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DRUG:

exarafenib (KIN-2787)

i
Other names: KIN-2787, KIN-002787, KIN002787, KIN 002787, KIN2787, KIN 2787, RAF/KIN_2787
Company:
Pierre Fabre
Drug class:
pan-RAF inhibitor
6ms
A Study to Evaluate KIN-2787 in Participants With BRAF and/or NRAS Mutation Positive Solid Tumors (clinicaltrials.gov)
P1, N=400, Recruiting, Pierre Fabre Medicament | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Mar 2024 --> Dec 2024
Trial completion date • Trial primary completion date
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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Mektovi (binimetinib) • exarafenib (KIN-2787)
10ms
The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition. (PubMed, J Med Chem)
However, the discovery of a potent and selective inhibitor with biopharmaceutical properties suitable to sustain robust target inhibition in the clinical setting has proven challenging. Herein, we report the discovery of exarafenib (15), a highly potent and selective inhibitor that intercepts the RAF protein in the dimer compatible αC-helix-IN conformation and demonstrates anti-tumor efficacy in preclinical models with BRAF class I, II, and III and NRAS alterations.
Journal
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation
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exarafenib (KIN-2787)
1year
Enrollment change
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation
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Mektovi (binimetinib) • exarafenib (KIN-2787)
over1year
Enrollment change
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation
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Mektovi (binimetinib) • exarafenib (KIN-2787)
over1year
Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF class II/III mutant and NRAS mutant melanoma (AACR 2023)
The superior kinome selectivity of exarafenib and its activity across multiple RAF-dependent melanoma models position it as a potentially class-leading pan-RAF inhibitor. In addition to efficacy in BRAF mutant tumors, these data support use of exarafenib in combination therapy with MEK inhibitors in NRAS mutant melanoma. A Ph I dose escalation clinical trial evaluating the safety and efficacy of exarafenib in monotherapy and in combination with binimetinib is ongoing (NCT04913285).
Preclinical
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation • BRAF V600 • BRAF wild-type • NRAS mutation + BRAF mutation
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Mektovi (binimetinib) • exarafenib (KIN-2787)
over1year
Trials in progress: a global phase 1/1b clinical trial evaluating exarafenib (KIN-2787), a highly selective pan-RAF inhibitor, in adult patients with BRAF-altered solid tumors and NRAS mutant melanoma (AACR 2023)
Exarafenib achieves therapeutically meaningful drug exposures and demonstrates promising tolerability & clinical activity in BRAF or NRAS alteration-driven solid tumors. Pt enrollment & exarafenib treatment at 300 mg bid continues.
Clinical • P1 data
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation
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exarafenib (KIN-2787)
over2years
Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF- and NRAS-mutation positive solid tumors (AACR 2022)
Part A1 assesses single agent KIN-2787; Part A2 assesses KIN-2787 in combination w/binimetinib. Enrollment began in August 2022. Trial is open globally.
Clinical • P1 data
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation • BRAF V600 • NRAS mutation + BRAF mutation
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Mektovi (binimetinib) • exarafenib (KIN-2787)
over2years
Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human RAF/RAS mutant melanoma (AACR 2022)
In contrast to vemurafenib, an approved BRAF inhibitor with activity limited to Class I BRAF alterations, KIN-2787 was active across all classes of BRAF mutant melanoma cells (EC50 values < 100 nM)...Additionally, KIN-2787 was efficacious in a pre-/post-treatment melanoma PDX pair in which the original tumor was Class I BRAF V600E but acquired a Class II BRAF kinase domain duplication upon progression on dabrafenib + trametinib... KIN-2787 is a next-generation, pan-RAF inhibitor with in vitro and in vivo activity against human melanoma driven by BRAF and/or NRAS mutations. Data supports KIN-2787 use in acquired BRAF dimer-dependent resistance to BRAF+MEK inhibitor therapy. A Phase I dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is ongoing (NCT04913285).
Preclinical
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • KRAS wild-type • RAS wild-type • NRAS mutation + BRAF mutation
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Mekinist (trametinib) • Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • exarafenib (KIN-2787)
almost3years
Antitumor Activity of KIN-2787, a Next-Generation pan-RAF Inhibitor, in Preclinical Models of Human BRAF-alteration Driven Non-small Cell Lung Cancer (NSCLC) (IASLC-TTLC 2022)
While the RAF inhibitor dabrafenib is approved for treatment of BRAF Class I-altered NSCLC (in combination with trametinib), there are no RAF targeted therapies for treatment of NSCLC patients with tumors driven by BRAF Class II or Class III dimer-dependent alterations, likely contributing to the inferior clinical outcomes of these patients (Dagogo-Jack et al...In contrast to dabrafenib or vemurafenib, approved BRAF inhibitors with activity limited to Class I BRAF alterations, KIN-2787 was most active in Class II and Class III BRAF mutant NSCLC cells (EC50 median values 264 nM and 24 nM, respectively)...A Phase I dose-escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 is actively enrolling (NCT04913285). Patients with advanced and metastatic solid tumors, including NSCLC patients, whose cancers are driven by BRAF Class I, II, or III alterations will receive KIN-2787 treatment on this study.
Preclinical
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • KRAS wild-type • BRAF wild-type • RAS wild-type
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Mekinist (trametinib) • Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • exarafenib (KIN-2787)
almost3years
Enrollment change
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BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
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BRAF mutation • NRAS mutation
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Mektovi (binimetinib) • exarafenib (KIN-2787)
over3years
A Study to Evaluate KIN-2787 in Subjects With BRAF Mutation Positive Solid Tumors (clinicaltrials.gov)
P1, N=115, Recruiting, Kinnate Biopharma | Not yet recruiting --> Recruiting
Clinical • Enrollment open
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BRAF (B-raf proto-oncogene)
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exarafenib (KIN-2787)
over3years
Clinical • New P1 trial
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BRAF (B-raf proto-oncogene)
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exarafenib (KIN-2787)