Landmark ctDNA molecular response represents an early predictor of immunotherapy outcomes in lung cancer: A clinical validity study

PURPOSE: Circulating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC); however, the clinical value of ctDNA molecular response requires further validation. PATIENTS AND METHODS: As part of a prospective clinical protocol (NCT05995821), we conducted targeted error-correction sequencing of ctDNA (n=328) and matched WBC DNA (n=109) from 109 patients with metastatic NSCLC who received anti-PD-(L)1 either as monotherapy or in combination. Following cellular origin resolution of 2,818 variants, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation. RESULTS: Pre-treatment ctDNA burden, but not blood tumor mutation burden, predicted survival. Implementing a tumor-naïve WBC DNA-informed approach increased the number of evaluable cases without compromising the overall accuracy of landmark ctDNA molecular responses. A direct comparison of single-timepoint on-therapy ctDNA assessment with ctDNA dynamics from baseline to the 3-9-week interval, along with an analysis of heterogeneity in molecular response within the 3-9-week window, showed that undetectable ctDNA at the landmark timepoint can effectively predict survival outcomes. A significant enrichment in landmark ctDNA mR was noted among patients with progression-free survival (PFS) ≥6 months on immunotherapy (p=2.5e-05) or chemo-immunotherapy (p=0.02). Patients in the landmark mR group had longer progression-free (p=1.6e-06) and overall survival (p=2.5e-05) than those with molecular progression. CONCLUSIONS: Landmark ctDNA molecular response provides a real-time, accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential validity of ctDNA as an early endpoint of immunotherapy response.

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Journal
Clinical Cancer Research
Published
2026-07-23
DOI
https://doi.org/10.1158/1078-0432.ccr-26-0656
Primary Topic
Cancer Genomics and Diagnostics
Type
article
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article

Landmark ctDNA molecular response represents an early predictor of immunotherapy outcomes in lung cancer: A clinical validity study

Lavanya Sivapalan, Victor E. Velculescu, Benjamin Levy, Julie R. Brahmer et al.
Clinical Cancer Research
Cancer Genomics and Diagnostics
article

Landmark ctDNA molecular response represents an early predictor of immunotherapy outcomes in lung cancer: A clinical validity study

Lavanya Sivapalan, Victor E. Velculescu, Benjamin Levy, Julie R. Brahmer, Archana Balan, Jamie E. Medina, Gavin Pereira, Susan C. Scott, Nisha Rao, Valsamo Anagnostou, Nicholas C. Dracopoli, Kristen Ashley Marrone, Patrick M. Forde, Christine L. Hann, Joseph C. Murray, Vincent K. Lam, Bryan Chesnick, Lorenzo Rinaldi, Paz J. Vellanki, Josephine Feliciano, Shreshtha Jolly, Noushin Niknafs, Wenming Xiao, Aliyah Pabani, Mark Sausen, Qing Kay Li, Kavya Velliangiri, Jaime Wehr, Samira Hosseini-Nami, Tiffany Loftus, Iiasha Beadles
article en

Abstract

PURPOSE: Circulating tumor DNA (ctDNA) analyses are informative as an early indicator of immunotherapy response in advanced non-small cell lung cancer (NSCLC); however, the clinical value of ctDNA molecular response requires further validation. PATIENTS AND METHODS: As part of a prospective clinical protocol (NCT05995821), we conducted targeted error-correction sequencing of ctDNA (n=328) and matched WBC DNA (n=109) from 109 patients with metastatic NSCLC who received anti-PD-(L)1 either as monotherapy or in combination. Following cellular origin resolution of 2,818 variants, landmark molecular response (mR) was defined as undetectable ctDNA within 3-9 weeks of treatment initiation. RESULTS: Pre-treatment ctDNA burden, but not blood tumor mutation burden, predicted survival. Implementing a tumor-naïve WBC DNA-informed approach increased the number of evaluable cases without compromising the overall accuracy of landmark ctDNA molecular responses. A direct comparison of single-timepoint on-therapy ctDNA assessment with ctDNA dynamics from baseline to the 3-9-week interval, along with an analysis of heterogeneity in molecular response within the 3-9-week window, showed that undetectable ctDNA at the landmark timepoint can effectively predict survival outcomes. A significant enrichment in landmark ctDNA mR was noted among patients with progression-free survival (PFS) ≥6 months on immunotherapy (p=2.5e-05) or chemo-immunotherapy (p=0.02). Patients in the landmark mR group had longer progression-free (p=1.6e-06) and overall survival (p=2.5e-05) than those with molecular progression. CONCLUSIONS: Landmark ctDNA molecular response provides a real-time, accurate approach for monitoring immunotherapy clinical outcomes. Although not currently validated for regulatory use, these findings demonstrate the potential validity of ctDNA as an early endpoint of immunotherapy response.

Clinical Cancer Research
United States Food and Drug Administration (US), Center for Drug Evaluation and Research (US), Johns Hopkins University (US), Trinity College (CA), Trinity College Dublin (IE), Johns Hopkins Medicine (US), LabCorp (United States) (US), CCC Diagnostics (United States) (US), CS Diagnostics (DE), Food and Drug Administration (TH), Johns Hopkins Hospital (US), Sidney Kimmel Comprehensive Cancer Center (US)
Good health and well-being
Openalex Percentile: Top 11%
Cancer Genomics and Diagnostics
DOIOpen Access PDFOpenAlex
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