encorafenib + alpelisib + cetuximab

A combination therapy comprised of **encorafenib** (a selective BRAF inhibitor), **alpelisib** (a selective PI3K alpha inhibitor), and **cetuximab** (an anti-EGFR monoclonal antibody). This triple therapy is under clinical investigation primarily for the treatment of **BRAF V600E-mutant metastatic colorectal cancer** (mCRC), especially in patients who have progressed on standard treatments. The rationale is to inhibit parallel signaling pathways (MAPK via BRAF and EGFR, and PI3K/AKT via PI3K alpha) that are known to drive resistance in BRAF-mutant mCRC. Preclinical and phase Ib/II studies have demonstrated that this combination shows tolerable safety and promising antitumor activity in this patient population[1][3]. - **Mechanism of action:** - Encorafenib blocks mutated BRAF kinase, halting MAPK pathway signaling. - Cetuximab inhibits EGFR, which provides feedback activation of MAPK in BRAF-mutant CRC. - Alpelisib blocks the PI3K/AKT pathway, which is another resistance mechanism to BRAF-targeted agents[3]. - **Primary Indication:** BRAF V600E-mutant metastatic colorectal cancer refractory to previous therapies[1][3]. - **Developer(s):** The component drugs have different original developers and manufacturers, but have also been tested together in academic-sponsored trials.