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J Clin Oncol. 2020 Mar 17:JCO1902654. doi: 10.1200/JCO.19.02654. [Epub ahead of print]

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

Author information

1
Royal Melbourne Hospital, Melbourne, Victoria, Australia.
2
Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
3
Olivia Newton-John Cancer Wellness & Research Centre, Austin Hospital, Heidelberg, Victoria, Australia.
4
La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
5
Department of Medicine, University of Melbourne, Heidelberg, Victoria, Australia.
6
Wellington Hospital, Wellington, New Zealand.
7
Waikato Hospital and University of Auckland Waikato Clinical Campus, Hamilton, New Zealand.
8
Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
9
The Alfred, Melbourne, Victoria, Australia.
10
Linear Clinical Research, Nedlands, Western Australia, Australia.
11
Mid North Coast Cancer Institute, Port Macquarie, New South Wales, Australia.
12
Royal Adelaide Hospital, Adelaide, South Australia, Australia.
13
Monash Health and Monash University, Clayton, Victoria, Australia.
14
The Queen Elizabeth Hospital, Woodville South, South Australia, Australia.
15
Tasman Oncology Research, Southport, Queensland, Australia.
16
Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.
17
Westmead Hospital, Westmead, New South Wales, Australia.
18
Cabrini Health, Malvern, Victoria, Australia.
19
Dunedin Hospital, Dunedin, New Zealand.
20
Prince of Wales Hospital, Randwick, New South Wales, Australia.
21
Eastern Health Monash University, Box Hill Hospital, Box Hill, Victoria, Australia.
22
BeiGene (Beijing) Co, Beijing, People's Republic of China.
23
BeiGene USA, San Mateo, CA.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSION:

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.

PMID:
32182156
DOI:
10.1200/JCO.19.02654

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