Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer.

3514 Background: In contrast to BRAFV600 mutated (BRAFm) advanced melanoma, BRAFm colorectal carcinoma (CRC) does not respond to BRAF inhibitors due to strong feedback activation of the epidermal growth factor receptor (EGFR) upon BRAF inhibition. However, combining a BRAF and an EGFR inhibitor resulted in strong synergistic activity with complete inhibition of tumor growth in vitro and in vivo. The addition of a phosphatidylinositol 3-kinase (PI3K) inhibitor increased synergy. Methods: This is a phase I study evaluating safety, tolerability and anti-tumor activity of encorafenib (LGX818), a highly selective BRAF V600 inhibitor, the EGFR mAb cetuximab, ± the α-specificPI3K inhibitor BYL719 in patients (pts) with advanced BRAFm/KRAS wild-type CRC. Cohorts of pts were treated with escalating doses of oral encorafenib once daily in combination with IV cetuximab (400 mg/m2 loading dose, 250 mg/m2weekly) (dual arm), or with escalating doses of oral encorafenib and oral BYL719 once daily in combination with cetuximab (triple arm). Results: By November 08, 2013, 18 pts were enrolled across four dual combination dose levels: 100 (n = 2), 200 (n = 4), 400 (n = 9) and 450 mg (n = 3) encorafenib. Three pts were enrolled in the triple arm at 200 mg encorafenib, 100 mg BYL719 and cetuximab. Dose escalation has been completed in the dual arm where a phase 2 dose has been identified; dose finding is ongoing in the triple arm. In the dual arm, 2 dose-limiting toxicities, vomiting grade 3 (400 mg) and QTc prolongation grade 3 (450 mg), were observed, and fatigue (33%) and vomiting (28%) were the most frequently observed treatment-related adverse events. Three partial responses, including one in the triple arm, have been observed and prolonged disease stabilization was frequently achieved including two pts that have remained on treatment for one year. Decrease in carcinoembryonic antigen (CEA) has also been observed. Updated data from the triple arm will be presented. Conclusions: These results indicate that combination treatment of encorafenib and cetuximab ± BYL719 is well tolerated with promising antitumor activity in pts with advanced BRAFm CRC who failed standard treatment. Clinical trial information: NCT01719380.