Phase I, open-label, dose-escalation/dose-expansion study of lifirafenib (BGB-283), an RAF family kinase inhibitor, in patients with solid tumors Academic Article uri icon

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.

authors

  • Desai, Jayesh
  • Gan, Hui
  • 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

publication date

  • 2020