Results from the first stage of a Phase II clinical trial suggest that measuring circulating tumor DNA (ctDNA) captured in blood-based liquid biopsies may help to identify those advanced non-small cell lung cancer (NSCLC) patients undergoing immunotherapy who could benefit from treatment with additional drugs. Data from this first stage of the international Phase II BR.36 study in the United States and Canada, which is led by investigators at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy, BC Cancer, and the Canadian Cancer Trials Group (CCTG), suggest that ctDNA analyses could be used as an early marker of immunotherapy response in certain immune-oncology (IO) settings, and may help to guide therapy.
“There is an unmet clinical need to implement real-time, minimally invasive molecular analyses to understand patients’ responses to cancer treatments and guide clinical decision-making,” said lead study author Valsamo “Elsa” Anagnostou, MD, PhD, director of the thoracic oncology biorepository at Johns Hopkins, leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board, and co-director of the Lung Cancer Precision Medicine Center of Excellence. “Our study demonstrates that ctDNA response correlated with tumor size seen on imaging, which is the gold standard for monitoring response to cancer treatments and seemed to be better correlated with survival. This suggests ctDNA could be used as a strategy to identify patients at high risk of disease progression who could benefit from a switch in their therapeutic regimen.”
The results from this first, independent observational stage of the BR.36 study were reported in Nature Medicine, in a paper titled “ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results.” In their paper, the team concluded, “Overall, our findings support the implementation of liquid biopsies in interventional IO clinical trials and further advance the evidentiary roadmap toward integration of ctDNA molecular responses in clinical decision-making for the increasing number of patients receiving immunotherapy.”
Immunotherapies are designed to unleash the power of the immune system against cancers, but despite their success in improving survival for some patients, they pose a challenge to the standard use of imaging to determine treatment response, because changes in imaging may not always reflect how well immunotherapy is working. “… we face emerging challenges related to heterogeneity in clinical responses and insufficiency of imaging to rapidly and accurately capture therapeutic response,” the authors noted.
Liquid biopsies may offer another way to help determine which patients are benefiting from available immunotherapies, and could represent a new endpoint for clinical trials that are testing these treatments. “Liquid biopsies are gaining momentum in immuno-oncology (IO) as they can be used to rapidly and accurately determine clinical response, especially in the metastatic setting,” the team noted. “Liquid biopsy analyses of circulating cell-free tumor DNA (ctDNA) have shown promise in capturing tumor burden dynamics during immune checkpoint blockade, allowing patients with primary resistance to be rapidly identified and redirected to receive alternative therapies.” But while initial reports are promising, the authors pointed out that “… several outstanding urgent questions need to be answered before implementation of liquid biopsy-guided ctDNA molecular responses in clinical decision-making.”
The BR.36 clinical trial (NCT04093167) is designed to establish the role of ctDNA as an early measurement of immunotherapy response by first defining ctDNA response, its timing and how it compares with the gold standard of imaging tests, and then by using ctDNA response to guide treatment for patients with advanced NSCLC.
The first stage of the trial enrolled patients with advanced/metastatic NSCLC who were eligible for standard-care immunotherapy using single-agent pembrolizumab. The aim was to evaluate, through serial liquid biopsy analyses, “ … the optimal definition, timing, and concordance of ctDNA molecular response with radiographic response.”
The investigators hypothesized that liquid biopsies would rapidly and accurately predict outcomes for patients. For this observational stage of the BR.36 study, they enrolled 50 patients with advanced or metastatic non-small cell lung cancer at six medical centers in the United States and Canada, between May 2020 and September 2022. Nearly all patients had been smokers, and 92% received no prior therapies. The group was 82% white, 52% female, and 56% age 65 years or older. The goals were to identify the optimal timepoint for ctDNA molecular response and to see how well molecular response correlated to response evaluation criteria in solid tumors (RECIST), the standard for measuring response to cancer treatment by monitoring changes in tumor size as seen on imaging.
Patients received the immunotherapy drug pembrolizumab based on standard of care, at a 200 mg or 2 mg/kg infusion every three weeks. After the first three cycles, investigators could switch to a 400 mg or 4 mg/kg infusion every six weeks. Patients remained in the trial until they received 24 months of therapy, had unacceptable drug toxicity, or imaging tests revealed progression of disease.
Investigators performed RECIST response assessments every six weeks until week twelve, and at longer intervals thereafter. They also collected blood samples from patients prior to treatment administration on the first day of the first cycle (baseline), the first day of the second cycle (three weeks into treatment), and the first day of the third cycle (six weeks) of treatment. These were used to conduct a ctDNA response assessment at these timepoints and to define molecular response as ctDNA clearance on the first day of the third cycle of treatment with pembrolizumab.
Analyses of molecular response were assessed using the Personal Genome Diagnostics (PGDx) elio liquid biopsy platform, which “represents an exciting opportunity for tailoring immunotherapy to enhance the interpretation of patterns of tumor response and progression during treatment,” stated study co-author Mark Sausen, PhD, executive director and head of technology innovation, PGDx, Labcorp.
The reported results indicated found that serial testing ctDNA using next-generation sequencing allowed early detection of immunotherapy responses, within an average of eight weeks after treatment started. A ctDNA response (ctDNA no longer detected in the blood) reflected tumor shrinkage by imaging. However, there were notable exceptions that indicated the ctDNA response may capture survival more accurately, especially for patients with stable disease on imaging.
Compared to patients who did not have a ctDNA response, patients with a ctDNA response had a longer progression-free survival, with a difference of 2.6 months versus 5.03 months respectively. In addition, patients with a ctDNA response had a longer overall survival (OS), with median survival not reached at the time of analysis, compared with 7.23 months. “ … ctDNA molecular response, defined as complete clearance of circulating tumor load after two cycles of pembrolizumab, was largely concordant with radiographic response assessments but, notably, was more informative in predicting OS,” the scientists stated.
“ctDNA response is particularly informative to understand the complexity of stable disease on imaging, which represents a sizable fraction of patients in whom imaging fails to timely and accurately detect the magnitude of therapeutic response,” Anagnostou said.
The study investigators will incorporate their findings into the second stage of the BR.36 trial, which will evaluate the potential clinical benefit of tailoring treatment for patients with lung cancer based on their ctDNA responses after two cycles of pembrolizumab treatment. ctDNA response will be used to identify patients with lung cancer at high risk for disease progression, who will be subsequently randomized to treatment intensification with pembrolizumab and chemotherapy, versus continuation of pembrolizumab.
“Taken together, we show that ctDNA molecular response can identify patients with metastatic NSCLC less likely to attain favorable clinical outcomes with single-agent anti-PD-1 therapy, and this opens a therapeutic window of opportunity for treatment intensification for patients with molecular disease progression,” the team noted in their published paper.
Co-corresponding study author Janet Dancey, MD, director of the Canadian Cancer Trials Group, further stated, “ctDNA has the potential to improve our ability to advise patients on the best treatment options for them. It may be better than traditional imaging in determining changes to treatments or providing assurance that patients should continue their current treatment. Our initial study indicates promising results, and we will move forward with a larger trial to clearly show whether ctDNA monitoring provides useful information based on treatment recommendations.”
“The 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 being designed as a registrational study, meaning if the study meets its primary endpoint, the ctDNA detection assay used in the BR.36 study could be approved. This could lead to molecular assessment by liquid biopsies becoming the standard means of assessing whether first-line patients with non-small cell lung cancer are responding to cancer immunotherapies, compared to conventional radiographical assessment of response.”
