133P - Phase 1/2 study of XTX101, a masked, tumor-activated Fc-enhanced anti-CTLA-4, in patients with advanced solid tumors

Background

XTX101 is a tumor-activated, Fc-enhanced, high affinity anti-CTLA-4 monoclonal antibody designed with masking peptides that block the CTLA-4 antigen-binding regions. The masking peptides, covalently linked, are cleaved by proteases upregulated in the tumor microenvironment compared to healthy tissues. XTX101 contains 2 mutations that facilitate Fcγ receptor binding and improve effector function.

Methods

XTX101-01/02-001 (NCT04896697) Part 1A examined XTX101 in 3+3 dose escalation in patients (pts) with advanced solid tumors. Part 1B examined pharmacodynamic (PD) biomarkers.

Results

As of August 3, 2023, 27 pts were evaluable for safety, median age 67, median 4 prior lines of therapy (1-12). In Part 1A, 5 dose levels (DL) were evaluated. Among 6 pts treated at 60 mg every 3 weeks (Q3W), 1 dose limiting toxicity (DLT) of colitis was seen. Among 6 pts treated at 180 mg Q3W, 2 DLTs of colitis were seen. At 150 mg every 6 weeks (Q6W) there were no DLTs and this was chosen as the recommended regimen[CF1] . There were no grade (G) 4/5 treatment-related adverse events (TRAEs), and no endocrine or liver-related TRAEs on the study. Among 18 pts treated with XTX101 at Q3W schedule (DL 7-180 mg), G3 TRAEs were colitis (n = 4), infusion reaction (n = 3), lymphopenia/lymph count decreased (n = 2), and diarrhea (n = 1). In 9 pts treated at 150 mg Q6W, the only G3 TRAEs were diarrhea and dermatitis (1 each). XTX101 exposure at 150 mg Q6W was comparable to 2 cycles of 60 mg Q3W. One pt, at 150 mg Q6W, with PD-L1 negative non-small cell lung cancer had a confirmed partial response (PR) ongoing at 36 weeks, with resolution of hepatic metastases and only TRAE of G1 fatigue. Supporting tumor-selective activity of XTX101, this pt had minimal changes in peripheral PD markers. Data from tumor biopsies from 2 other pts showed >70% activated molecule in tumor vs 13% in plasma.

Conclusions

XTX101, an Fc-enhanced, tumor-activated, anti-CTLA-4, has a differentiated safety profile from systemically active anti-CTLA4 and showed evidence of monotherapy clinical activity with a confirmed PR. Part 1B is ongoing at 150 mg Q6W. Development of XTX101 is planned in combination with atezolizumab for pts with microsatellite stable colorectal cancer.

Clinical trial identification

NCT04896697.

Legal entity responsible for the study

Xilio Development, Inc.

Funding

Xilio Therapeutics, Inc.

