1128P - A phase I dose escalation and expansion study of FHD-286, a novel BRG1/BRM (SMARCA4/SMARCA2) inhibitor, for the treatment of metastatic uveal melanoma

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.