Emergence of RAS mutations in RAS wild type metastatic colorectal cancer patients receiving cetuximab as first-line treatment: A prospective study.

38 Background: Metastatic colorectal cancers (mCRC) with wild-type KRAS are often sensitive to anti-EGFR, but occasionally develop resistance within treatment. A major limitation of treatment that selectively target kinase signaling pathways is the emergence of secondary resistance. However, interlink between emergence of KRAS mutations and secondary resistance to anti-EGFR remains to be further elucidated. In this study, we investigate evolutional changes of KRAS mutations through liquid biopsy in mCRC patients under cetuximab-treatment. Methods: Patients enrolled to receive cetuximab plus FOLFIRI or mFOLFOX6 as first-line treatment. The treatment was anticipated to be continued until disease-progression, intolerable toxic effects, or withdrawal of consent. Blood samples from patients were collected before and every three months during the cetuximab-treatment, and were required at disease-progression. These samples were evaluated for KRAS mutation using the MassARRAY platform. The primary endpoint was the percentage of patients with KRAS mutation detected during treatment. The clinical outcomes of these patients with emergence of mutant KRAS were further analyzed. Results: 108 mCRC cetuximab-treated patients, 95 patients combined with FOLFIRI and 13 patients with mFOLFOX6, were enrolled between January 2018 and June 2020. The median follow-up time was 26.5 months [interquartile range (IQR), 17.0-37.0 months]. The median duration of cetuximab-treatment was 9.0 months (IQR, 5.0-12.0 months). The percentage of detected KRAS mutations during cetuximab-treatment was 9.26%. Median emergent time of KRAS mutation from initial treatment was 5.0 months (IQR, 2.0-7.5 months). The median duration from KRAS mutation to disease-progression was 3.0 months (IQR, 2.0-6.5 months). The median progression-free survival (PFS) and overall survival (OS) of emergent RAS mutations and RAS wild-type were 8.0 versus 19.0 months ( P = 0.002) and 20.0 versus not-reach months ( P = 0.027), respectively. Conclusions: The identified KRAS mutations as a predictor of early resistance during cetuximab therapy, indicating that emergence of KRAS-mutant clones can be detected 3 months prior to radiographic progression. Emergent RAS mutations were associated with less favorable patient outcomes. Clinical trial information: NCT03401957 .