Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.

Abstract

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 <i>B-RAF</i>- or <i>K-RAS/N-RAS</i>-mutated solid tumors. 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 <i>B-RAF</i> and <i>K-RAS/N-RAS</i> mutations during dose expansion. 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 <i>B-RAF</i>-mutated melanoma achieved complete response, and 8 patients with <i>B-RAF</i> mutations had confirmed objective responses: <i>B-RAF</i>^V600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), <i>B-RAF</i>^V600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and <i>B-RAF</i>^V600E low-grade serous ovarian cancer (LGSOC; n = 1). One patient with <i>B-RAF</i>-mutated non-small-cell lung cancer (NSCLC) had unconfirmed partial response (PR). Patients with <i>K-RAS</i>-mutated endometrial cancer and <i>K-RAS</i> codon 12-mutated NSCLC had confirmed PR (n = 1 each). No responses were seen in patients with <i>K-RAS/N-RAS</i>-mutated colorectal cancer (n = 20). Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with <i>B-RAF</i>^V600-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as <i>K-RAS</i>-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 <i>RAS</i> mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.