Abstract 160TiP
Background
BRAF is a serine/threonine protein kinase that acts as a signal transducer to regulate the mitogen-activated protein kinase pathway. Mutant BRAF V600 can signal as a monomer, leading to dysregulation of cellular proliferation. Currently approved BRAF inhibitors (BRAFi) are selective for mutant BRAF V600X, but their activity is limited by intrinsic or acquired resistance often mediated by RAF dimer-inducing mechanisms. BRAFi are often used in combination with anti-EGFR antibodies such as cetuximab in CRC and MEK inhibitors in melanoma and NSCLC. CFT1946 is an orally bioavailable BiDAC™ degrader that selectively inhibits and degrades mutant BRAF V600 protein. CFT1946 was designed to overcome limitations of BRAFi, as degradation of BRAF V600 mutant protein is hypothesized to abrogate RAF dimer-driven resistance and paradoxical activation. Single agent CFT1946 and CFT1946+ cetuximab outperformed the standard of care (SoC) encorafenib + cetuximab at clinically relevant doses in a panel of BRAF V600E CRC xenograft models.
Trial design
This is a first-in-human, multicenter, phase 1/2 dose escalation clinical trial of CFT1946. Phase 1 will include CFT1946 monotherapy arms across mutated BRAF V600 solid tumors, CFT1946+trametinib in BRAF V600 mutant NSCLC and melanoma, and CFT1946+cetuximab in BRAF V600 mutant CRC. Among other monotherapy and combination phase 2 arms, the study includes an expansion arm in BRAF V600 mutant CRC patients treated with CFT1946 + cetuximab. The CFT1946+cetuximab phase 1 arm will include BRAF V600 mutant CRC with prior BRAFi or BRAFi naïve, if BRAFi is not available per local SoC, while phase 2 will enroll BRAF V600E CRC with prior BRAFi. Phase 2 will initiate once an RP2D has been identified. Eligible subjects are ≥18yo with documented BRAF V600 mutant cancers who have received ≥1 prior therapy. CFT1946 will be administered orally in 28-day cycles until disease progression or intolerable toxicity. Primary objectives include safety, tolerability, and preliminary antitumor activity. Secondary objectives include assesment of PK and PD. The study is currently enrolling at 15 US and European sites with additional sites planned (NCT05668585).
Clinical trial identification
NCT05668585; 2022-12-06.
Legal entity responsible for the study
C4 Therapeutics.
Funding
C4 Therapeutics.
Disclosure
M. Vieito Villar: Financial Interests, Personal, Invited Speaker: Novocure; Financial Interests, Personal, Other, Steering committee member: BMS; Non-Financial Interests, Principal Investigator: Roche, BMS, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. M. McKean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, Eisai, IQVIA, Merck, Moderna; Financial Interests, Personal, Other, Consulting: iTeos; 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. A. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role/Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, IONCTURA SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V., Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology, Loxo Oncology. V. Moreno: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Invited Speaker, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer Ingelheim, Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. O. Saavedra Santa Gadea: Financial Interests, Institutional, Other, Travel: Affimed. 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, Invited Speaker: AbbVie, Amgen, Blueprint, Boehringer Inglheim, Bristol Meyer Squibb, Exelixis, GSK, Incyte, Janssen, Loxo/Eli Lilly, Novartis, Roche, Taiho, Toray Industries, Transgene; Non-Financial Interests, Institutional, Product Samples: Plexxikon, Novartis, MSD, AstraZeneca, GSK. I. Korakis: Financial Interests, Other, Travel Grant: Roche; Non-Financial Interests, Invited Speaker: MSD. B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune Limited; Financial Interests, Personal, Other, Consulting. Also attended and Ad Board meeting. Travel was paid to attend an Ad board meeting: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise: ADRx; Financial Interests, Personal, Advisory Board, tenosynovial giant cell tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting and Ad Board: Bayer; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere LLC; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: PTC Therapeutics, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Advenchen, Deciphera Pharmaceuticals, Inc, EcoR1, Putnam, Salarius Pharm, Boxer Capital LLC, Acuta Capital Partners, LLC, Aadi; Financial Interests, Personal, Invited Speaker, Telephone interview Sarcoma Expert: