Early ctDNA Dynamics Predict Response to Mosperafenib in BRAF V600-Mutant Metastatic Colorectal Cancer.

UNLABELLED: The serine-threonine protein kinase B-RAF (BRAF) V600 mutation confers a poor prognosis in metastatic colorectal cancer (mCRC). Mosperafenib is a novel, paradox-breaking BRAF inhibitor (BRAFi). In this analysis of a phase I study (ISRCTN13713551), we evaluated circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker for mosperafenib monotherapy in BRAF V600-mutant mCRC. We analyzed 49 biomarker-evaluable patients with mCRC (BRAF V600-mutant; 23 BRAFi-naive, and 26 BRAFi-experienced). Plasma samples were collected at baseline and longitudinally. ctDNA levels were quantified using tumor-naive and tumor-informed assays and correlated with RECIST 1.1 response and progression-free survival (PFS). Mutational profiles were assessed to identify resistance mechanisms. Low baseline ctDNA (≤10% tumor fraction) was prognostic for longer median PFS (mPFS; 284 vs. 59 days; HR = 0.32, P = 0.00051). Early ctDNA dynamics were highly predictive; a ≥75% ctDNA reduction at cycle 1 day 15 (C1D15; "molecular response") correlated with longer mPFS (281 vs. 43 days, P < 0.0001). This molecular response occurred in all BRAFi-naive patients versus 48% of BRAFi-experienced patients. Preexisting MAPK pathway resistance mutations were prevalent and prognostic for poor outcomes in the BRAFi-experienced cohort (HR = 3.5, P = 0.003), whereas BRAFi-naive patients acquired these at progression. ctDNA is a powerful biomarker for mosperafenib-treated BRAF V600-mutated mCRC. Low baseline ctDNA is highly prognostic, whereas an early, deep molecular response at C1D15 predicts durable benefit. This response is largely confined to BRAFi-naive patients, as preexisting MAPK pathway alterations in BRAFi-experienced patients correlate with lack of response. These findings support using early ctDNA dynamics as an efficacy endpoint in future trials.

SIGNIFICANCE: This study in BRAF V600-mutant mCRC treated with mosperafenib confirms ctDNA's translational utility. Low baseline ctDNA associated with longer PFS and an early deep molecular response predicted durable clinical benefit, supporting its use as an early efficacy endpoint. In addition, ctDNA monitoring enables identification of resistance mechanisms.