Treatment of patients with BRAF-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset

Background: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600Emutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is w4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. Methods: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. Results: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P ¼ 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after secondline TT, combinatory chemotherapy   anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridineetipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P ¼ 0.07; PPS: 6.5 versus 4.4 months, P ¼ 0.04). Conclusions: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy anti-VEGF appears the preferred treatment choice after TT failure.