Single Liquid Biopsy Predicts Early Immunotherapy Benefit in Advanced Lung Cancer

Early scans can also be difficult to interpret because of pseudoprogression or mixed responses, potentially delaying a switch from ineffective treatment. A blood-based marker that identifies therapeutic benefit sooner could help reduce unnecessary toxicity and costs. A new study suggests that a single liquid-biopsy measurement obtained within weeks of treatment initiation can predict outcomes and support earlier clinical decisions.

Researchers at the Johns Hopkins University School of Medicine, Johns Hopkins Kimmel Cancer Center, and Bloomberg Kimmel Institute for Cancer Immunotherapy evaluated circulating tumor DNA (ctDNA) molecular response using a tumor-naive, single-time-point liquid biopsy. The approach detects and quantifies ctDNA in a plasma sample collected during a predefined treatment window without requiring tumor tissue. To improve analytical specificity, the investigators also sequenced DNA from matched white blood cells to filter out variants associated with clonal hematopoiesis.

The prospective clinical validity study included 109 patients with advanced non-small cell lung cancer receiving anti-PD-(L)1 immunotherapy. Researchers analyzed 328 plasma samples collected during treatment, along with matched pretreatment white blood cell specimens. They compared a single blood draw obtained during a 3- to 9-week “landmark” interval after treatment initiation with serial blood sampling and standard imaging assessments. The single-time-point strategy performed as well as repeated sampling in predicting therapeutic benefit.

Patients whose ctDNA became undetectable during the 3‑ to 9‑week interval had a median progression‑free survival of 26.6 months versus 3.4 months when ctDNA remained detectable. Median overall survival was 46.9 months versus 11.4 months, respectively. The findings were published on July 23 in Clinical Cancer Research.

According to the authors, early molecular assessment from a blood sample could complement interpretation of ambiguous scans, helping clinicians determine whether to continue or switch therapy sooner. Because the method does not require tumor tissue and incorporates white blood cell sequencing to exclude clonal hematopoiesis, the investigators describe it as practical for routine oncology settings. They also note that landmark ctDNA molecular response may function as an early surrogate endpoint in immunotherapy trials, enabling faster decisions and more adaptive designs.

“Our findings establish landmark ctDNA molecular response as an early predictor of immunotherapy benefit and demonstrate that a practical, tumor-naive, single-time-point 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,” said Valsamo “Elsa” Anagnostou, M.D., Ph.D., co-director of the Upper Aerodigestive Malignancies and Cancer Genetics and Epigenetics programs and the Lung Cancer Precision Medicine Center of Excellence.

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