Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery			2024 Apr 30		Cancer Discov

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PF-07799933	PF-07799933	9	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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
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
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 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 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 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 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 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 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 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 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
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 del exon2-8 BRAF V600E	papillary thyroid 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 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