A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• RAF inhibitors offer improved outcomes for BRAFV600-mutant cancers.
• Treatment limitations include adaptive ERK signaling, BRAF dimerization, and poor brain penetration.
• Next-generation pan-RAF dimer inhibitors face challenges with a narrow therapeutic index.

Purpose of the Study:

• To evaluate PF-07799933, a selective, brain-penetrant, pan-mutant BRAF inhibitor.
• To assess the safety and efficacy of PF-07799933, alone and with binimetinib, in patients with refractory BRAF-mutant solid tumors.
• To explore a novel pharmacokinetics-informed dose escalation design for rapid therapeutic development.

Main Methods:

• In vitro assessment of PF-07799933's signaling inhibition and dimer disruption.
• Evaluation of PF-07799933 ± binimetinib in mouse xenograft models of BRAF-mutant cancers.
• First-in-human clinical trial (NCT05355701) with a flexible, PK-informed dose escalation design.

Main Results:

• PF-07799933 inhibited mutant BRAF signaling, disrupted mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling.
• PF-07799933 ± binimetinib demonstrated efficacy in preclinical models, including those with acquired resistance and dimeric BRAF.
• The clinical trial showed PF-07799933 ± binimetinib was well-tolerated with confirmed responses in the brain and systemically in refractory patients.

Conclusions:

• PF-07799933 exhibits preclinical and clinical antitumor activity against various BRAF-mutant cancers, including treatment-refractory cases.
• PF-07799933 can be safely combined with MEK inhibitors like binimetinib.
• The PK-informed dose escalation strategy accelerates the clinical development of novel targeted therapies.