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Ref Type | Journal Article | ||||||||||||
PMID | (38691346) | ||||||||||||
Authors | Yaeger R, McKean MA, Haq R, Beck JT, Taylor MH, Cohen JE, Bowles DW, Gadgeel SM, Mihalcioiu C, Papadopoulos KP, Diamond EL, Sturtz KB, Feng G, Drescher SK, Reddy MB, Sengupta B, Maity AK, Brown SA, Singh A, Brown EN, Baer BR, Wong J, Mou TC, Wu WI, Kahn DR, Gadal S, Rosen N, Gaudino JJ, Lee PA, Hartley DP, Rothenberg SM | ||||||||||||
Title | A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation. | ||||||||||||
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Abstract Text | RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by 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 BRAF V600E 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 BRAF-mutant cancer patients refractory to approved RAF inhibitors. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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PF-07799933 | PF-07799933 | 9 | 1 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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PF-07799933 | PF07799933|PF 07799933|ARRY440|ARRY 440|ARRY-440 | BRAF Inhibitor 25 | PF-07799933 inhibits BRAF mutations, including class 1, 2, and 3 mutations, which potentially leads to decreased downstream Erk signaling and inhibition of tumor growth (PMID: 38691346). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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BRAF | del exon2-8 | deletion | gain of function - predicted | BRAF del exon2-8 indicates the deletion of exons 2-8 of the BRAF gene (PMID: 38691346). Del exon2-8 has been associated with resistance to Mek inhibitors (PMID: 35724767) and RAF inhibitors (PMID: 22113612) in culture, and is predicted to lead to a gain of Braf protein function due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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BRAF V600E | pleomorphic xanthoastrocytoma | predicted - sensitive | PF-07799933 | Case Reports/Case Series | Actionable | In a Phase I trial, PF-07799933 treatment resulted in a complete response in a patient with pleomorphic xanthoastrocytoma harboring BRAF V600E (PMID: 38691346; NCT05355701). | 38691346 |
BRAF V600E | colorectal cancer | predicted - sensitive | PF-07799933 | Preclinical - Biochemical | Actionable | In a preclinical study, PF-07799933 inhibited Erk phosphorylation in colorectal cancer cells harboring BRAF V600E in culture (PMID: 38691346). | 38691346 |
BRAF V600K | colorectal cancer | predicted - sensitive | PF-07799933 | Preclinical - Biochemical | Actionable | In a preclinical study, PF-07799933 inhibited Erk phosphorylation in colorectal cancer cells harboring BRAF V600K in culture (PMID: 38691346). | 38691346 |
BRAF L597R | prostate cancer | predicted - sensitive | PF-07799933 | Preclinical - Biochemical | Actionable | In a preclinical study, PF-07799933 inhibited Erk phosphorylation in prostate cancer cells harboring BRAF L597R in culture (PMID: 38691346). | 38691346 |
BRAF del exon4-8 BRAF V600E | melanoma | sensitive | Binimetinib + PF-07799933 | Preclinical - Pdx | Actionable | In a preclinical study, treatment with the combination of PF-07799933 and Mektovi (binimetinib) resulted in tumor regression in a patient-derived xenograft (PDX) model of melanoma harboring BRAF V600E and a BRAF exon 4-8 deletion variant (reported as p61 splice variant) (PMID: 38691346). | 38691346 |
BRAF V600E | high grade glioma | predicted - sensitive | Binimetinib + PF-07799933 | Case Reports/Case Series | Actionable | In a Phase I trial, the addition of Mektovi (binimetinib) to treatment with PF-07799933 resulted in a partial response in a patient with high grade glioma harboring BRAF V600E (PMID: 38691346; NCT05355701). | 38691346 |
BRAF G469A | lung non-small cell carcinoma | sensitive | PF-07799933 | Preclinical - Pdx | Actionable | In a preclinical study, PF-07799933 treatment resulted in tumor regression in a patient-derived xenograft (PDX) model of non-small cell lung cancer harboring BRAF G469A (PMID: 38691346). | 38691346 |
BRAF del exon2-8 BRAF V600E | thyroid gland papillary carcinoma | predicted - sensitive | Binimetinib + PF-07799933 | Case Reports/Case Series | Actionable | In a Phase I trial, treatment with the combination of PF-07799933 and Mektovi (binimetinib) resulted in a partial response with a tumor reduction of 80% in a patient with papillary thyroid carcinoma harboring BRAF V600E and a deletion of BRAF exons 2-8 (reported as p48 splice variant) (PMID: 38691346; NCT05355701). | 38691346 |
BRAF V600E NRAS Q61K | lung non-small cell carcinoma | predicted - sensitive | PF-07799933 | Preclinical - Biochemical | Actionable | In a preclinical study, PF-07799933 inhibited Erk phosphorylation in melanoma cells harboring BRAF V600E and NRAS Q61K in culture (PMID: 38691346). | 38691346 |
BRAF V600E | melanoma | predicted - sensitive | Binimetinib + PF-07799933 | Case Reports/Case Series | Actionable | In a Phase I trial, treatment with the combination of PF-07799933 and Mektovi (binimetinib) resulted in a partial response in 2 patients with melanoma harboring BRAF V600E and stable disease in 1 patient (PMID: 38691346; NCT05355701). | 38691346 |
BRAF D594G NRAS G12D | melanoma | predicted - sensitive | PF-07799933 | Preclinical - Biochemical | Actionable | In a preclinical study, PF-07799933 inhibited Erk phosphorylation in melanoma cells harboring BRAF D594G and NRAS G12D in culture (PMID: 38691346). | 38691346 |
BRAF K601E | melanoma | sensitive | PF-07799933 | Preclinical - Pdx | Actionable | In a preclinical study, PF-07799933 treatment resulted in tumor regression in a patient-derived xenograft (PDX) model of melanoma harboring BRAF K601E (PMID: 38691346). | 38691346 |
BRAF G466V | lung non-small cell carcinoma | predicted - sensitive | PF-07799933 | Preclinical - Biochemical | Actionable | In a preclinical study, PF-07799933 inhibited Erk phosphorylation in non-small cell lung cancer cells harboring BRAF G466V in culture (PMID: 38691346). | 38691346 |