Landmark ctDNA molecular response represents an early predictor of immunotherapy outcomes in lung cancer: A clinical validity study.
Abstract
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.
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.
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.
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.
EDRN PI Authors
Medline Author List
- Anagnostou V
- Balan A
- Beadles I
- Brahmer JR
- Chesnick B
- Dracopoli NC
- Feliciano J
- Forde PM
- Hann CL
- Hosseini-Nami S
- Jolly S
- Lam VK
- Levy B
- Li QK
- Loftus T
- Marrone KA
- Medina J
- Murray JC
- Niknafs N
- Pabani A
- Pereira G
- Rao N
- Rinaldi L
- Sausen M
- Scott SC
- Sivapalan L
- Velculescu VE
- Vellanki PJ
- Velliangiri K
- Wehr J
- Xiao W