Abstract The 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 1 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 mCRC patients (BRAF V600 mutant; 23 BRAFi-naive, 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 C1D15 ("molecular response") correlated with longer mPFS (281 vs. 43 days, p0.0001). This molecular response occurred in all BRAFi-naive patients versus 48% of BRAFi-experienced. Pre-existing MAPK pathway resistance mutations were prevalent and prognostic for poor outcomes in the BRAFi-experienced cohort (HR=3.5, p=0.003), while 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, while an early, deep molecular response at C1D15 predicts durable benefit. This response is largely confined to BRAFi-naive patients, as pre-existing 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.
Serrano-Serrano et al. (2026) studied this question.