Phase 1 first-in-human study of dalutrafusp alfa, an anti-CD73-TGF-β-trap bifunctional antibody, in patients with advanced solid tumors

Abstract

Background: Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-β pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-β signaling in patients with advanced solid tumors.

Methods: Dose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity.

Results: In total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1-14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-β 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively.

Conclusions: Dalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-β pathways in oncology.

Keywords: adenosine; immunomodulation; immunotherapy; tumor biomarkers; tumor microenvironment.

Conflict of interest statement

Competing interests: AWT reports being a consultant for AbbVie, Aclaris Therapeutics, Agenus, Asana Biosciences, Ascentage Pharma, Axlmmune, Bayer, Daiichi Sankyo, Eli Lilly, Gilde Healthcare Partners, HBM Partners, Immuneering Corporation, Immunomet Therapeutics, Impact Therapeutics US, Karma Oncology B.V., Lengo Therapeutics, Mekanistic Therapeutics, Menarini Ricerche, Mersana Therapeutics, Mirati Therapeutics, Nanobiotix, Ocellaris Pharma, Partner Therapeutics, Pfizer, Laboratories Pierre Fabre, Ryvu Therapeutics, Seattle Genetics, SK Life Science, SOTIO Biotechnology, Spirea Limited, Sunshine Guojian Pharmaceutical (Shanghai), Transcenta Therapeutics, and Trillium Therapeutics; reports being an advisory board member for Adagene, Aro Biotherapeutics, Bioinvent, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Biosciences, Elucida Oncology, EMD Serono/Merck KGaA, Hiber Cell, Ikena Oncology, Immunome, Janssen Global Services, NBE Therapeutics, Pelican, Pieris Pharma, PYXIS Oncology, Vincerx Pharma, ZielBio, and Zymeworks Biopharmaceuticals; and reports receiving compensation for open studies from Gilead Sciences. MG reports potential conflicts with AbbVie, Aeglea BioTherapeutics, Agenus, Arcus Biosciences, Astex Pharmaceuticals, BeiGene, BluePrint Medicines, BMS Amgen, Calithera Biosciences, CellDex Therapeutics, Corcept Therapeutics, Clovis Oncology, Deciphera Pharmaceuticals, Eli Lilly, Endocyte, Five Prime Therapeutics, Genocea Biosciences, Medimmune, Merck, Neon, Plexxikon, Revolution Medicines, Seattle Genetics, EMD Serono, SynDevRx, Tesaro, Tolero Pharmaceuticals, TRACON Pharmaceuticals, and Salarius Pharmaceuticals; and reports being a consultant for Agenus, Daiichi Sankyo, Imaging Endpoints, Salarius Pharmaceuticals, and TRACON Pharmaceuticals. KMM reports no conflicts of interest. AS, SZ, TT, JMJ, SS, AAO, TC reports being an employee of Gilead Sciences, and reports stock ownership in Gilead Sciences. MZ and C-HH reports being a former employee of Gilead Sciences, and a shareholder of Gilead Sciences. JS reports being a part-time employee of Dialectic Therapeutics; reports common stock ownership in AbbVie, Abbott Laboratories, Bristol Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck, and Regeneron Pharmaceuticals; reports stock option ownership in Dialectic Therapeutics; reports being an advisory board member for Synlogic and Binhui Biopharmaceuticals; and reports being a site principal investigator for studies funded by Agenus Bio, Alkermes, Arvinas, AstraZeneca, BerGenBio, Daiichi Sankyo, Epizyme, Gan & Lee Pharmaceuticals, Genmab, GlaxoSmithKline, Harpoon Therapeutics, Hutchison Medipharma, Jounce, Mirati Therapeutics, Mundipharma, Laekna Limited, Novartis Pharmaceuticals, Odonate Therapeutics, Onconova Therapeutics, ORIC Pharma, Pfizer, Rgenix, Shasqi, Surface Oncology, Synlogic Therapeutics, Takeda Pharmaceutical, and Xencor.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patient disposition (all-enrolled analysis set).

Figure 2

Mean (SD) dalutrafusp alfa plasma concentrations versus time during Cycle 1 (semi-log scale). LLOQ, lower limit of quantitation.

Figure 3

Peripheral TGF-β, CD73 TO, and sCD73 levels across all dalutrafusp alfa cohorts. (A) TGF-β1 in plasma on-treatment with dalutrafusp alfa. (B) CD73 TO on B cells in whole blood on-treatment with dalutrafusp alfa. (C) Free sCD73 in plasma on-treatment with dalutrafusp alfa. (D) sCD73 activity in plasma on-treatment with dalutrafusp alfa. CD, cluster of differentiation; s, soluble; TGF, tumor growth factor; TO, target occupancy.