The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

BRAFi Next Generation

Geo Regions

BRAFi Next Generation

PF-07799933, ARRY-440 is an investigational compound. Its safety and efficacy have not been established.

Overview + Rationale

OVERVIEW

  • PF-07799933 is a selective ATP-competitive small-molecule RAF kinase inhibitor, which has been shown to suppress the RAF/MEK/ERK pathway in tumor cells expressing BRAF V600-mutant (Class I) and non-V600-altered (Class II and III) kinase
  • In various xenograft models, PF-07799933 has shown anti-tumor activity alone and in combination with clinically relevant targeted therapeutics and drug exposure in the brain

RATIONALE FOR CANCER TYPE

  • BRAF, a serine/threonine protein kinase, plays a role in regulating the MAP kinase/ERKs signaling pathway, which may be constitutively activated due to BRAF gene mutations 
  • Oncogenic BRAFV600E signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling 
  • Class I BRAF inhibitors are thought to be inactive against BRAF altered dimers 
  • Approximately 15%-30% of resistance to Class I BRAF inhibitors in melanoma is driven by drug-acquired splice variants that signal as dimers 
  • Additionally, Class II and III BRAF alterations (alterations which signal as dimers) can occur de novo, as point mutations, fusions or deletions 
  • Patients with Class II/III (non-V600) mutations/alterations currently have no targeted therapeutic option and represent a population of unmet need

Mechanism of Action

  • PF-07799933 binds to and inhibits BRAF Class I mutants (activated, monomeric V600 mutations), BRAF Class II mutants (activated, dimeric mutations), and BRAF Class III mutants (loss-of-function mutations that transactivate wildtype BRAF heterodimers) and has the potential to treat tumors with these de novo and acquired mutations in the BRAF gene. 
  • PF-07799933 is also highly brain-penetrant, which could address primary or metastatic CNS disease.
  • PF-07799933 is highly selective for inhibition of only BRAF, which provides a wide therapeutic safety index that allows for maximal target coverage and tolerability

Inhibition

Updated BRAFi MOA

Stage of Development

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Advanced Solid Tumors
Phase 1 Monotherapy and Combination