Disclosure

D. Davar: Financial Interests, Institutional, Research Grant: Arcus, CellSight Technologies, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK; Financial Interests, Personal, Speaker, Consultant, Advisor: ACM Bio, Ascendis Pharma, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Merck, Medical Learning Group (MLG), Xilio Therapeutics Inc.; Financial Interests, Personal, Speaker’s Bureau: Castle Bioscience; Other, Personal, Other, US Patent 63/124,231: University of Pittsburgh Cancer Institute; Other, Personal, Officer, US Patent 63/208,719: University of Pittsburgh Cancer Institute. J.G. Knecht: Financial Interests, Personal, Full or part-time Employment: Cardinal Health, CLS Health, Incyte; Financial Interests, Personal, Leadership Role: Kindred Hospital Clear Lake; Financial Interests, Personal, Stocks/Shares: Beckton Dickinson, Checkpoint Therapeutics, Fortress Biotech, Myovant Sciences, Reviva Pharmaceuticals; Financial Interests, Personal, Advisory Role, Honoraria: OMNI Health Media; Financial Interests, Personal, Research Funding: Atossa Therapeutics, Cosmo Pharmaceuticals, EQRx, Phanes Therapeutics, Takeda, Xilio Therapeutics, Inc.; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Cardinal Health. A.L. Vandross: Financial Interests, Personal, Full or part-time Employment: Next Oncology, Texas Oncology; Financial Interests, Institutional, Research Funding: AbbVie, Ascentage Pharma, BiOneCure, Chugai Pharma, Deciphera, Exelixis, Immunomedics, Lyvgen Biopharma, Medikine, Nanjing, NGM Biopharmaceuticals, Nitto BioPharma, OncoResponse, PMV Pharma, Sirnaomics, Tachyon Therapeutics, Teon Therapeutics, Xilio Therapeutics, Inc. C.A. Perez: Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Other, Steering Committee: Kinnate Biopharma Inc., BeiGene; Financial Interests, Institutional, Local PI: Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc, Kura Oncology, Hyamab Inc, Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribbon Therapeutics, Mirati Therpeutics, Elpiscience Biopharmaceuticals, Dracen Pharmaceuticals, Zhuhai Yufan Biotechnologies Co., Genentech, Inc., Jazz Pharmaceuticals, Artios Pharma, Ayala Pharmaceuticals, Elevation Oncology, Merus. D.M. Miller: Financial Interests, Personal, Stocks or ownership: Checkpoint Therapeutics; Financial Interests, Personal, Advisory Role: Castle Biosciences, Checkpoint Therapeutics, Merck Sharp & Dohme, Pfizer/EMD Serono, Regeneron, Sanofi/Regeneron; Financial Interests, Personal, Research Funding: Incyte; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Merck Sharp & Dohm, Pfizer, Regeneron, Sanofi/Aventis. J. Powderly: Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Writing Engagement, Consulting: Aavocyte; Financial Interests, Personal, Member of Board of Directors, Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic.: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Local PI: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics, PEEL Therapeutics, CUE BioPharma, Pieris Pharmaceuticals, RiboScience, Moderna TX, Simcere, Phanes Therapeutics, SK Life Science, Harbour BioMed, Allarity, Aulos, GI Innovation, IGM BioSciences, Aptevo, Medikine, IconOVir Bio, Qurgen; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, Stemcell Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: Pioma; Financial Interests, Personal and Institutional, Local PI, Also funding for contract laboratory services: Nuvation; Financial Interests, Personal and Institutional, Funding, Wugen is sponsor of contract laboratory translational research: Wugen; Financial Interests, Personal and Institutional, Other, AavoCyte & AavoBioCytics are jointly developing cellular therapies with BioCytics Human Applications Lab for point of care manufacturing: AavoCyte; Other, Personal, Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc. K. Montazeri: Financial Interests, Personal, Advisory Role, Consultant: Immunocore. M.J. Mooradian: Financial Interests, Personal, Advisory Role, Consultant/Honorarium: AstraZeneca, Bristol Myers Squibb, Regeneron Pharmaceuticals; Financial Interests, Personal, Research Funding: Foundation Medicine. A. Gupta: Financial Interests, Personal, Full or part-time Employment: Xilio Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Xilio Therapeutics, Inc. E. Patel: Financial Interests, Personal, Full or part-time Employment: Xilio Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Xilio Therapeutics, Inc.; Non-Financial Interests, Personal, Other, US Patent: TCR2 Therapeutics; Non-Financial Interests, Personal, Officer, US Patent: Mustang Bio. D. Fantini: Financial Interests, Personal, Full or part-time Employment: Xilio Therapeutics, Inc., Merck, ELi Lilly and Company; Financial Interests, Personal, Stocks/Shares: Xilio Therapeutics, Inc. , Merck, Eli Lilly and Company. S. Paramasivan: Financial Interests, Personal, Full or part-time Employment: Xilio Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Xilio Therapeutics, Inc., ADMA Biologics, Allogene Therapeutics, Amylyx Pharmaceuticals, Avadel Pharmaceuticals, Aurinia Pharmaceuticals, Iovance Therapeutics, Voyager Therapeutics, Deciphera Pharmaceuticals, Baudax Bio Inc., CRISPR Therapeutics, GRI Bio Inc., GSK, Novartis, Roche, Selecta Biosciences. D. Crowe: Financial Interests, Personal, Stocks/Shares: Xilio Therapeutics Inc. M. Duncan, S. Uptain, K. Luptakova: Financial Interests, Personal, Full or part-time Employment: Xilio Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Xilio Therapeutics, Inc. R. Sullivan: Financial Interests, Personal, Research Funding: Merck; Financial Interests, Personal, Advisory Board, Consulting: BMS, Marengo, Merck, Novartis, Pfizer, Replimune. All other authors have declared no conflicts of interest.