Liquid biopsy may be used as early marker of immunotherapy response, study finds

A liquid biopsy is a blood test that can continuously measure circulating tumor DNA (cell-free DNA shed into the bloodstream by dead cancer cells). When used in patients with advanced non-small cell lung cancer receiving immunotherapy, it may identify patients who would benefit from treatment with additional drugs, according to a Phase 2 clinical trial conducted in the United States and Canada. The trial is led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg Kimmel Cancer Immunotherapy Institute, the British Columbia Cancer Center and the Canadian Cancer Trials Group (CCTG).

The results were published in the journal Oct. 9 natural medicinesuggesting that ctDNA analysis can be used as an early marker of immunotherapy response and may help guide treatment.

Immunotherapy is a drug that does not harness the power of the immune system against cancer. Despite success in improving survival rates, the standard use of imaging to determine treatment response is challenged as changes in imaging do not necessarily reflect the effectiveness of immunotherapy. is occurring. Liquid biopsies could help determine which patients benefit from available immunotherapies and could become a new endpoint for clinical trials testing these treatments. Although initial reports are promising, how these approaches can best be used remains to be established through clinical trials.

The BR.36 clinical trial (NCT04093167) first defines ctDNA responses, their timing, and comparison to the gold standard of imaging tests, and then uses ctDNA responses to explore the role of ctDNA as an early measure of immunotherapy response. is designed to establish. Guide the treatment of patients with advanced non-small cell lung cancer.

The first phase of the BR.36 trial will use next-generation sequencing, an advanced technology that can rapidly sequence millions of gene targets, to serially test ctDNA to determine whether immunotherapy response is detected after treatment begins. It was found that it can be detected early, within eight weeks on average. Although ctDNA response (no longer detectable ctDNA in the blood) reflected tumor shrinkage on imaging, ctDNA response was associated with greater survival, especially in patients with stable disease on imaging. There were notable exceptions that indicated that it might be accurate.

Compared with patients who did not have a ctDNA response, patients who had a ctDNA response had longer progression-free survival (time without disease worsening), by 2.6 months versus 5.03 months, respectively. Additionally, patients with ctDNA responses had longer overall survival, with median survival not yet reached at the time of analysis.

There is an unmet clinical need to implement real-time, minimally invasive molecular analysis to understand patient responses to cancer treatments and guide clinical decision-making. Our study demonstrates that ctDNA response correlates with tumor size seen on imaging studies. This is the gold standard for monitoring response to cancer treatment and appears to correlate better with survival. This suggests that ctDNA could be used as a strategy to identify patients at high risk of disease progression who may benefit from a change in treatment regimen. ”

Valsamo “Elsa” Anagnostou, MD, Ph.D., principal study author, director of the Johns Hopkins Thoracic Oncology Biorepository, leader of precision oncology analytics, and co-leader of the Johns Hopkins Molecular Tumor Committee; Co-Director of Lung Cancer Precision Medicine Center of Excellence

The researchers hypothesized that liquid biopsy would quickly and accurately predict patient outcomes. In the first phase of the BR.36 study, researchers enrolled 50 patients with advanced or metastatic non-small cell lung cancer at six medical centers in the United States and Canada from May 2020 to September 2022. . Almost all patients were smokers, and 92% received no prior treatment. This group was 82% white, 52% female, and 56% over the age of 65. The goal was to identify the optimal time points for ctDNA molecular responses and to determine how well molecular responses correlated with Response Evaluation Criteria in Solid Tumors (RECIST). RECIST is the standard for measuring response to cancer treatment by monitoring changes in tumor size seen on images.

Patients received infusions of the immunotherapy drug pembrolizumab at 200 mg or 2 mg/kg every three weeks based on standard of care. After her first three cycles, researchers were able to switch her to 400 mg or 4 mg/kg infusions every six weeks. Patients remained in the study until 24 months of treatment, unacceptable drug toxicity, or imaging revealed disease progression.

