A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation Journal Article
| Authors: | Yaeger, R.; McKean, M. A.; Haq, R.; Beck, J. T.; Taylor, M. H.; Cohen, J. E.; Bowles, D. W.; Gadgeel, S. M.; Mihalcioiu, C.; Papadopoulos, K. P.; Diamond, E. L.; Sturtz, K. B.; Feng, G.; Drescher, S. K.; Reddy, M. B.; Sengupta, B.; Maity, A. K.; Brown, S. A.; Singh, A.; Brown, E. N.; Baer, B. R.; Wong, J.; Mou, T. C.; Wu, W. I.; Kahn, D. R.; Gadal, S.; Rosen, N.; Gaudino, J. J.; Lee, P. A.; Hartley, D. P.; Rothenberg, S. M. |
| Article Title: | A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation |
| Abstract: | RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 +/- binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 +/- binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. |
| Keywords: | melanoma; tumors; spectrum; mechanisms; acquired-resistance |
| Journal Title: | Cancer Discovery |
| Volume: | 14 |
| Issue: | 9 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-09-01 |
| Start Page: | 1599 |
| End Page: | 1611 |
| Language: | English |
| ACCESSION: | WOS:001305886700016 |
| DOI: | 10.1158/2159-8290.Cd-24-0024 |
| PROVIDER: | wos |
| PMCID: | PMC11372368 |
| PUBMED: | 38691346 |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Rona Yaeger -- Source: Wos |
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