Ultrasensitive Liquid Biopsy Demonstrates Efficacy in Predicting Immunotherapy Response

Clinicians currently lack reliable tools to predict early on which patients will respond, continue to benefit, or develop resistance, leading to prolonged ineffective treatment and delayed clinical decisions. A highly sensitive blood-based approach has now demonstrated the ability to predict outcomes, track treatment responses, and distinguish true disease progression in patients receiving immunotherapy across multiple tumor types.

The work was led by the Vall d’Hebron Institute of Oncology (VHIO, Barcelona, Spain) through its IMMUNOMICS-VHIO platform, which is designed to discover and validate liquid biopsy biomarkers that inform immunotherapy outcomes in early-phase clinical trials. The approach relies on ultrasensitive analysis of circulating tumor DNA, small fragments of tumor-derived genetic material found in blood. By sequencing and monitoring ctDNA before treatment and at multiple time points during therapy, the platform captures tumor evolution and treatment-related changes without the need for invasive tissue biopsies.

The study analyzed 1,455 longitudinal plasma samples from a retrospective cohort of 136 patients with refractory metastatic solid tumors spanning 24 cancer types, all treated with immunotherapy in phase 1 trials. The findings were independently validated in a prospective cohort of 66 patients, with an additional 374 samples. Results showed that lower baseline ctDNA levels were associated with longer progression-free and overall survival. Early changes in ctDNA at three weeks correlated with disease control, while complete clearance of ctDNA at any time strongly predicted radiological response and prolonged survival.

Importantly, ctDNA dynamics were able to distinguish true disease progression from pseudoprogression, a major clinical challenge in immunotherapy, and predicted outcomes in patients treated beyond initial progression. These findings, published in Clinical Cancer Research, suggest that ultrasensitive liquid biopsy could guide earlier treatment decisions, optimize patient stratification, and reduce reliance on repeated imaging. The researchers plan to further validate this approach to predict clinical benefit before standard imaging assessments in phase 1 trials, to improve patient management and accelerate therapeutic decision-making.

“In conclusion, our comprehensive analysis of ultrasensitive ctDNA in patients with advanced cancers undergoing treatment with immunotherapy has demonstrated notable utility for early patient stratification, treatment response monitoring, and detection of disease progression,” said Rodrigo Toledo, co-corresponding author. “Anticipating response to therapy is key to optimizing patient management and therapeutic decision-making. It also enables us to more rapidly assess whether it is advisable for the patient to continue participating in the clinical trial or, if not, whether we should propose a new therapeutic strategy.”

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