcia Enrique
Аннотация
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.