Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors
Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael P. Brown, Ben Markman, W. K. Patterson, Andrew Hill, Lisa G. Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedländer, Phillip Parente, Ben Tran, Lai Wang, Yunxin Chen, Zhiyu Tang, Wendy Huang, John Wu, Dewan Zeng, Lusong Luo, Benjamin Solomon
Abstract
PURPOSE Lifirafenib is an investigational, reversible inhibitor of B-RAF V600E , wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and efficacy of lifirafenib in patients with B-RAF– or K-RAS/N-RAS–mutated solid tumors. METHODS During dose escalation, adult patients with histologically/cytologically confirmed advanced solid tumors received escalating doses of lifirafenib. Primary end points were safety/tolerability during dose escalation and objective response rate in preselected patients with B-RAF and K-RAS/N-RAS mutations during dose expansion. RESULTS The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade ≥ 3 treatment-emergent adverse events were hypertension (n = 23; 17.6%) and fatigue (n = 13; 9.9%). One patient with B-RAF–mutated melanoma achieved complete response, and 8 patients with B-RAF mutations had confirmed objective responses: B-RAF V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF V600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAF V600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with B-RAF–mutated non–small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with K-RAS–mutated endometrial cancer and K-RAS codon 12–mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with K-RAS/N-RAS–mutated colorectal cancer (n = 20). CONCLUSION Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF V600 –mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS–mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.