Longitudinal methylated ctDNA increases predict immunotherapy progression across solid tumors.

Area of Science:

• Oncology
• Molecular Diagnostics
• Immunotherapy

Background:

• Identifying treatment failure during immune checkpoint blockade is crucial for effective cancer therapy.
• Current methods for monitoring treatment response can be delayed, impacting patient outcomes.

Purpose of the Study:

• To evaluate a novel, tissue-free, methylation-based circulating tumor DNA (ctDNA) assay for serial monitoring of treatment response in patients receiving immune checkpoint inhibitors.
• To establish a molecular progression (mPD) rule and assess its predictive value for progression-free survival (PFS) and overall survival (OS).

Main Methods:

• A prospective study involving 142 patients with advanced solid tumors treated with immune checkpoint inhibitor monotherapy or chemo-immunotherapy.
• Serial blood collection pre-treatment, at Cycle 2 Day 1 (C2D1), and Cycle 3 Day 1 (C3D1).
• Definition of molecular progression (mPD) as an increase in ctDNA levels while on therapy.

Main Results:

• Molecular progression (mPD) significantly stratified PFS and OS across both cohorts (PFS HR 5.8; OS HR 4.1).
• ctDNA monitoring at C2 identified more molecular rebounders and was significant for OS in stable disease subgroups where imaging is less informative (HR 8.4).
• ctDNA monitoring predicted progression with a median lead time of 62 days and demonstrated utility across multiple cancer types.

Conclusions:

• A methylation-based ctDNA assay provides a clinically practical method for early detection of treatment failure in patients receiving immune checkpoint inhibitors.
• Serial ctDNA monitoring, defined by molecular progression (mPD), is predictive of survival outcomes and offers a lead time over traditional imaging.
• This tissue-free approach has broad applicability across various solid tumors treated with immunotherapy.