Reference Detail

Ref Type

abstract

PMID

Authors

P. Cassier, J.M. Mehnert, R. Kim, B. Chmielowski, M. Millward, C.A. Perez, M. Gonzalez Cao, V. Gambardella, M. Mckean, M.S. Brose, Y. Xing, G.V. Long, A. Kelly, G. Lee, P. Severson, R. Williams, C. Gaudy Marqueste

Title

613MO A phase I clinical trial evaluating exarafenib, a selective pan-RAF inhibitor in combination with binimetinib in NRAS-mutant (NRASMut) melanoma (Mel) & BRAF-altered solid tumors

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	35	Supplement 2	2024

URL

https://www.annalsofoncology.org/article/S0923-7534(24)02199-9/fulltext

Abstract Text

Background Patients (pts) with cancers driven by NRAS mutations or BRAF Class II (Cl. II) alterations do not benefit from approved BRAF-targeted therapies. Exarafenib (Ex) is a potentially best in class, potent & selective pan-RAF inhibitor. The MEK inhibitor binimetinib (B) synergizes with Ex in pathway & growth inhibition of NRASMut& BRAF-altered cancer cell lines. Methods KN-8701 (NCT04913285) is an ongoing Ph 1 dose escalation & expansion study evaluating Ex monotherapy & Ex+B combination in pts with NRASMut Mel or solid tumors harboring oncogenic BRAF alterations. Results Across six Ex+B combination cohorts 52 pts were treated. Ex doses ranged from 100 to 200 mg bid; B doses ranged from 15 mg qd to 45 mg bid. Median pt age, % male, & median prior therapies were 64y, 46% and 2, respectively. Treated pts had NRASMut Mel (n=39) or solid tumors driven by BRAF Cl. I (n=10) or Cl. II (n=3) alterations. Steady state Ex, B drug exposures increased dose proportionally. Pathway inhibition in paired tumor biopsies & ctDNA decrease (>50%) in 67% of NRASMut pts were observed. Three individual Ex+B cohorts (Ex 100 mg bid + B 15 mg bid, Ex 150 mg bid + B 15 mg bid, Ex 200 mg bid + 15 mg qd) were tolerable. DLTs included blurred vision (n=1), CPK increased (n=1), GI bleed, nausea, neuralgia, & renal injury (n=1 each). Most common AEs were skin toxicity, including dermatitis acneiform (48%) & rash (31%) and diarrhea (44%); most were Gr. 1 or 2. Among NRASMut Mel pts, 11 of 31 efficacy evaluable pts (35.5%) had partial response (PR) including 9 (29%) confirmed PRs (cPR); One cPR & 1 uPR were noted among 3 pts with BRAF Cl. II fusion-driven cancers. Conclusions Ex + B can be safely administered, achieve meaningful drug exposures & show promising activity in NRASMut Mel & BRAF Cl. II fusion-driven cancer pts. Pt enrollment continues under Pierre Fabre sponsorship ahead of a planned expansion phase.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF fusion	Advanced Solid Tumor	predicted - sensitive	Binimetinib + Exarafenib	Case Reports/Case Series	Actionable	In a Phase I trial, treatment with the combination of Exarafenib (KIN-2787) and Mektovi (binimetinib) demonstrated safety in patients with NRAS-mutant melanoma (n=39) or other advanced solid tumors driven by BRAF class I or II alterations (n=10 and n=3) and resulted in one confirmed and one unconfirmed partial response in patients harboring BRAF fusions (n=3) (Ann Oncol (2024) 35 (Suppl_2): S491-S492; NCT04913285).	detail...
NRAS act mut	melanoma	predicted - sensitive	Binimetinib + Exarafenib	Case Reports/Case Series	Actionable	In a Phase I trial, treatment with the combination of Exarafenib (KIN-2787) and Mektovi (binimetinib) demonstrated safety in patients with NRAS-mutant melanoma (n=39) or other advanced solid tumors driven by BRAF class I or II alterations (n=10 and n=3) and resulted in a partial response in 35.5% (11/31, 9 confirmed partial responses) of efficacy evaluable NRAS-mutant melanoma patients (Ann Oncol (2024) 35 (Suppl_2): S491-S492; NCT04913285).	detail...