Researchers conducted RECIST response assessments every 6 weeks until week 12 and at longer intervals thereafter. Blood samples were also taken from patients before treatment administration on the first day of the first cycle of treatment (baseline), the first day of the second cycle (3 weeks from the start of treatment), and the first day of the third cycle (6 weeks of treatment). . . We used these to perform ctDNA response assessment at these time points and defined molecular response as ctDNA clearance on the first day of the third cycle of treatment with pembrolizumab. Analysis of molecular responses was evaluated using the Personal Genomic Diagnostics (PGDx) elio liquid biopsy platform. This “represents an exciting opportunity to tailor immunotherapy to enhance interpretation of patterns of tumor response and progression during treatment,” said Dr. Mark Thorsen. ., Executive Director and Head of Innovation at Labcorp, PGDx.

“ctDNA responses are particularly useful in understanding the complexity of stable disease with imaging, which accounts for a significant proportion of patients for whom imaging cannot timely and accurately detect the extent of treatment response. ” says Anagnostou.

Taking the results from the first phase of the BR.36 study, researchers will proceed to the second phase of the study to assess the potential clinical benefit of tailored treatment for lung cancer patients based on ctDNA responses after two cycles. To do. About pembrolizumab treatment. ctDNA responses are used to identify lung cancer patients at high risk of disease progression, who are then randomized to intensify treatment with pembrolizumab and chemotherapy or continue pembrolizumab.

“Cancer Research Institute (CRI) is pleased to invest in Stage 2 of this clinical trial,” said Jay Campbell, managing director of the CRI Anna Maria Kellen Clinical Accelerator. “This is planned as a registration study, meaning that the ctDNA detection assay used in the BR.36 study could be approved if the study meets its primary endpoints. This could lead to molecular evaluation by liquid biopsy. may become a standard means of assessing whether first-line patients with non-small cell lung cancer are responding to cancer immunotherapy compared to traditional radiographic response assessment . ”

“ctDNA has the potential to improve our ability to advise patients on the best treatment options,” said Janet Dancy, MD, director of the Canadian Cancer Trials Group. “It has the potential to be superior to traditional image processing in certain situations.” “Patients should continue their current treatment. Our initial study shows promising results and will provide a clear indication of whether ctDNA monitoring provides useful information on which to base treatment recommendations. We will proceed with larger-scale trials.”

Co-authors of the study include Cheryl Ho, Canada Research Chair at the BCCA Vancouver Cancer Center in British Columbia, Canada, and Johns Hopkins’ Benjamin Levy, Julie Brahmah, Archana Balan, and Nohsin It was Mr. Niknafus. Other authors were from the Ottawa Hospital Research Institute in Canada. Juravinski Cancer Center (Hamilton, Canada) Princess Margaret Cancer Center in Toronto, Canada. Kingston Health Sciences Center, Kingston, Canada. Canadian Cancer Trials Group, Kingston, Canada. Personal Genome Diagnostics (Labcorp) in Baltimore.and the Cancer Institute, New York, NY.

The study was funded by the Cancer Institute, Mark Foundation for Cancer Research and Personal Genomic Diagnostics. The analysis was supported in part by the Canadian Cancer Society (grant 707213). National Institutes of Health (grant CA121113) and Commonwealth Foundation.

Anagnostou received research funding from AstraZeneca and Personal Genome Diagnostics to Johns Hopkins University. She has received research funding from Bristol-Myers Squibb and Delphi Diagnostics to Johns Hopkins University over the past five years, and serves on advisory boards for AstraZeneca and NeoGenomics. She is an inventor on several patent applications filed by Johns Hopkins University related to cancer genomic analysis, ctDNA treatment response monitoring, and immunogenomic signatures of response to immunotherapy, which are one of her Licensed to more than one entity. Under the terms of these license agreements, the University and the inventor are entitled to a share of fees and royalties. These relationships are managed by Johns Hopkins University in accordance with its conflict of interest policy.