Combined Transcriptome and Circulating Tumor DNA Longitudinal Biomarker Analysis Associates With Clinical Outcomes in...

Area of Science:

• Oncology
• Immunotherapy
• Biomarker Discovery

Background:

• Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO).
• VIGex is a 12-gene expression classifier validated across laboratories, categorizing tumors into hot, intermediate-cold (I-Cold), and cold subgroups.
• VIGex-Hot has shown association with better IO treatment outcomes.

Purpose of the Study:

• To investigate the performance of the VIGex classifier and other IO biomarkers.
• To evaluate VIGex in an independent dataset of patients treated with pembrolizumab in the INSPIRE phase II clinical trial.
• To assess the combined predictive performance of VIGex and changes in circulating tumor DNA (ctDNA).

Main Methods:

• Patients with advanced solid tumors received pembrolizumab.
• Tumor RNA sequencing data were analyzed using the VIGex algorithm.
• Circulating tumor DNA (ctDNA) was measured at baseline and cycle 3, and changes (ΔctDNA) were calculated.
• VIGex subgroups were combined with ΔctDNA to define predictive groups.

Main Results:

• Objective response rates were 24% in VIGex-Hot and 10% in I-Cold/Cold subgroups.
• VIGex-Hot was associated with higher overall survival (OS) and progression-free survival (PFS) in multivariable models.
• The addition of ΔctDNA to baseline VIGex classification improved the predictive performance for both OS and PFS.

Conclusions:

• Baseline VIGex classification shows predictive value for immunotherapy outcomes.
• The addition of ctDNA dynamics (ΔctDNA) to VIGex may refine prediction for immunotherapy response.
• This combined approach offers potential for improved patient selection for IO treatments.