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

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.

Concepts Keywords
Codon Treatment of cancer
Combination Therapy Protein kinase inhibitor
Cytologically Ras GTPase
EGFR Non-small-cell lung carcinoma
Endometrial RTT
Endometrial Carcinoma MEK inhibitor
Fatigue Melanoma
Histologically Lung cancer
Hypertension Oncogenes
Inhibitor Clinical medicine
Lung Cancer
Maximum Tolerated Dose Fatigue
Melanoma Advanced solid tumors
RAF NSCLC
RAS Thrombocytopenia
Refractory Solid tumors
Reversible Inhibitor
Serous
Small Cell
Thrombocytopenia
Thyroid
Thyroid Cancer
Tolerability
Toxicity
Wild Type

Semantics

Type Source Name
disease MESH Tumors
drug DRUGBANK Rasagiline
disease MESH thrombocytopenia
disease MESH hypertension
disease MESH melanoma
pathway KEGG Melanoma
disease MESH thyroid cancer
pathway KEGG Thyroid cancer
disease MESH papillary thyroid cancer
disease MESH ovarian cancer
disease MESH lung cancer
disease MESH endometrial cancer
pathway KEGG Endometrial cancer
disease MESH colorectal cancer
pathway KEGG Colorectal cancer
disease MESH tumorigenesis
disease MESH carcinomas
drug DRUGBANK Serine
drug DRUGBANK L-Threonine
disease MESH squamous carcinoma
disease MESH keratoacanthomas
disease MESH relapse
drug DRUGBANK Vemurafenib
drug DRUGBANK Dabrafenib
disease MESH pancreatic cancer
pathway KEGG Pancreatic cancer
drug DRUGBANK Coenzyme M
disease MESH death
disease MESH dermatitis
disease MESH syndrome
disease MESH spasms
disease MESH chest pain
disease MESH candidiasis
disease MESH respiratory tract infection
disease MESH hypertrophy
disease MESH drug toxicity
disease MESH sepsis
disease MESH pleural effusion
disease MESH intestinal obstruction
disease MESH infection
disease MESH adenocarcinoma
drug DRUGBANK Etoperidone
disease MESH point mutations
drug DRUGBANK Bismuth subgallate
drug DRUGBANK (S)-Des-Me-Ampa
disease MESH growth
drug DRUGBANK Afatinib
pathway KEGG Platelet activation
pathway KEGG Apoptosis
disease MESH atherosclerosis
drug DRUGBANK Trapidil
disease MESH multiple myeloma
drug DRUGBANK Pirenzepine

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