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

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 NRAS^Mut & 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 NRAS^Mut 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 NRAS^Mut 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 NRAS^Mut 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. Table: 613MO

Among NRASM^ut 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 NRAS^Mut Mel & BRAF Cl. II fusion-driven cancer pts. Pt enrollment continues under Pierre Fabre sponsorship ahead of a planned expansion phase.

Clinical trial identification

NCT04913285.

Editorial acknowledgement

Legal entity responsible for the study

Kinnate Biopharma.

Funding

Kinnate Biopharma.

Disclosure

P. Cassier: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: Roche, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Other, Advisor: OSE immunotherapeutics; Financial Interests, Institutional, Local PI: AbbVie, Blueprint, Boehringer Ingelheim, Bristol Meyer Squibb, Exelixis, GSK, Incyte, Janssen, Loxo/Eli Lilly, Novartis, Roche, Taiho, Toray Industries; Financial Interests, Institutional, Coordinating PI: Amgen, Transgene; Non-Financial Interests, Institutional, Product Samples: Plexxikon, Novartis, MSD, AstraZeneca, GSK. J.M. Mehnert: Financial Interests, Institutional, Advisory Board, Scientific advisory board: Merck; Financial Interests, Institutional, Advisory Board: Regeneron. R. Kim: Financial Interests, Personal, Advisory Board: Servier, Roche, Taiho, Ipsen, Lilly, Bayer, Pfizer, AbbVie; Financial Interests, Personal, Other, Speaker Bureau: Incyte. B. Chmielowski: Financial Interests, Personal, Other, DMC: Nektar; Financial Interests, Personal, Advisory Board: Novartis, Delcath Systems, Instil Bio, Replimune; Financial Interests, Institutional, Local PI, Clinical trial support: Bristol Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Biotherapeutics, Xencor, Compugen, Iovance, PACT Pharma, RAPT Therapeutics, Immunocore, Ascentage, Atreca, Replimune, Ideaya Biosciences, Instil Bio; Financial Interests, Institutional, Local PI, clinical trial support: Adagene, TriSalus Life Sciences, Kinnate Biopharma, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Professor of Clinical Cancer Research: University of Western Australia; Financial Interests, Personal, Full or part-time Employment, Medical Oncology Director: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. C.A. Perez: Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Other, Steering Committee: Kinnate Biopharma Inc., BeiGene; Financial Interests, Institutional, Local PI: Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc, Kura Oncology, Hyamab Inc, Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribbon Therapeutics, Mirati Therpeutics, Elpiscience BioPharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies Co., Genentech, Inc., Jazz Pharmaceuticals, Artios Pharma, Ayala Pharmaceuticals, Elevation Oncology, Merus. M. Gonzalez Cao: Financial Interests, Personal, Invited Speaker, Member of the steering committe, payments for talks: Spanish Melanoma Group; Financial Interests, Personal, Invited Speaker: Sanofi, MSD, BMS; Financial Interests, Institutional, Research Grant, IIT grant: Roche; Financial Interests, Institutional, Research Grant, IIT trial: AZ; Financial Interests, Institutional, Research Grant, IIT: Regeneron; Non-Financial Interests, Member of Board of Directors: SPANISH Melanoma Group. V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer, Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscienc, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InconVir, Jazz Pharmaceutical, Krystal Biotech, NucMito Pharmaceuticals, OnKure, Remix Therapeutics. G.V. Long: Financial Interests, Personal, Other, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, AstraZeneca UK Limited, Bayer Healthcare Pharmaceuticals, BioNTech SE, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG, Highlight Therapeutics S.L., IOBiotech, Immunocore Ireland Limited, Innovent Bioilogics USA Inc, Merck Sharp & Dohme, Novartis Pharma AG, PHMR Limited, Pierre Fabre, Regeneron Pharmaceuticals Inc, Scancell Limited, SkylineDX B.V.; Non-Financial Interests, Principal Investigator, GL is PI on over 30 clinical trials. A. Kelly, G. Lee, P. Severson: Financial Interests, Personal, Full or part-time Employment: Kinnate Biopharma. R. Williams: Financial Interests, Personal, Full or part-time Employment: Kinnate. All other authors have declared no conflicts of interest.