Iterion Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker, 2023 West Oncology Talk. Travel provided: Total Health conference; Financial Interests, Personal, Advisory Board, VISTA Ad Board: Curtis; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer, Merck, Tracon Pharm, GSK; Financial Interests, Personal and Institutional, Research Grant, Research Grant for trial: Polaris; Non-Financial Interests, Member of Board of Directors, Non-paid: Polaris. J.S. Wang: Financial Interests, Personal, Invited Speaker, Previous Member of Speaker's Bureau for Tagrisso and Imfinzi, stopped speaking engagements in 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, Single consultancy engagement, 4/28/22: Kanaph Therapeutics; Financial Interests, Personal, Invited Speaker, Speaker for Speaker's Bureau for Levatinib, stopped in 7/2022: Eisai; Financial Interests, Personal, Advisory Board, on Safety Advisory Board, single engagement 6/22/23: Fusion Pharma; Financial Interests, Institutional, Funding, Clinical Trial PI/Sub-I: 7,8 Pharma, Accutar, Adagene, Artios Pharma, Astellas, AstraZeneca, Bayer Healthcare, BeiGene, Bicycle Therapeutics, BioNTech, BioTheryX, Blueprint, Boehringer Ingelheim, Celgene/BMS, Cullinan, Cyteir, Daiichi Sankyo, Erasca, Forty Seven, Genentech/Roche, GSK, H3 Biomedicine, Hotspot, IGM Biosciences, Immuno-Gen, ImmunoOnc, Janssen, Jazz Pharma, Klus Pharma, Kymab, LSK BioPartners, MabSpace, Macrogenics, Medikine, Moderna, NGM Bio, Novartis, Nurix, ORIC, Olema Therapeutics, Phoenix Molecular Designs, Pionyr, Prelude Therapeutics, PureTech Health, Pyxis, Qilu Pugent Sound, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Sanofi, StingThera, Syndax, Teneobio, TopAlliance, Treadwell Therapeutics, Xencor, Zymeworks, Compass, OnCusp, Tango, Vividion, Allorion, Kura, Georgimmune, Conjupro, Duality Bio, Ellipses, Compugen, Biostar, Centessa, Kineta, C4 Therapeutics. V.T. Ma: Financial Interests, Advisory Board: Immunocore, Regeneron, Teiko.bio, Incyte, Replimune, Partner Therapeutics, BMS. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffmann-La Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda, Boehringer Ingelheim, Cure Teq AG, Repare Therapeutics Inc., RIN Institute Inc., Janssen; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer, BMS, Lilly, Medscape; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd., Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGaA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune, AbbVie Deutschland GmbH & Co KG, Bayer Pharma AG, Bioncotech Therapeutics, S.L., BioNTech Rna Pharmaceuticals GmbH, BioNTech Small Molecules GmbH, Boehringer Ingelheim de España S.A., Daiichi Sankyo, Inc, Gercor, Hutchinson Medipharma Limited, Iovance Biotherapeutics, Inc., Janssen Research & Development, Menarini Ricerche SPA, Merck, Sharp & Dohme De España S.A., Nouscom SRL., Pledpharma AB, Redx Pharma PLC, Scandion Oncology, Seattle Genetics Inc., Sotio A.S., Wntresearch AB; Non-Financial Interests, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics - Immunotherapy: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Leadership Role, Member of the Scientific Program Committee and Developmental Therapeutics-Immunotherapy Track Leader, 2023-2024 term: American Society for Clinical Oncology (ASCO); Non-Financial Interests, Other, Member of the Scientific Committee 2024: European Society for Medical Oncology (ESMO); Other, Travel, accommodation, expenses: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol Myers Squibb. M. Pelster: Financial Interests, Institutional, Other, Consulting: AstraZeneca, CytomX, Daiichi Sankyo, Ipsen, Pfizer, Seagen, Arcus Biosciences, Elevation Oncology, EMD Serono, Jazz Pharmaceuticals, Stemline Therapeutics; Financial Interests, Institutional, Invited Speaker: Agenus, Arcus Biosciences, Astellas, BeiGene, BioNTech, Bristol Myers Squibb, Codiak Biosciences, Eisai, Gilead, HiberCell, Immune-Onc Therapeutics, Leap Therapeutics, Novartis, OncXerna Therapeutics, Panbela Therapeutics, Revolution Medicines, Surface Oncology, SQZ Biotechnologies, Translational Genomics, TransThera Sciences, ZielBio, 1200 Pharma, Actuate Therapeutics, Compass Therapeutics, CytomX, Elevation Oncology, Exelixis, Impact Therapeutics, Tachyon Therapeutics. E. Hinojosa, R. Lobbardi, E. Hurh: Financial Interests, Full or part-time Employment: C4 Therapeutics. E. Buchbinder: Financial Interests, Personal, Advisory Board: Instilbio, Nektar, Novartis, BMS, Iovance, Merck, Sanofi, Xilio; Financial Interests, Institutional, Invited Speaker: Genentech, Partners therapeutics; Other, Spouse employment: AstraZeneca, Takeda. All other authors have declared no conflicts of interest.