Publication date: Mar 17, 2020
Lifirafenib is an investigational, reversible inhibitor of B-RAF, 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.
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.
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 melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAF thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAF 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).
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-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.
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Desai, J., Gan, H., Barrow, C., Jameson, M., , Atkinson, Haydon, A., Millward, M., Begbie, S., Brown, M., Markman, B., Patterson, W., Hill, A., Horvath, L., Nagrial, A., Richardson, G., Jackson, C., Friedlander, M., Parente, P., Tran, B., Wang, L., Chen, Y., Tang, Z., Huang, W., Wu, J., Zeng, D., Luo, L., and Solomon, B. Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors. 26130. 2020 J Clin Oncol.