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Ref Type Abstract
PMID
Authors Aleksandra Franovic, Nichol Miller, Paul Severson, Toufike Kanouni, Noelito Timple, Ping Jiang, Eric Murphy, Eric Martin
Title The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models.
Journal Vol Issue Date Pages Journal Short Title
Journal of Clinical Oncology 39 15_suppl May 28, 2021
URL https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.3116
Abstract Text Background: Oncogenic BRAF gene alterations, leading to aberrantly activated BRAF monomers (Class I mutations) or dimers (Class II and Class III mutations), are observed in approximately 6% of all human cancers. First-generation BRAF inhibitors targeting Class I BRAF mutants, including dabrafenib, encorafenib, and vemurafenib, provide significant clinical benefit to patients with BRAF V600 mutation-driven melanoma and select solid tumors as monotherapies or in combination with other targeted therapies. The currently approved BRAF inhibitors have not, however, proven to be effective in patients with Class II or III BRAF alterations which account for a large proportion (34%) of BRAF mutations. KIN-2787 is an orally available, potent and selective small molecule pan-RAF inhibitor specifically designed to inhibit Class II and III BRAF dimers, in addition to Class I mutants. Methods: The efficacy and tolerability of the pan-RAF inhibitor, KIN-2787, was evaluated in vitro and in vivo in Class I, II, and III BRAF mutation-driven human cancer models. Results: In biochemical assays, KIN-2787 showed low nanomolar to picomolar potency against RAF1, BRAF, and ARAF (IC50 0.06-3.46 nM) with minimal activity towards non-RAF kinases. In cell-based assays, KIN-2787 inhibited RAF activity, as measured by inhibition of downstream ERK phosphorylation (pERK), across multiple BRAF mutant cancer cell lines. Class II and III BRAF mutant cell lines were the most responsive when treated with KIN-2787 (IC50 < 50 nM); 19- and 7-fold more sensitive compared to cells harboring wild-type BRAF, respectively. Dose-dependent inhibition of A-375 (Class I), BxPC-3 (Class II), and WM3629 (Class III) BRAF mutant human xenograft tumor growth was attained with daily KIN-2787 treatment and was well-tolerated. A trend towards greater tumor responses was observed with twice daily (BID) compared to once daily (QD) dosing of KIN-2787; however, the two dosing regimens led to similar tumor growth inhibition (TGI) and regressions (mean TGI up to 101-118%; p ≤0.0001) at equivalent total daily doses. Furthermore, KIN-2787 led to a significant in vivo pharmacodynamic response using either regimen, however, prolonged target coverage, as measured by pERK, was achieved with BID dosing. The impact of KIN-2787 treatment on additional biomarkers, including transcriptional changes and MAPK pathway modulation in cell-based models and patient-derived samples, will be presented at the meeting. Conclusions: KIN-2787 is a next-generation pan-RAF inhibitor with pronounced in vitro and in vivo activity against human cancers driven by Class II and III BRAF mutations. A phase 1 dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 monotherapy in patients with advanced or metastatic solid tumors harboring BRAF gene alterations, including Class II and III mutations, is expected to initiate in 2021.

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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
Exarafenib Exarafenib 7 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Exarafenib KIN-2787|KIN2787|KIN 2787 RAF Inhibitor (Pan) 28 Exarafenib (KIN-2787) is a small molecule pan-RAF inhibitor with activity against BRAF Class II and Class III mutants, which inhibits downstream signaling, potentially resulting in decreased growth of BRAF-mutant tumors (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 3116-3116).
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 class 1 melanoma predicted - sensitive Exarafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Exarafenib (KIN-2787) treatment led to inhibition of tumor growth in a melanoma cell line xenograft model harboring a BRAF class 1 mutation (J of Clin Oncol 39, no. 15_suppl (May 20, 2021) 3116-3116). detail...
BRAF class 2 pancreatic cancer predicted - sensitive Exarafenib Preclinical - Cell culture Actionable In a preclinical study, Exarafenib (KIN-2787) treatment led to inhibition of tumor growth in a pancreatic cell line xenograft model harboring a BRAF class 2 mutation (J of Clin Oncol 39, no. 15_suppl (May 20, 2021) 3116-3116). detail...
BRAF class 3 melanoma predicted - sensitive Exarafenib Preclinical - Cell line xenograft Actionable In a preclinical study, Exarafenib (KIN-2787) treatment led to inhibition of tumor growth in a melanoma cell line xenograft model harboring a BRAF class 3 mutation (J of Clin Oncol 39, no. 15_suppl (May 20, 2021) 3116-3116). detail...