Abstract
Background: First-generation BRAF inhibitors (BRAFi) such as vemurafenib and dabrafenib demonstrated high response rates and prolonged survival in some BRAFV600-mutated cancers; however, most patients ultimately develop resistance. Furthermore, treatment-emergent skin and other epithelial malignancies present safety concerns. PLX8394 is a next-generation, orally available, small-molecule BRAFi. Unlike first-generation BRAFi, PLX8394 [a] does not induce paradoxical activation of the RAF/MEK/ERK pathway in cells with stimulated RAS signaling, and [b] blocks signaling from both monomeric BRAFV600 and dimeric BRAFnon-V600 mutations. Thus, we hypothesize that PLX8394 may yield improved safety and broader, more durable efficacy than first-generation BRAFi. Methods: Trial protocol PLX120-03 (NCT02428712) incorporates an open-label, multicenter, phase I study using a 3+3 design to determine the recommended phase II dose (RP2D) in patients with refractory or relapsed solid tumors with or without BRAF mutation. Other endpoints are safety, including dermatologic and ophthalmic adverse events (AEs), pharmacokinetics (PK), and response per RECIST1.1. Dose escalation includes cohorts with either PLX8394 monotherapy or PLX8394 coadministered with an oral CYP3A4 inhibitor, cobicistat 150mg, to enhance systemic PK. Enrollment at the RP2D continues in the subsequent phase II study. Results: Of 26 patients who received at least 1 dose of PLX8394, 15 patients (10 with BRAF mutation) were enrolled to cohorts with PLX8394 monotherapy: 450mg BID (n=8), 900mg BID (n=3), 450mg TID (n=4). PK studies demonstrated lower than expected drug exposures; the protocol was amended and 11 additional patients (8 with BRAF mutation) were enrolled in cohorts with PLX8394 coadministered with cobicistat: 450mg BID (n=5) and 900mg BID (n=6). As of 31 May 2017 cutoff, 15 subjects terminated the study: 14 for disease progression, 1 subject withdrawal. Duration of study drug exposure was a median of 56 (22 - 727) days. Reversible Grade (G) 3 transaminitis in a patient treated with PLX8394 900mg BID + cobicistat was the only dose-limiting toxicity (DLT); rechallenge with PLX8394 alone was tolerated without recurrence of transaminitis. PLX8394 900mg BID + cobicistat was declared as RP2D. Treatment-related G>3 AEs other than DLT included G3 diarrhea (n=1), G3 anorexia (n=1), both in PLX8394 monotherapy cohorts and both manageable with supportive care. There were no cutaneous or ocular AEs. Cobicistat coadministration resulted in a 2-3 fold increase in PLX8394 systemic exposure, with RP2D achieving the projected efficacious exposure range based on preclinical models. There were no objective responses in PLX8394 monotherapy cohorts; however, to date 2 (28%) of 7 evaluable BRAF mutant patients treated with PLX8394 + cobicistat achieved partial responses (BRAFV600E-mutated colorectal cancer, 42% and BRAFV600E-mutated glioma, 65%; both BRAFi naive), which were confirmed by 8-wk serial scans. Tumors without BRAF mutation showed no response. Conclusion: PLX8394 with cobicistat was very well tolerated and showed promising activity in refractory solid tumors with BRAF mutation. A phase II study in BRAF-mutated cancers is ongoing.
Citation Format: Filip Janku, Ulka Vaishampayan, Vivek Khemka, Minny Bhatty, Chao Zhang, Henry H. Hsu, Paul S. Lin, Sandra Tong, Sunil Sharma. Results of a phase I study of PLX8394, a next-generation BRAF inhibitor, in refractory solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B176.