Background: Probody ® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1)., Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1)., Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1)., Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression., Trial Registration Number: NCT03013491., Competing Interests: Competing interests: AN: Research funding from Amplimmune, Arcus Biosciences, ARMO BioSciences, Atterocor, BMS, Calithera Biosciences, CytomX Therapeutics, Eli Lilly, EMD, HealiosOnc, ImmuneOncia, Incyte, Karyopharm Therapeutics, Kymab, MedImmune, Merck, NCI, NeoimmuneTech, Neon Therapeutics, Novartis, Nutrition, Pfizer, PsiOxus, Regeneron, Serono, Surface Oncology, and TopAlliance Biosciences. Advisory boards for CytomX Therapeutics, Genome & Company, Kymab, Novartis, OncoSec KEYNOTE-695, and STCube Pharmaceuticals. Travel expenses from ARMO BioSciences. AN’s spouse has received research funding from Baxalta, Chao physician-scientist, Immune Deficiency Foundation, and Jeffery Modell Foundation; and has served on advisory boards for Behring, CSL, Horizon, Pharming, and Takeda. FT: Research funding and conference registration from Novartis. Consultancy/advisory role for Achilles Therapeutics, Bayer, BMS, Enara Bio, GSK, T-Knife, and Zelluna. EGEDV: Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon. Institutional financial support for advisory boards from Daiichi Sankyo, Merck, NSABP, Pfizer, and Sanofi; all outside the submitted work. FALME: Consultancy/advisory role for Servier, Novartis, Eisai, and Ipsen. NU: Consultant for AstraZeneca, Eli Lilly, Ipsen, QED, and Taiho. Research support from EMD, Ipsen, Serono, and Taiho. Holds stock in Exact Sciences and Natera. PAO: Research funding from and advisory role for Amgen, Armo BioSciences, Array, AstraZeneca/MedImmune, Bristol-Meyers Squibb, Celldex, CytomX, Merck, Neon Therapeutics, Novartis, Pfizer, and Roche/Genentech. PL: Consultant/advisory board for AbbVie, ABL Bio, Agenus, Agios, Astellas, AstraZeneca, Black Diamond, Cybrexa, CytomX, EMD Serono, GenMab, Genentech, Glaxo-Smith Kline, ImmunoMet, IQVIA, Kineta Inc., Kyowa Kirin Pharmaceutical Development, MacroGenics, Molecular Templates, Pfizer, QED Therapeutics, Salarius, Shattuck, Silverback, SK Life Science, SOTIO, STCube Pharmaceuticals, Takeda, TRIGR, and Zentalis Pharmaceuticals. Data safety monitoring committee for Five Prime, Halozyme, and Tyme. Participant in imCORE Alliance (Roche/Genentech). JG-C: Speaker’s bureau for Bayer; fees to support registration and attending scientific meetings from BMS and Novartis. VB: Consulting/advisory role for CytomX Therapeutics, Guidepoint, Ideaya Biosciences, Loxo Therapeutics, Oncoart, and Puma Biotechnology. Institutional financial support for clinical trials from Abbvie, ACEO, Adaptaimmune, Amcure, AMGEN, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Boston Therapeutics, Cytomx Therapeutics, Daiichi, DebioPharm, Dynavax, GSK, Genentech/Roche, H3, Incyte, Innovio, Janssen, Kura, Lilly, Loxo, Macrogenics, Menarini, Merck, Mersana, Merus, Millenium, MSD, Nanobiotix, Nektar, Novartis, ORCA, Pfizer, PharmaMar, Principia, PsiOxus, PUMA, Regeneron, Rigontec, Sanofi, Seattle Genetics, Spectrum, Synthon, Taiho, Tesaro, Transgene, Takeda, and Zenith. JB: Institutional financial support for clinical trials or contracted research from AbbVie, Acerta Pharma, ADC, Agios, Amgen, Apexigen, Arch Oncology, Arcus Bio, ARMO, Array, Arrys, AstraZeneca, AtlasMedx, Bayer, Beigene, Bellicum, BI, Bicycle Therapeutics, Blueprint, BMS, Boston Biomedical, CALGB, Calithera, Celgene, Celldex, Cyteir Therapeutics, Cytomx, Daiichi Sankyo, Effector, Eisai, EMD Serono, Evelo, Five Prime, FORMA, Forty Seven, Foundation Bio, Genentech/Roche, Gilead, Gossamer Bio, GSK, Harpoon, Hutchinson MediPharma, IGM Biosciences, Imclone, Incyte, Innate, Innate Pharma, Ipsen, Jacobio, Koltan, LEAP, Lilly, Mabspace, Macrogenics, Marshall Edwards, MedImmune, Merck, Merrimack, Mersana, Merus, Millennium, Morphotex, Nektar, NeoImmune Tech, NGM Biopharma, Novartis, Novocare, NuMab, Oncogenex, OncoMed, Ongologie, Onyx, Pfizer, Pieris, Prelude Oncology, PureTech Health, Regeneron, Relay Therapeutics, REPARE Therapeutics, Revolution Medicines, Rgenix, Sanofi, Scholar Rock, Seattle Genetics, Shattuck Labs, Sierra, Stemcentrx, SynDevRex, Synthorx, Taiho, Takeda, Tarveda, TempestTx, TG Therapeutics, Tracon, Treadwell Therapeutics, Tyrogenex, Unum Therapeutics, Vyriad, and Zymeworks. Institutional financial support for advisory boards/consulting from Array, Agios, Amgen, Apexigen, Arch Oncology, ARMO, AstraZeneca, Bayer, Beigene, BI, Bicycle Therapeutics, BMS, Celgene, Continuum Clinical, Cyteir, Daiichi Sankyo, Evelo, Five Prime, FORMA, Fusion Therapeutics, Genentech/Roche, Gilead, GSK, Incyte, Innate, Ipsen, Janssen, LEAP, Lilly, Macrogenics, MedImmune, Merck, Merrimack, Moderna Therapeutics, Molecular Partners, Novartis, Oncogenex, OncoMed, Pfizer, Phoenix Bio, Piper Biotech, Prelude Therapeutics, Relay Therapeutics, Samsung Bioepios, Sanofi, Seattle Genetics, Taiho, Tanabe Research Laboratories, TD2 (Translational Drug Development), TG Therapeutics, Tizona, Tolero, and Torque. Food, beverages and/or travel expenses from ARMO, BI, BMS, Celgene, FORMA, Genentech/Roche, Gilead, Ipsen, Lilly, MedImmune, Merck, Novartis, Oncogenex, OncoMed, and Taiho. KAA: Advisory board for CytomX (unpaid). Institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, CytomX, GSK, Merck, Pfizer, and Tizona. MR: Honoraria from Bayer. GD: Research funding from AstraZeneca, Bristol Myers Squibb, and Merck. Honoraria from AstraZeneca. Advisory board for Curio Science. MG-M: Speaker’s bureau for Astra Zeneca, Pharmamar, and Roche. Financial support for registration and attendance at scientific meetings from MDS, Pharmamar, and Roche. MS is a former employee and ALH is a current employee of CytomX Therapeutics, Inc. Both are stockowners in CytomX Therapeutics Inc. H-TA: Advisor for Bayer, Beigene, Bicycle, Engitix, Guardant, iOnctura, Roche, and Servier. Employed by HCA Healthcare UK and Sarah Cannon Research Institute. AS: Consultant for Amgen, AstraZeneca, BMS, Merck, Mirati, and Novartis. Institutional financial support for clinical trials or contracted research from CytomX., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. 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