Abstract
Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3Ka inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Doselimiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed and median progression-free survival was 3.7 and 4.2 months for the dual-and triple-therapy groups, respectively.
SIGNIFICANCE: Herein, we demonstrate that dual-(encorafenib plus cetuximab) and triple-(encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC. (C) 2017 AACR.
Original language | English |
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Pages (from-to) | 610-619 |
Number of pages | 10 |
Journal | Cancer Discovery |
Volume | 7 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2017 |
Keywords
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents
- Antineoplastic Combined Chemotherapy Protocols
- Carbamates
- Cetuximab
- Colorectal Neoplasms
- Disease-Free Survival
- Female
- Humans
- Male
- Maximum Tolerated Dose
- Middle Aged
- Mutation
- Phosphatidylinositol 3-Kinase
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins B-raf
- Sulfonamides
- Thiazoles
- Clinical Trial, Phase I
- Journal Article
- Multicenter Study
- EGFR
- COLON-CANCER
- INHIBITION
- GENE COPY NUMBER
- WILD-TYPE
- FLUOROURACIL
- BIOMARKERS
- RAF
- KRAS
- MAPK PATHWAY