612O - Preliminary results from a phase I study of CFT1946, a novel BIDAC degrader in mutant BRAF V600 solid tumors

Background

CFT1946, an oral BiDAC™ degrader that selectively degrades and inhibits mutant BRAF V600 protein, is designed to overcome RAF dimer-driven resistance and paradoxical activation of approved BRAF inhibitors (BRAFi).

Methods

CFT1946-1101 (NCT05668585) is an ongoing first-in-human, multicenter, phase 1/2 dose-escalation and cohort-expansion clinical trial. Phase 1 escalation monotherapy arm of CFT1946 includes patients (pts) with refractory BRAF-V600 mutant solid tumors (non-CNS), melanoma (mel), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or anaplastic thyroid cancer. Primary objectives include safety and tolerability. Secondary objectives include pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy. Blood samples were collected for PK analysis and ctDNA analysis. Tumor tissue was collected to measure BRAF V600 degradation and inhibition of the relevant pathways.

Results

As of April 12, 2024, 25 pts were treated with CFT1946 monotherapy at doses of 20 to 320 mg BID. Tumor types were mel (40%), CRC (40%), other (12%), and NSCLC (8%). 22/25 pts had a V600E mutation, 2 had a V600K mutation and 1 had a V600R mutation. 24/25 pts were BRAFi exposed, and all received ≥2 prior lines (median=3). No DLT occurred. Treatment-emergent adverse events (TEAEs) that occurred in >15% of pts included: anemia (any grade, 20%/grade ≥3, 4%), abdominal pain (20%/4%), and pyrexia (16%/0%). 8/25 pts experienced grade ≥3 TEAEs, none were treatment related. Plasma exposure of CFT1946 increased dose-proportionally up to 80 mg BID and less than proportionally at higher doses. Available BRAF V600E immunohistochemistry staining shows target degradation at 80mg and 160mg. BRAF V600E/K/R allele fraction decline is observed with CFT1946. At data cut, 1 pt had an unconfirmed partial response (uPR) and 7/14 (50%) efficacy evaluable pts had a best response of stable disease or better. After data cutoff, 1 recently enrolled pt (PD on BRAFi) had an uPR with a 64% reduction of target lesions.

Conclusions

CFT1946 was well tolerated with evidence of BRAF V600E degradation and relevant pathway inhibition. Early evidence of monotherapy efficacy was observed; further dose exploration is ongoing. Updated data will be presented at the conference.

Clinical trial identification

NCT05668585.

Editorial acknowledgement

Legal entity responsible for the study

C4 Therapeutics.

Funding

C4 Therapeutics.

Disclosure

M. Vieito: 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, 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. A.I. 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, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; 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, Local PI: 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, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. 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: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology, Loxo Oncology. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, 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, 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, Roche; Financial Interests, Institutional, Other, Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. S. Cousin: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Lilly, Roche; Non-Financial Interests, Principal Investigator: AstraZeneca, Daiichi, Gilead, Takeda, Sanofi, MSD, GSK, BMS. 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. I. Korakis: Financial Interests, Institutional, Coordinating PI, M20-431 coordinating PI for France: AbbVie; Financial Interests, Institutional, Coordinating PI, DS 1103-74 coordinating PI for France: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI, ANV600-001 trial, coordinating PI for France: Anaveon; Other, Travel expenses for ASCO 2023 meeting: Roche. 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, Advisory Board, 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. V.T. Ma: Financial Interests, Advisory Board: Immunocore, Regeneron, Teiko.bio, Incyte, Replimune, Partner Therapeutics, BMS. A. Ali, E. Hinojosa, R. Lobbardi, H. Liu, L. Reyno: Financial Interests, Personal, Full or part-time Employment: C4 Therapeutics. E. Hurh: Financial Interests, Advisory Board: C4 Therapeutics. E. Buchbinder: Financial Interests, Personal, Advisory Board: Instilbio, Nektar, Novartis, BMS, Iovance, Merck, Sanofi, Xilio; Financial Interests, Institutional, Coordinating PI: Genentech, Partners therapeutics; Other, Spouse employment: AstraZeneca, Takeda. All other authors have declared no conflicts of interest.