Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors

• Published in: Journal for immunotherapy of cancer 2021-02, Vol.9 (2), p.e002015
• Main Authors: Luke, Jason J, Barlesi, Fabrice, Chung, Ki, Tolcher, Anthony W, Kelly, Karen, Hollebecque, Antoine, Le Tourneau, Christophe, Subbiah, Vivek, Tsai, Frank, Kao, Steven, Cassier, Philippe A, Khasraw, Mustafa, Kindler, Hedy L, Fang, Hua, Fan, Frances, Allaire, Kathryn, Patel, Maulik, Ye, Shiming, Chao, Debra T, Henner, William R, Hayflick, Joel S, McDevitt, Michael A, Fong, Lawrence
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antibodies; Antibodies, Bispecific - adverse effects; Antibodies, Bispecific - pharmacokinetics; Antibodies, Bispecific - therapeutic use; Antigens; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - pharmacokinetics; Antineoplastic Agents, Immunological - therapeutic use; Bone marrow; Cancer; CD40 Antigens - agonists; Clinical/Translational Cancer Immunotherapy; Cytokines; Drug dosages; Female; France; Humans; Immunotherapy; Ligands; Male; Maximum Tolerated Dose; Mesothelin - agonists; Mesothelioma; Middle Aged; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - mortality; Neoplasms - pathology; Pharmacokinetics; Progression-Free Survival; Time Factors; Tumor Microenvironment; Tumor necrosis factor-TNF; Tumors; United States
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-002015

BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.MethodsABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression.ResultsFifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population.ConclusionsABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity