Researching an Early Marker for Immunotherapy Response

Immunotherapy: ImmunotherapyLiquid biopsies are blood tests that can serially measure circulating tumor DNA. When used in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy, they may identify patients who could benefit from treatment with additional drugs, according to a Phase II clinical trial in the U.S. and Canada. The trial 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. The results suggest that ctDNA analyses could be used as an early marker of immunotherapy response and may help guide therapy (Nat Med 2023; https://doi.org/10.1038/s41591-023-02598-9). Immunotherapies are drugs that unleash the power of the immune system against cancers. Despite their success in improving survival, 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. Liquid biopsies may help determine which patients are benefiting from available immunotherapies and could be a new endpoint for clinical trials testing these treatments. Although initial reports are promising, how these approaches can best be used has not been established through a clinical trial. Study Details 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 BR.36 trial found that, by serial testing ctDNA using next-generation sequencing, immunotherapy responses were detected early, within an average of 8 weeks after treatment started. A ctDNA response (i.e., ctDNA no longer detected in the blood) reflected tumor shrinkage by imaging. However, there were notable exceptions showing that 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—a difference of 2.6 months versus 5.03 months, respectively. In addition, patients with a ctDNA response had a longer overall survival, with median survival not reached at the time of analysis. “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,” noted Valsamo “Elsa” Anagnostou, MD, PhD, lead study author and Director of the Thoracic Oncology Biorepository at Johns Hopkins. “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 it 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.” Research Findings Investigators hypothesized that liquid biopsies would rapidly and accurately predict outcomes for patients. During the first stage of the BR.36 study, investigators enrolled 50 patients with advanced or metastatic non-small cell lung cancer at six medical centers in the U.S. and Canada between May 2020 and September 2022. Nearly all patients had been smokers and 92 percent received no prior therapies. The group was 82 percent White, 52 percent female, and 56 percent age 65 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 with 200 mg or 2 mg/kg infusion every 3 weeks. After the first 3 cycles, investigators could switch to a 400 mg or 4 mg/kg infusion every 6 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 6 weeks until Week 12 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 (3 weeks into treatment), and the first day of the third cycle (6 weeks) of treatment. These were used to conduct a ctDNA response assessment at these timepoints and define molecular response as ctDNA clearance on the first day of the third cycle of treatment with pembrolizumab. Anagnostou noted, “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.” Implementing the results from the first stage of the BR.36 trial, investigators moved forward with the second stage of the trial, in which they will evaluate the potential clinical benefit of tailoring treatment for patients with lung cancer based on their ctDNA responses after 2 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. Oncologists' Guide to Genomics Discover highlights of the latest trends in genomics and molecular diagnostics for oncology. Each month, a new feature will explore the latest tests and treatments developing in this fast-paced field. Read more at https://tinyurl.com/w9a4kxp4.

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