Abstract 1128P
Background
The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes regulates the chromatin landscape of the genome. Through its ATP-dependent chromatin remodeling activity, BAF regulates the accessibility of gene-control elements, allowing for the binding of transcription factors. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complex, SMARCA4 and SMARCA2 (BRG1 and BRM, respectively).
Methods
As of a 31 December 2022 data cutoff, FHD-286 was administered in patients with metastatic uveal melanoma at escalating doses either on a daily dosing regimen ranging from 2.5 mg QD to 10 mg QD or an intermittent regimen of 1-week-on/1-week-off at 10 mg or 15 mg doses. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of the recommended phase II dose(s) (RP2D). Secondary endpoints included pharmacokinetic (PK) and preliminary efficacy.
Results
At data cutoff, 52 patients had received at least 1 dose of FHD-286. Any grade (Gr) treatment-related adverse events (TRAEs) occurred in 83% of patients, most commonly dysgeusia (39%), fatigue (31%), AST increased (29%), nausea/vomiting (29%), dry mouth (25%) and rash (25%). Gr ≥ 3 TRAEs occurred in 25% of patients, most commonly anemia, asthenia, ALP increased, hypokalemia, muscular weakness and rash each occurring in 4% of patients. One patient with Gr 3 keratitis and 2 patients with Gr 3 rash met DLT criteria at the 7.5 mg QD dose level. These AEs were non-serious and improved with dose interruption. No treatment-related deaths occurred. Ongoing PK analysis indicates that FHD-286 accumulates with QD dosing and PK exposure increases with increasing dose. One patient assigned to the 10 mg QD dosing cohort achieved a partial response and remained on treatment for 16 months; prolonged stable disease and reductions in tumor burden have also been observed across dose levels.
Conclusions
FHD-286 has been generally well-tolerated and preliminary anti-tumor activity has been observed. The RP2D(s) has not yet been established. Updated dosing, safety, tolerability, PK and anti-tumor activity data will be shared at the meeting.
Clinical trial identification
NCT04879017 (May 10, 2021) EudraCT Number: 2021-001529-35.
Editorial acknowledgement
Legal entity responsible for the study
Foghorn Therapeutics Inc.
Funding
Foghorn Therapeutics Inc.
Disclosure
S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Novartis, BMS, Pfizer, Immatics; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Advisory Board, Advisory Board and Corporate Day speaker (unbranded): Delcath; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Immunocore; Financial Interests, Personal, Other, Consultant: Guidepoint Global; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Lyvgen, InxMed, Foghorn Therapeutics, IDEAYA, Novartis, Seagen, Syntrix Bio; Financial Interests, Institutional, Steering Committee Member: TriSalus Life Sciences; Non-Financial Interests, Member: ASCO, AACR, International Society of Ocular Oncology, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. 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: Ascentage 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 Therapeutics, 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. S. Piperno-Neumann: Financial Interests, Personal, Advisory Board: Immunocore, Pierre Fabre, Atlanthera. A.N. Shoushtari: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Immunocore, Novartis, Erasca; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Immunocore, Pfizer, Novartis, Checkmate Pharmaceuticals, Linnaeus Therapeutics, Foghorn Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics; Financial Interests, Institutional, Coordinating PI: Polaris, Xcovery, Targovax ASA; Non-Financial Interests, Member: ASCO. L. Hernandez-Aya: Financial Interests, Personal and Institutional, Advisory Board: BMS, CASTLE Bioscience, Replimune; Non-Financial Interests, Institutional, Principal Investigator: Foghorn Therapeutics, Immatics, Syntrix Pharmaceuticals. M. Orloff: Financial Interests, Personal, Advisory Board: Trisalus, Delcath, Replimune, IDEAYA, Immunocore; Financial Interests, Personal, Speaker, Consultant, Advisor: Immunocore. S. Khan: Financial Interests, Personal, Advisory Board: Castle Biosciences, Replimune Inc. K. Montazeri: Financial Interests, Personal, Speaker, Consultant, Advisor: Immunocore. E. Kapiteijn: Financial Interests, Institutional, Advisory Board: BMS, Novartis, Pierre Fabre, Merck, Delcath, Bayer, Lilly; Financial Interests, Institutional, Coordinating PI: BMS, Pierre Fabre, Delcath. 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. S. Agresta: Financial Interests, Personal, Full or part-time Employment: Foghorn Therapeutics; Financial Interests, Personal, Stocks/Shares: Foghorn Therapeutics; Financial Interests, Personal, Officer: Foghorn Therapeutics. S. Reilly: Financial Interests, Personal, Full or part-time Employment: Foghorn Therapeutics; Financial Interests, Personal, Stocks/Shares: Foghorn Therapeutics, Adaptimmune Therapeutics, Johnson & Johnson, Procter & Gamble; Financial Interests, Personal, Other, Investor: Luna Genetics. C.M. Patriquin: Financial Interests, Personal, Stocks/Shares: Foghorn Therapeutics, Roche; Financial Interests, Personal, Full or part-time Employment: Foghorn Therapeutics. D. Hickman, L. Granlund, M. Hentemann, J. Piel: Financial Interests, Personal, Full or part-time Employment: Foghorn Therapeutics; Financial Interests, Personal, Stocks/Shares: Foghorn Therapeutics. D. Corrigan: Financial Interests, Personal, Stocks/Shares: Foghorn Therapeutics. P. Martin: Financial Interests, Personal, Full or part-time Employment: Certara. I. Mehmi: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS; Financial Interests, Personal, Advisory Board: AZ.
Resources from the same session
1130P - Tebentafusp (tebe) in an ongoing cohort of 72 French patients (pts) with metastatic uveal melanoma (mUM)
Presenter: Leah Mailly-Giacchetti
Session: Poster session 13
1131P - Management of metastatic uveal melanoma (MUM) patients on tebentafusp in a real-world setting
Presenter: Mauricio Fernando Ribeiro
Session: Poster session 13
1132P - Chemokine expression in uveal melanoma and association with tumor genetics and response to immunotherapy
Presenter: Aparna Nallagangula
Session: Poster session 13
1133P - SF3B1 mutation predicts improved overall survival in metastatic uveal melanoma patients: Molecular and clinical correlates
Presenter: Luis del Carpio Huerta
Session: Poster session 13
1134P - Safety and efficacy of low dose (LD) ipilimumab (Ipi) + pembrolizumab (pem) in checkpoint inhibitor (CPI) naïve patients (pts) with melanoma brain metastases (MBM)
Presenter: Isabella Glitza
Session: Poster session 13
1135P - Comparison of intracranial (IC) response assessment criteria in patients (pts) with melanoma brain metastases (MBM) treated with combination nivolumab (NIVO) plus ipilimumab (IPI) in CheckMate 204
Presenter: Raymond Huang
Session: Poster session 13
1136P - Regorafenib combined with BRAF-/MEK-inhibitors for the treatment of refractory melanoma brain metastases
Presenter: Iris Dirven
Session: Poster session 13
1138P - Intralesional administration of L19IL2/L19TNF in difficult-to-treat non-melanoma skin cancer shows a favorable safety profile and preliminary clinical activity
Presenter: Lukas Flatz
Session: Poster session 13
1139P - Final results of a phase II study of pembrolizumab as first-line treatment in advanced cutaneous squamous cell carcinomas (CSCCs)
Presenter: Eve Maubec
Session: Poster session 13