Researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy have reported that a single liquid biopsy may reveal within weeks whether patients with advanced non-small cell lung cancer are benefiting from immunotherapy. The blood test measures circulating tumor DNA (ctDNA), fragments of genetic material released by cancer cells into the bloodstream. If validated in larger studies, the approach could help oncologists make treatment decisions months earlier than is possible with conventional imaging.
The study, published July 23 in Clinical Cancer Research, evaluated 109 patients with advanced non-small cell lung cancer who were receiving anti-PD-(L)1 immunotherapy. Researchers analyzed 328 plasma samples collected during treatment, together with matched white blood cell samples obtained before therapy began. The investigators focused on a predefined interval of three to nine weeks after immunotherapy started, seeking to determine whether ctDNA levels during this early window could predict later clinical outcomes.
Patients whose ctDNA became undetectable during the three-to-nine-week interval experienced markedly better outcomes than those whose tumor-derived DNA remained detectable. Median progression-free survival was 26.6 months among patients with undetectable ctDNA, compared with 3.4 months among patients with persistent ctDNA. Median overall survival was 46.9 months and 11.4 months, respectively. These results indicate that an early molecular response in the bloodstream closely reflected the ability of immunotherapy to control disease over the longer term.
The findings are particularly relevant because immunotherapy can make early imaging difficult to interpret. Unlike chemotherapy, which often produces more readily measurable changes, immune-based treatments may trigger inflammation around tumors or temporarily increase their apparent size. This phenomenon, known as pseudoprogression, can resemble disease growth on a scan. Patients may also develop mixed responses, with some tumors shrinking while others continue to grow. A molecular signal from the blood could provide an additional measure of treatment activity when radiographic findings are ambiguous.
The Johns Hopkins team found that one blood draw collected during the early treatment interval was nearly as informative as repeated sampling for predicting progression-free and overall survival. A single-timepoint test could therefore be more practical for routine oncology care than a monitoring strategy requiring multiple collections. The approach is also described as “tumor-naïve,” meaning that it does not require sequencing a tissue sample from the patient’s tumor before testing begins. This feature could be important for people with metastatic disease, in whom tissue biopsies may be difficult, unsafe, or insufficient for comprehensive analysis.
A major technical obstacle in ctDNA testing is that not every mutation detected in blood originates from a tumor. As people age, blood-forming stem cells can acquire genetic alterations that are passed to their descendants, a process called clonal hematopoiesis. These mutations can enter the bloodstream and resemble cancer-derived changes, potentially producing false signals or weakening the association between ctDNA and treatment response. To address this problem, the researchers sequenced DNA from matched white blood cells and used those results to identify and remove mutations likely to have originated in blood cells rather than tumors.
“When we did not remove these blood-cell mutations, the prognostic value of the test disappeared,” said lead author Noushin Niknafs, a research associate in Valsamo “Elsa” Anagnostou’s laboratory. By filtering out alterations associated with clonal hematopoiesis, the team was able to isolate tumor-derived DNA more accurately. The investigators say this blood-cell correction generated prognostic information comparable to methods that depend on tumor tissue, while reducing the logistical demands of testing in advanced cancer.
The study was conducted through the Johns Hopkins Immunobiology Blood and Tissue Collection Protocol, a prospective biobanking program for thoracic cancers. Patients were enrolled before sample collection, blood was drawn according to a standardized schedule, and clinical data and matched normal DNA were gathered using uniform procedures. This prospective design distinguishes the work from retrospective analyses based on stored specimens and was intended to improve reproducibility. The researchers emphasize that the clinical infrastructure supporting schedule-compliant sampling and consistent specimen processing was essential to the study.
The authors propose that early ctDNA response could eventually serve not only as a treatment-monitoring tool but also as a surrogate endpoint in immunotherapy trials. A molecular readout available within several weeks could help investigators make faster decisions about whether an experimental therapy warrants further development. However, the test is not yet presented as a replacement for imaging or as a universally established standard of care. Independent validation in broader patient populations and clinical trials will be needed before physicians can use the strategy to change treatment routinely. The work was supported by the National Institutes of Health, the U.S. Food and Drug Administration’s Oncology Center of Excellence, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, ECOG-ACRIN, the International Lung Cancer Foundation, and the Robyn Adler Fellowship Award.
Subject of Research: Early circulating tumor DNA response as a predictor of immunotherapy benefit in advanced non-small cell lung cancer.
News Publication Date: July 23.
Web References: Johns Hopkins Kimmel Cancer Center; Bloomberg~Kimmel Institute for Cancer Immunotherapy; Johns Hopkins Immunobiology Blood and Tissue Collection Protocol.
References: Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-26-0656.
Image Credits: Vincent Lam.
Keywords: Lung cancer, non-small cell lung cancer, immunotherapy, liquid biopsy, circulating tumor DNA, ctDNA, cancer biomarkers, clonal hematopoiesis, precision oncology, Johns Hopkins.
