Results from the first phase of a Phase II clinical trial, which measures circulating tumor DNA (ctDNA) captured with a blood-based liquid biopsy, showed that patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy suggests that it may help identify patients who may benefit from treatment. With additional medicine. Data from the first phase of the international Phase II BR.36 trial in the United States and Canada led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg Kimmel Cancer Immunotherapy Institute., BC Cancer and the Canadian Cancer Trials Group (CCTG) suggest that ctDNA analysis can be used as an early marker of immunotherapy response in certain immuno-oncology (IO) settings and may help guide treatment. .
“There is an unmet clinical need to perform real-time, minimally invasive molecular analyzes to understand patient responses to cancer treatments and guide clinical decision-making,” said the study’s senior authors. Yes, said Valsamo “Elsa” Anagnostou, MD, director of the institute. Johns Hopkins Thoracic Oncology Biorepository, Precision Oncology Analytics Leader, Johns Hopkins Molecular Tumor Committee Co-Leader, and Lung Cancer Precision Medicine Center of Excellence Co-Director. “Our study demonstrates that ctDNA response correlates with tumor size seen on imaging tests, which is the gold standard for monitoring response to cancer treatment and is the gold standard for survival and better outcomes. There appears to be a correlation.” This suggests that ctDNA can be used as a strategy to identify patients at high risk of disease progression who may benefit from a change in treatment regimen. ”
BR.36 The results of this first independent observational phase of the study were: natural medicineIn a paper titledctDNA response after pembrolizumab in non-small cell lung cancer: results from a phase 2 adaptive trial“Overall, our findings support the implementation of liquid biopsies in interventional IO clinical trials, and the use of ctDNA molecules in clinical decision-making as the number of patients receiving immunotherapy increases,” the research team wrote in their paper. “This further advances the evidence roadmap towards response integration.” ”
Immunotherapy is designed to unleash the power of the immune system against cancer, but although it has been successful in improving survival rates for some patients, changes in imaging are not always effective. This poses challenges to the standard use of imaging to determine treatment response. Immunotherapy is working. “…we face new challenges related to the heterogeneity of clinical responses and the inadequacy of imaging to rapidly and accurately capture treatment responses,” the authors noted. .
Liquid biopsies may provide another method to help determine which patients benefit from available immunotherapies and represent a new endpoint for clinical trials testing these treatments. There is a possibility. “Liquid biopsy is gaining momentum in immuno-oncology (IO) as it can be used to quickly and accurately determine clinical response, especially in the metastatic setting,” the research team noted. “Liquid biopsy analysis of circulating cell-free tumor DNA (ctDNA) has shown promise in understanding tumor burden dynamics during immune checkpoint blockade and can rapidly identify patients with primary resistance. However, while the initial reports are promising, the authors note that “how much more remains to be done before implementing liquid biopsy-based ctDNA molecular responses in clinical decision-making.” We need to answer those unanswered and urgent questions.”
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 evaluate the use of ctDNA as an initial measure of immunotherapy response. Designed to establish roles. Guide the treatment of patients with advanced NSCLC.
The first phase of the study enrolled patients with advanced/metastatic NSCLC eligible for standard-of-care immunotherapy with single-agent pembrolizumab. The aim was to assess “the optimal definition, timing, and agreement of ctDNA molecular responses with radiographic responses” through sequential liquid biopsy analysis.
Researchers hypothesized that liquid biopsy could quickly and accurately predict patient outcomes. This observational phase of the BR.36 study enrolled 50 patients with advanced or metastatic non-small cell lung cancer at his six medical centers in the United States and Canada between May 2020 and September 2022. I did. Almost all patients were smokers. and 92% had not received 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. They also took blood samples from patients on the first day of the first cycle (baseline), the first day of the second cycle (three weeks after starting treatment), and the first day of the third cycle (six weeks) before treatment administration. process. 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 study co-author Mark Thorsen. , Ph.D., Executive Director and Head of Innovation at Labcorp, PGDx.
The reported results showed that serial testing of ctDNA using next-generation sequencing allows early detection of immunotherapy responses, within an average of 8 weeks after starting treatment. The ctDNA response (no longer detectable ctDNA in the blood) reflected tumor shrinkage by imaging. However, there were notable exceptions indicating that ctDNA responses may more accurately capture survival, especially in patients with stable disease on imaging.
Compared with patients without a ctDNA response, patients with a ctDNA response had a longer progression-free survival, with a difference of 2.6 months vs. 5.03 months, respectively. Furthermore, the overall survival (OS) of patients who showed a ctDNA response was longer compared to 7.23 months, and median survival had not been reached at the time of analysis. “…ctDNA molecular response, defined as complete removal of circulating tumor burden after two cycles of pembrolizumab, was broadly consistent with radiographic response assessment but was more informative, particularly in predicting OS.” the scientists said.
“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 is unable to timely and accurately detect the magnitude of treatment response.” Anagnostou said.
Study researchers plan to incorporate their results into the second phase of the BR.36 trial, which will assess the potential clinical benefit of tailored treatment for lung cancer patients based on ctDNA responses after two cycles of pembrolizumab treatment. It’s planned. ctDNA responses are used to identify lung cancer patients at high risk of disease progression, and patients are then randomized to either intensify treatment with pembrolizumab and chemotherapy or continue pembrolizumab.
“Taken together, we show that ctDNA molecular responses can identify patients with metastatic NSCLC who are unlikely to achieve good clinical outcomes with single-agent anti-PD-1 therapy, thereby enhancing treatment for patients with molecular disease.” “This opens up opportunities for ongoing research,” the research team wrote in their paper.
Co-study author Janet Dancy, MD, PhD, director of the Canadian Cancer Trials Group, added: “ctDNA has the potential to improve our ability to advise patients on the most appropriate treatment. Changes in Treatment may be better than traditional imaging in determining the Now that the results have been shown, we will move forward with larger trials to clearly demonstrate whether ctDNA monitoring provides useful information on which to base treatment recommendations.”
“The Cancer 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 designed as a registration study, meaning that the ctDNA detection assay used in the BR.36 study may be approved if the study meets its primary endpoint. Compared to traditional radiographic response assessment, liquid biopsy enables molecular assessment to become the standard means of assessing whether first-line patients with non-small cell lung cancer are responding to cancer immunotherapy. there is a possibility.”
