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@article{Serrano-Serrano:2026:10.1158/2767-9764.CRC-26-0196,
author = {Serrano-Serrano, ML and Godfried, Sie C and Bechter, O and Pretelli, G and Vieito, M and Fontana, E and Han, CH and Casta帽贸n, 脕lvarez E and Matos, I and Pinato, DJ and Moreno, I and Eefsen, RL and Plummer, R and Dummer, R and Prenen, H and Sutton, J and Cinato, E and Schnetzler, G and Keshelava, N and Roller, A},
doi = {10.1158/2767-9764.CRC-26-0196},
journal = {Cancer Res Commun},
title = {Early ctDNA dynamics predict response to mosperafenib in BRAF V600-mutant metastatic colorectal cancer.},
url = {http://dx.doi.org/10.1158/2767-9764.CRC-26-0196},
year = {2026}
}
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TY  - JOUR
AB  - 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, p<0.0001). 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.
AU  - Serrano-Serrano,ML
AU  - Godfried,Sie C
AU  - Bechter,O
AU  - Pretelli,G
AU  - Vieito,M
AU  - Fontana,E
AU  - Han,CH
AU  - Casta帽贸n,脕lvarez E
AU  - Matos,I
AU  - Pinato,DJ
AU  - Moreno,I
AU  - Eefsen,RL
AU  - Plummer,R
AU  - Dummer,R
AU  - Prenen,H
AU  - Sutton,J
AU  - Cinato,E
AU  - Schnetzler,G
AU  - Keshelava,N
AU  - Roller,A
DO  - 10.1158/2767-9764.CRC-26-0196
PY  - 2026///
TI  - Early ctDNA dynamics predict response to mosperafenib in BRAF V600-mutant metastatic colorectal cancer.
T2  - Cancer Res Commun
UR  - http://dx.doi.org/10.1158/2767-9764.CRC-26-0196
UR  - https://www.ncbi.nlm.nih.gov/pubmed/42127914
ER  -
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