Study Finds Liquid Biopsy May Provide Predictive Biomarkers for Checkpoint Inhibitor Response


Key Points

  • Liquid biopsy may be a viable diagnostic tool to help predict response to checkpoint inhibitor–based immunotherapy.
  • Patients with more than three variants of unknown significance in their circulating tumor DNA had significantly higher response rates to immunotherapy. Patients with a high number of alterations also had longer median progression-free survival.

Although checkpoint inhibitor–based immunotherapy has revolutionized treatment for a variety of cancers, the majority of patients with cancer do not respond to the therapy, and a subset of patients may even experience hyperprogression. Many patients also experience some degree of immune-related side effects from this treatment. All these issues make it imperative to determine predictive biomarkers of response to immune checkpoint inhibitors.

A small study by Khagi et al investigating the association between hypermutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response may offer an important clue regarding the viability of liquid biopsy as a diagnostic tool to predict response to immune checkpoint inhibitors. The study found that the number of alterations detected in the liquid biopsies of patients treated with immune checkpoint inhibitors was associated with response to the treatment. Patients with more than three variants of unknown significance (VUS) in their ctDNA had a 45% response rate to the therapy, compared with 15% for those with three or fewer VUS.

In addition, liquid biopsy is more easily obtained and less expensive than tissue biopsy and has the additional advantage of representing shed DNA from multiple metastatic sites. The study was published in Clinical Cancer Research.

Study Methodology

The researchers analyzed the ctDNA of 69 patients with diverse solid malignancies who had received checkpoint inhibitor–based immunotherapy from December 2011 to December 2016. They used the Guardant360 (54–70 gene) assay to identify the VUS tumor-related genomic alterations within the cancer-related genes. The most common tumor types were melanoma, lung cancer, and head and neck cancer, and the most common type of immunotherapy used was anti–programmed cell death protein 1 (PD-1) or its ligand (PD-L1) monotherapy.

The rates of stable disease ≥ 6 months, partial and complete response, progression-free survival, and overall survival were assessed based on total and VUS alterations.

Study Findings

The investigators found that statistically significant improvement in progression-free survival was associated with high- vs low-alteration number in VUS (> 3 alterations vs ≤ 3 alterations). After being treated with an immune checkpoint inhibitor, patients with more than three VUS in their ctDNA had significantly higher response rates (stable disease ≥ 6 months/partial response/complete response) compared with those who had three or fewer VUS (45% vs 15%, respectively; P = .014). Similar results were seen with high vs low total alteration number (characterized plus VUS, ≥ 6 vs < 6).

Statistically significant overall survival improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders vs nonresponders with VUS > 3 had a median progression-free survival of 23 months vs 2.3 months (P = .0004).

“Given the association of alteration number on liquid biopsy and checkpoint inhibitor–based immunotherapy outcomes, further investigation of hypermutated ctDNA as a predictive biomarker is warranted,” concluded the study authors.

Counting Mutations in DNA and Predicting Treatment Response

“Mutations lead to the production of abnormal proteins; the more mutations and abnormal proteins the tumors produce, the better the chance that one or more of these proteins will be 'detected' by the immune system,” said Razelle Kurzrock, MD, Director of the Center for Personalized Cancer Therapy at the University of California San Diego Moores Cancer Center and senior author of this study. “We showed that counting the mutations in the DNA floating in the bloodstream could help predict response to these new and exciting drugs that boost the immune system to attack cancer.”

Yulian Khagi, MD, of the University of California San Diego Moores Cancer Center, is the corresponding author of this study.

This study was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.