Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type ARAF, BRAF, CRAF and BRAF V600E, as well as EGFR. We report here the initial findings of the dose escalation component of an ongoing phase I first-in-human, dose escalation and expansion trial of BGB-283.

Methods: Safety, tolerability, pharmacokinetics, recommended phase 2 dose and antitumor activity of BGB-283 were evaluated in patients (pts) with advanced BRAF, N- or KRAS mutant solid tumors. The phase Ia dose escalation study utilized a modified 3+3 dose escalation design. Adverse events (AEs) are reported per CTCAE V4.03 and responses per RECIST V1.1.

Results: As of 31st Oct 2015, 31 pts (mutations: 18 KRAS; 3 NRAS; 7 BRAF V600E; 2 BRAF non-V600 and 1 NRAS/BRAF non-V600) enrolled in 7 cohorts received BGB-283 from 5 mg QD to 60 mg QD. BGB-283 was well tolerated. MTD was determined to be 40 mg/QD and dose-limiting toxicity (DLT) was thrombocytopenia. Most frequent treatment-related AEs were fatigue (68%), anorexia (48%), constipation (42%), thrombocytopenia (39%), nausea (39%), vomiting (39%), dermatitis acneiform (39%), hand-foot syndrome (35%), hypertension (35%) and dysphonia (32%). Frequent treatment-related Grade 3/4 AEs included thrombocytopenia (13%), fatigue (10%) and ALT increase (10%). Cutaneous malignancies associated with the approved first-generation BRAF inhibitors have not been observed in pts treated with BGB-283, with a mean follow-up of 6 months. The plasma concentrations of BGB-283 increased proportionally from 5 mg QD through 50 mg QD. The mean t½ of BGB-283 was around 110 hours. Among 29 evaluable pts, one of the only two melanoma pts with a BRAF V600E mutation had a partial response (PR) (on treatment over 249 days). In addition, there were two confirmed PRs including 1 pt with KRAS mutated endometrial cancer (on treatment over 456 days) and 1 thyroid cancer pt with BRAF V600E mutation (on treatment over 481 days); and one unconfirmed PR for 1 pt with KRAS mutated NSCLC (stable disease with transient PR and on treatment for over 572 days). Except for the K-RAS mutated endometrial cancer patient, all other three responders are still on study treatment at the cutoff date. Furthermore, 14 of the 29 evaluable pts achieved prolonged stable disease (3 pts have been on treatment for over 300 days), with the disease control rate at 62%. Finally, 18F-FDG uptake was measured at baseline and at the end of cycle 1 to evaluate BGB-283 pharmacodynamic activity. Partial metabolic responses were observed in 13/30 (43%) pts.

Conclusions: BGB-283 was well tolerated and the MTD on a continuous once daily dosing was determined at 40 mg/day. Promising clinical activity was observed at multiple dose levels in pts with BRAF or KRAS mutated tumors. BGB-283 activity and safety are being further investigated in a number of molecularly-defined tumors in an ongoing phase Ib expansion study.

Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Grant Mcarthur, Ben Tran, Michael Lam, Laird Cameron, Andrew Weickhardt, Jason Yang, Lai Wang, Zhen Qin, Lusong Luo, Ben Solomon. Phase I study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT005.