Vroege daling van circulair tumor-DNA voorspelt verbeterde overleving bij gevorderde kanker

BACKGROUND: Circulating tumor DNA (ctDNA) dynamics have emerged as a promising biomarker of treatment response in oncology drug development. Early decreases in ctDNA levels after treatment initiation are associated with improved long-term outcomes in patients with advanced cancer. To be considered for regulatory decision-making, patient-level meta-analyses evaluating individual-(I-) and trial-(T-) associations between early ctDNA changes and clinical outcomes using randomized controlled trial (RCT) datasets are necessary. METHODS: While not fit-for-purpose, the Friends of Cancer Research ctMoniTR Project patient-level dataset included 10 RCTs in advanced cancer that were aggregated. Cox proportional hazards models assessed I-associations between molecular response (MR) and overall survival (OS) or progression-free survival (PFS) using either 90% decrease (MR90) or clearance (MR100) as MR cutoffs. T-associations compared treatment effects on MR with treatment effects on OS or PFS. RESULTS: In pooled analyses across all trials, MR90 and MR100 were significantly associated with improved OS (MR90 adjusted hazard ratio [aHR] = 0.51, 95% CI 0.44-0.59; MR100 aHR = 0.45, 95% CI 0.39-0.53; both p < 0.0001) and improved PFS (MR90 aHR = 0.62, 95% CI 0.54-0.71; MR100 aHR = 0.56, 95% CI 0.48-0.64; both p < 0.0001). Associations were generally consistent across cancer types and treatment modalities. Trial-level associations between MR and OS were weak (R2 ~ 0.08-0.13), whereas associations between MR and PFS were stronger, particularly in aNSCLC (R2 up to 0.74). CONCLUSIONS: Early decreases in ctDNA were consistently associated with improved clinical outcomes at the individual-level across advanced cancers. Although trial-level associations were modest, stronger relationships with PFS support continued prospective evaluation of ctDNA dynamics as potential early endpoints in oncology drug development. Additional work using datasets that prospectively included plasma collection for ctDNA analyses is warranted.