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|Ref Type||Journal Article|
|Authors||Desai J, Gan H, Barrow C, Jameson M, Atkinson V, 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, Solomon B|
|Title||Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.|
|Journal||Journal of clinical oncology : official journal of the American Society of Clinical Oncology|
|Date||2020 Jul 01|
|Abstract Text||Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, 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-RAFV600E/K melanoma (n = 5, including 1 patient treated with prior B-RAF/MEK inhibitor therapy), B-RAFV600E thyroid cancer/papillary thyroid cancer (PTC; n = 2), and B-RAFV600E 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-RAFV600-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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Lifirafenib||BGB-283||BRAF Inhibitor 22 EGFR Inhibitor (Pan) 58||Lifirafenib (BGB-283) is a dual RAF kinase and EGFR inhibitor, which may lead to decreased tumor cell proliferation and reduced growth of tumors with activation of BRAF and/or EGFR (PMID: 26208524, PMID: 32182156).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF V600X||Advanced Solid Tumor||predicted - sensitive||Lifirafenib||Phase I||Actionable||In a Phase I trial, Lifirafenib (BGB-283) treatment demonstrated safety and resulted in partial response (PR) in 15.1% (8/53) of advanced solid tumor patients harboring a BRAF mutation, including 5 patients with BRAF V600E/K-mutant melanoma, 2 patients with BRAF V600E-mutant thyroid cancer, and 1 patient with BRAF V600E-mutant low-grade serous ovarian carcinoma, complete response in 1.9% (1/53), in a patient with melanoma, and stable disease in 50.9% (27/53) (PMID: 32182156; NCT02610361).||32182156|
|BRAF V600E||ovarian serous carcinoma||predicted - sensitive||Lifirafenib||Case Reports/Case Series||Actionable||In a Phase I trial, Lifirafenib (BGB-283) treatment demonstrated safety and resulted in partial response (PR) in 15.1% (8/53) of advanced solid tumor patients harboring a BRAF mutation, including 1 patient with BRAF V600E-mutant low-grade serous ovarian cancer (PMID: 32182156; NCT02610361).||32182156|
|BRAF V600E/K||melanoma||predicted - sensitive||Lifirafenib||Case Reports/Case Series||Actionable||In a Phase I trial, Lifirafenib (BGB-283) treatment resulted in partial response in 15.1% (8/53) of solid tumor patients with BRAF mutations, including 5 of 23 patients with melanoma harboring BRAF V600E or V600K overall, and in the dose expansion phase 57.1% (4/7) patient with BRAF V600-mutant melanoma had a partial response (PMID: 32182156; NCT02610361).||32182156|
|BRAF V600E||thyroid gland cancer||predicted - sensitive||Lifirafenib||Case Reports/Case Series||Actionable||In a Phase I trial, Lifirafenib (BGB-283) treatment resulted in partial response in 15.1% (8/53) of solid tumor patients with BRAF mutations, including 2 thyroid cancer patients harboring BRAF V600E (1 in dose-escalation phase, 1 in the dose-expansion), and in the dose-expansion phase 1 of 3 thyroid cancer patients harboring a BRAF V600 mutation demonstrated a partial response and 2 demonstrated stable disease, resulting in a disease control rate of 100% (3/3) (PMID: 32182156; NCT02610361).||32182156|