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Title: Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors.
Austin Authors: Desai, Jayesh;Gan, Hui K ;Barrow, Catherine;Jameson, Michael;Atkinson, Victoria;Haydon, Andrew;Millward, Michael;Begbie, Stephen;Brown, Michael;Markman, Ben;Patterson, William;Hill, Andrew;Horvath, Lisa;Nagrial, Adnan;Richardson, Gary;Jackson, Christopher;Friedlander, Michael;Parente, Phillip;Tran, Ben;Wang, Lai;Chen, Yunxin;Tang, Zhiyu;Huang, Wendy;Wu, John;Zeng, Dewan;Luo, Lusong;Solomon, Benjamin
Affiliation: Wellington Hospital, Wellington, New Zealand
Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
Dunedin Hospital, Dunedin, New Zealand
Waikato Hospital and University of Auckland Waikato Clinical Campus, Hamilton, New Zealand
BeiGene (Beijing) Co, Beijing, People's Republic of China
Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, Victoria, Australia
La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
Royal Melbourne Hospital, Melbourne, Victoria, Australia
Eastern Health Monash University, Box Hill Hospital, Box Hill, Victoria, Australia
Prince of Wales Hospital, Randwick, New South Wales, Australia
Cabrini Health, Malvern, Victoria, Australia
Westmead Hospital, Westmead, New South Wales, Australia
Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
Tasman Oncology Research, Southport, Queensland, Australia
The Queen Elizabeth Hospital, Woodville South, South Australia, Australia
Monash Health and Monash University, Clayton, Victoria, Australia
Royal Adelaide Hospital, Adelaide, South Australia, Australia
Mid North Coast Cancer Institute, Port Macquarie, New South Wales, Australia
Linear Clinical Research, Nedlands, Western Australia, Australia
The Alfred, Melbourne, Victoria, Australia
BeiGene USA, San Mateo, CA
Issue Date: Jul-2020
Date: 2020-03-17
Publication information: Journal of Clinical Oncology 2020; 38(19): 2140-2150
Abstract: 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.
DOI: 10.1200/JCO.19.02654
Journal: Journal of Clinical Oncology
PubMed URL: 32182156
Type: Journal Article
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