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

Jayesh Desai, Hui Gan, Catherine Barrow, Michael Jameson, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Ben Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, Phillip Parente, Ben Tran, Lai Wang, Yunxin Chen, Zhiyu Tang, Wendy Huang, John Wu, Dewan Zeng, Lusong Luo, Benjamin Solomon, Jayesh Desai, Hui Gan, Catherine Barrow, Michael Jameson, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Ben Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, Phillip Parente, Ben Tran, Lai Wang, Yunxin Chen, Zhiyu Tang, Wendy Huang, John Wu, Dewan Zeng, Lusong Luo, Benjamin Solomon

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.

Trial registration: ClinicalTrials.gov NCT02610361.

Figures

FIG 1.
FIG 1.
(A and B) Responses in patients with B-RAF–mutated cancers (both phases). (>) Ongoing treatment indicates ongoing response at time of data cutoff. An additional 6 patients not included in this figure had prior B-RAF inhibitor treatment (4 had melanoma, 1 had colorectal cancer, and 1 had adenocarcinoma with unknown primary origin). (*) Patients who received prior B-RAF/MEK inhibitor treatment. CR, complete response; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.
FIG 2.
FIG 2.
(A and B) Responses in patients with K-RAS–mutated cancers (excluding colorectal cancer; both phases). NE, not evaluable; NSCLC, non–small-cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.
FIG 3.
FIG 3.
Responses across lifirafenib dose cohorts by 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) analysis. Two patients were missing a postbaseline PET scan. (*) Patients who were treated beyond progression. CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; SUVave, average standardized uptake volume.

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