A single blood draw performed three to nine weeks after treatment begins predicted progression-free and overall survival months before standard imaging.
Researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy have determined that a liquid biopsy can predict within weeks whether patients with advanced non-small cell lung cancer are benefiting from immunotherapy.
The study, published in Clinical Cancer Research, found that a single blood draw performed during a window of three to nine weeks after starting anti-programmed death-ligand 1 immunotherapy accurately detected circulating tumor DNA. This molecular response served as a predictor for both progression-free and overall survival, providing results months earlier than standard imaging.
“Our findings establish landmark ctDNA molecular response as an early predictor of immunotherapy benefit and demonstrate that a practical, tumor-naïve, single-timepoint liquid biopsy approach can provide clinically meaningful information weeks before conventional imaging, supporting further evaluation of the strategy in routine patient care and future clinical trials,” says Valsamo Anagnostou, MD, PhD, co-director of the Upper Aerodigestive Malignancies and Cancer Genetics and Epigenetics programs and the Lung Cancer Precision Medicine Center of Excellence, in a release.
Survival Data and Molecular Response
The study included 109 patients with advanced non-small cell lung cancer. Researchers analyzed 328 plasma samples and matched white blood cell samples collected during treatment.
According to the study, patients whose circulating tumor DNA became undetectable during the three-to-nine-week interval remained free of disease progression for a median of 26.6 months. In contrast, patients with detectable circulating tumor DNA had a median progression-free survival of 3.4 months. The median overall survival for the undetectable group was 46.9 months, compared to 11.4 months for those with detectable levels.
To improve accuracy, the researchers utilized an approach that does not require tumor tissue. Instead, they analyzed DNA from white blood cells to distinguish true tumor DNA from age-related genetic changes known as clonal hematopoiesis.
“When we did not remove these blood-cell mutations, the prognostic value of the test disappeared,” says Noushin Niknafs, PhD, research associate in the Anagnostou lab and lead author of the study, in a release. “By incorporating matched white blood cell sequencing, we were able to accurately identify the tumor-derived DNA that truly reflects treatment response.”
Clinical Utility and Real-World Adoption
Immunotherapy can produce ambiguous early imaging results, such as pseudoprogression, where tumors appear larger before shrinking. An early molecular assessment provides clinicians with a tool to determine if a therapy is effective, potentially sparing patients from ineffective, toxic, and costly treatments.
The researchers noted that the single-timepoint format is specifically designed for real-world clinical adoption because it reduces costs and the logistical burden of requiring tumor tissue.
“The tumor-naïve, single-timepoint format matters for real-world adoption,” says Anagnostou, in a release. “It removes the need for tumor tissue and reduces costs and logistical burden, making the test more deployable in routine oncology settings rather than only in specialized centers.”
The study was supported by the Oncology Center of Excellence at the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the Bloomberg-Kimmel Institute for Cancer Immunotherapy. Researchers suggest that this molecular readout could eventually serve as an early surrogate endpoint for immunotherapy response in clinical trials, supporting faster decisions and more adaptive trial designs.
Photo caption: The Johns Hopkins Kimmel Cancer Center Thoracic Clinical Research Program Team
Photo credit: Vincent Lam
