Phase I dose escalation study of HFB200603, a best-in-class BTLA antagonist monoclonal antibody (mAb), in monotherapy and in combination with the anti-PD-1 mAb tislelizumab (TIS) in adult patients (pts) with advanced solid tumors

BackgroundBTLA is a checkpoint found on a variety of immune cells. When antagonized, it has the potential to enhance anti-tumor immunity. HFB200603, a best-in-class anti-BTLA antagonistic mAb, activates immune responses by inhibiting BTLA signaling. We report initial results from an ongoing Phase I dose escalation, multicenter trial evaluating HFB200603 in monotherapy and in combination with TIS.MethodsThis Phase I trial assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HFB200603 in pts with advanced refractory solid tumors. Pts were enrolled in 4 monotherapy dose escalation cohorts (Q3W dosing) and 3 TIS combination cohorts (Q3W dosing). Selection of solid tumor types was powered via Drug Intelligence Science (DIS®), which integrates expression of immune markers with bulk and single-cell RNA-seq analyses using AI/ML. Sequential analysis of peripheral blood and tumor tissue biomarkers was performed.ResultsBy April 19, 2024, 29 pts were enrolled – 14 in monotherapy and 15 in combination with TIS. Microsatellite stable (MSS) colorectal cancer (CRC) was the focused tumor type (52%). All pts had received prior systemic therapy (median 3, range 1-6); 7 pts (24%) had prior checkpoint inhibitors. There were no dose-limiting toxicities. Increased AST (11%), asthenia (7%), fatigue (7%), and pruritis (7%) were the most common treatment-related adverse events (TRAEs), with no Grade 3 TRAEs, nor any drug discontinuations due to TRAEs. HFB200603 PK analysis revealed proportional exposures, linear clearance, and 100% peripheral receptor occupancy across all doses. PD results indicated immune activation and T cell expansion in peripheral blood. Initial efficacy indicated monotherapy clinical benefit > 3 mo in non-small cell lung cancer and renal cell carcinoma, and 7 (88%) MSS CRC pts in combination therapy remain on treatment > 2 mo.ConclusionsHFB200603 shows favorable safety and dose-dependent PK with receptor saturation. Proof-of-concept is demonstrated by peripheral T cell activation. Accrual is ongoing in pts with heavily pretreated refractory solid tumors.Clinical trial identificationNCT05789069.Legal entity responsible for the studyHiFiBiO Therapeutics Inc.FundingHiFiBiO Therapeutics Inc.DisclosureM. De Miguel: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. A. Landa Magdalena: Financial Interests, Personal, Other, Educational and travel support: Pfizer, Roche, Merck, Sanofi, Rovi, PharmaMar, AstraZeneca, Incyte. 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. 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. J. Menis: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Roche, MSD, Novartis; Financial Interests, Institutional, Other, Travel grant: Ipsen; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, MSD, Novartis. G. Daniele: Financial Interests, Personal, Invited Speaker: GSK, Gilead, Bayer; Financial Interests, Institutional, Research Grant: Gilead. A.B. El-Khoueiry: Financial Interests, Personal, Advisory Board: Exelixis, AstraZeneca, Genentech, Agenus, Tallac, ABL Bio, Senti Biosciences, Qurient; Financial Interests, Institutional, Funding: Fulgent, Astex, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Merck; Financial Interests, Personal, Coordinating PI: Genentech; Financial Interests, Institutional, Coordinating PI, trial funding: Auransa; Non-Financial Interests, Principal Investigator: Agenus, Affimed, Bayer. 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. A. Gravina: Financial Interests, Institutional, Local PI, Grants for Clinical Trials: Pfizer, Janssen, Roche, Daiichi Sankyo, Exelixis, Incyte, MSD, Bayer, Merck; Financial Interests, Institutional, Coordinating PI, Grants for Clinical Trials: AstraZeneca; Financial Interests, Institutional, Local PI, Grants for Clinical Trial: GSK-Tesaro, Sutro, Boehringer Ingelheim, HiFiBiO Inc.; Non-Financial Interests, Member: AIOM, ESMO. A.J. Olszanski: Financial Interests, Personal, Advisory Board: BMS, Merck, Oncosec, Replimune; Financial Interests, Personal, Invited Speaker, Lecture to Pfizer personnel regarding melanoma: Pfizer; Financial Interests, Institutional, Local PI: BMS, GSK, Regeneron, Sound Biologics, SpringBank, Takeda, Anaveon, Antegene, Lantern, Kezar, HiFiBio, Shionogi, Immatics; Non-Financial Interests, Other, Data Safety Monitoring Board: Pfizer; Non-Financial Interests, Member, Member of melanoma panel and IO adverse event panel: NCCN. O. Rapaic: Financial Interests, Personal, Full or part-time Employment: HiFiBiO Inc. J. Li, H. Poullain, G. Margall: Financial Interests, Personal, Full or part-time Employment: HiFiBiO Therapeutics. G. Wong: Financial Interests, Personal, Full or part-time Employment: HiFiBio Therapeutics; Financial Interests, Personal, Ownership Interest: HiFiBio Therapeutics; Financial Interests, Personal, Stocks/Shares: Novartis Institutes for Biomedical Research; Financial Interests, Personal, Other, Patent: Novartis Institutes for Biomedical Research. W. Hedrich: Financial Interests, Institutional, Full or part-time Employment: HiFiBiO Therapeutics, Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J. Russella Pollard: Financial Interests, Personal, Full or part-time Employment, Employer: HiFiBio; Financial Interests, Personal, Stocks/Shares, Share Options: HiFiBio; Financial Interests, Personal, Stocks/Shares, Shares: Moderna, Sanofi. J. Gan: Financial Interests, Personal, Full or part-time Employment: HiFiBiO Therapeutics; Financial Interests, Personal, Stocks/Shares: HiFiBiO Therapeutics. R.H.I. Andtbacka: Financial Interests, Personal, Full or part-time Employment: HiFiBiO Therapeutics, Seven and Eight BioPharmaceuticals Inc.; Financial Interests, Personal, Stocks/Shares: HiFiBiO Therapeutics, Seven and Eight BioPharmaceuticals Inc. All other authors have declared no conflicts of interest.