Abstract 741P
Background
Ipilimumab (Ipi), the only approved anti-CTLA-4 mAb, is associated with severe AEs in >20% of Pts as monotherapy at 3 mg/kg (mpk), and 1 mpk is used in combination with nivolumab to mitigate safety concerns. ADG126 SAFEbody applies precision masking peptide to the anti-CTLA-4 ADG116 NEObody™ for 6-fold greater safety over ADG116, and has an improved safety and efficacy profile over Ipi. ADG126 targets a unique epitope of CTLA-4, inducing strong ADCC-mediated Treg depletion and CD8+ Teff cells in the tumor microenvironment (TME) to limit on-target AEs in normal tissues. It prolongs exposure and accumulation of activated ADG126 in the TME, widens the therapeutic window and enhances Teff/Treg ratio for efficacy. We present interim dose escalation results from our ongoing phase 1b/2 study (ADG126-1001; NCT04645069).
Methods
ADG126 monotherapy (0.1, 0.3, 1, 3, 10 mpk) was given Q3W IV to Pts with advanced solid tumors. Primary endpoints are safety and tolerability. Secondary endpoints are PK, ORR per RECIST 1.1, and PFS.
Results
16 Pts were treated (median age=65 years; 31% had ≥3 lines of prior therapies; 31% progressed from immunotherapy). No DLTs was observed, nor MTD was reached. Only Grade 1 (G1) TRAEs were reported; most frequent were fatigue (19%) & pruritis (13%). Linear PK was observed with ∼1.5-fold increase in mean t1/2z for total drug over ADG116, correlating with steady state mean accumulation of activated ADG126 to ≥3-fold, and resulting in predicted target saturation at 6-10 mpk. 5 Pts had stable disease with one for >36 weeks. Durable reductions in target lesions by CT and increased CD8+ T cells were observed in one ovarian cancer & another uveal melanoma Pts. The ovarian Pt had 77% reduction in CA-125 and 22% tumor shrinkage after 7 cycles at 1 mpk; the uveal melanoma Pt had 24% tumor reduction after two cycles at 10 mpk.
Conclusions
ADG126 shows a compelling safety profile with superior PK and early efficacy signals, with only G1 TRAEs as monotherapy given by Q3W for >4 cycles at 10 mpk and >12 cycles at 1 mpk. Combination studies with anti-PD1 therapy are initiated aiming to transform anti-CTLA-4 therapy with improved safety & efficacy.
Clinical trial identification
NCT04645069.
Editorial acknowledgement
We would like to acknowledge Ami Knoefler for providing editorial support.
Legal entity responsible for the study
Adagene Inc.
Funding
Adagene Inc.
Disclosure
G. Richardson: Non-Financial Interests, Institutional, Principal Investigator: Adagene. A.W. Tolcher: Financial Interests, Institutional, Advisory Board, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which he is the CEO and Founder: Adagene, Inc., ARO Biotherapeutics, Bioinvent, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, Elucida, EMD Serono/ Merk KGaA, Immunome, NBE Therapeutics, Pelican, Pieris Pharma, Pyxis Oncology, Vincerx, Zymeworks Inc., MIRATI; Financial Interests, Institutional, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a Next Oncology of which he is the CEO and Founder.: Asana BioSciences, LLC., Axlmmune, Bayer, Gilde Healthcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Menarini Ricerche, Mersana, Nanobiotix, Partner Therapeutics, Pfizer Inc., Pierre Fabre, Ryvu Therapeutics, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., AbbVie, Inc, Agenus, Inc., Ascentage, Mekanistic Therapeutics; Financial Interests, Institutional, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a Next Oncology of which he is the President and Founder.: Aclaris Therapeutics; Financial Interests, Institutional, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a Next Oncology of which he is President and Founder.: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Note: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a Next Oncology of which he is President and Founder.: Immuneering, Impact Therapeutics US, Inc., Ocellaris Pharma, Inc. & Eli Lilly, SK Life Science, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd; Financial Interests, Institutional, Advisory Board, Note: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, LLC d/b/a Next Oncology of which he is President and Founder.: ZielBio, Inc., Ikena Oncology, Hiber Cell, Inc.; Financial Interests, Institutional, Invited Speaker, Dr. Tolcher is the Director of Research, CEO and Founder of Next Oncology: Next Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a Next Oncology of which Dr. Anthony Tolcher is CEO and Founder: Adagene Inc, AbbVie, Inc, Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, Effector Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc, Mabspace Biosciences (Suzhou) Co., Limited, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc, Nitto BioPharma, Inc., Odonate Therapeutics, Inc., Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, LLC, Seattle Genetics, Inc., Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, Zymeworks Inc.; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics SA, Agenus Inc.; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a Next Oncology of which Dr. Anthony Tolcher is CEO and Founder.: ORIC Pharmaceuticals; Non-Financial Interests, Principal Investigator: AbbVie, Inc; Non-Financial Interests, Principal Investigator, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, LLC d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: ABL Bio Inc., Adagene Inc, ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, LLC., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, LLC, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., Impact Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc.. M. Morris: Non-Financial Interests, Institutional, Principal Investigator: Adagene. P. de Souza: Non-Financial Interests, Institutional, Principal Investigator: Adagene. A. Hamid: Non-Financial Interests, Institutional, Principal Investigator: Adagene. X.K. She: Financial Interests, Institutional, Full or part-time Employment: Adagene. L. Zhu: Financial Interests, Institutional, Full or part-time Employment: Adagene. S. Zheng: Financial Interests, Institutional, Full or part-time Employment: Adagene. G. Liu: Financial Interests, Institutional, Full or part-time Employment: Adagene. Y. Li: Financial Interests, Institutional, Full or part-time Employment: Adagene. F. Du: Financial Interests, Institutional, Full or part-time Employment: Adagene. S. Fischkoff: Financial Interests, Institutional, Advisory Role: Adagene. H. Gong: Financial Interests, Institutional, Full or part-time Employment: Adagene. J. Zha: Financial Interests, Institutional, Full or part-time Employment: Adagene. P.P. Luo: Financial Interests, Institutional, Full or part-time Employment: Adagene.