Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer.

3516 Background: BRAF V600 mutations, present in 5-10% of patients (pts) with metastatic colorectal cancer (mCRC), are considered poor prognostic markers, and <10% of BRAF-mutated mCRC pts respond to a combination of cetuximab (C) and irinotecan (I). Vemurafenib (V), an oral kinase inhibitor to the mutated V600 isoform of BRAF, demonstrated a 5% response rate in a phase I trial with BRAF-mutated mCRC. In vitro data in CRC cell lines has shown that blockade of mutated BRAF by vemurafenib triggers compensatory activation of EGFR. Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, further augmented by irinotecan. The safety and efficacy of the combination in pts with BRAF-mutated advanced malignancies have not been studied. Methods: In this 3+3 phase I study, pts with refractory BRAF-mutated cancer received escalating doses of vemurafenib in combination with cetuximab and irinotecan over a 14-day cycle. Radiographic responses were evaluated every 4 cycles ...