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

Our plain-English summary of Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors, by J.J. Luke, F. Barlesi, K. Chung, et al (Journal for Immunotherapy of Cancer, 2021).

The study

• Authors: J.J. Luke, F. Barlesi, K. Chung, A.W. Tolcher, K. Kelly, A. Hollebecque, C. Le Tourneau, V. Subbiah, F. Tsai, S. Kao, P.A. Cassier, M. Khasraw, H.L. Kindler, H. Fang, F. Fan, K. Allaire, M. Patel, S. Ye, D.T. Chao, W.R. Henner, J.S. Hayflick, M.A. McDevitt, L. Fong
• Journal: Journal for Immunotherapy of Cancer
• Published: 2021;9(2)
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: CD40 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.

Methods: ABBV-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.

Results: Fifty-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.

Conclusions: ABBV-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 in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer.

Trial Registration Number: NCT02955251.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This was an early-stage (phase I) drug trial, not a study of asbestos exposure. The authors gave ABBV-428 to 59 patients with advanced solid tumors between November 2016 and June 2018. ABBV-428 is an antibody designed to activate the immune system near tumors carrying a protein called mesothelin. Twenty-five of the patients had mesothelioma and 14 had ovarian cancer. The drug was given by vein every 2 weeks, at doses from 0.01 to 3.6 mg/kg. No dose-limiting side effects occurred, and 3.6 mg/kg was chosen as the recommended dose. Severe (grade 3 or higher) treatment-related side effects occurred in 3 patients (5%), all at 3.6 mg/kg. No cytokine release syndrome was reported. Among 53 patients evaluable for response, none had a confirmed complete or partial response. Among 25 evaluable patients at 3.6 mg/kg, 9 (36%) had stable disease. Three patients with mesothelioma had stable disease for more than 6 months. Paired tumor biopsies showed no consistent changes in CD8+ T-cells or PD-L1+ cells. The authors concluded that the drug had an acceptable safety profile but minimal clinical activity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open-label, first-in-human phase I drug trial, with dose escalation followed by expansion cohorts at the recommended dose
• Who was studied: 59 patients with advanced solid tumors treated from November 2016 through June 2018. 25 (42%) had mesothelioma and 14 (24%) had ovarian cancer. The expansion cohort at 3.6 mg/kg included 10 patients with ovarian cancer and 12 with mesothelioma.
• Exposure: No asbestos exposure was studied. The exposure was the experimental drug ABBV-428, given intravenously every 2 weeks at nine dose levels from 0.01 to 3.6 mg/kg.
• Main results:
  • The maximum tolerated dose was not reached and no dose-limiting toxicities were observed. 3.6 mg/kg was chosen as the recommended dose.
  • Across all 59 patients, 39 (66%) had a treatment-related adverse event. Grade 3 or higher treatment-related events occurred in 3 patients (5%), all in the 3.6 mg/kg cohort: pericardial effusion, colitis, infusion-related reaction and pleural effusion (1 patient each).
  • Seven patients (12%) had infusion-related reactions. No cytokine release syndrome was reported.
  • Of 53 patients evaluable for response across all doses, none had an objective response (confirmed complete or partial response). 25 (47%) had stable disease and 28 (53%) had progressive disease as their best response.
  • Of 25 response-evaluable patients at 3.6 mg/kg, 9 (36%) had stable disease and 16 (64%) had progressive disease as their best response.
  • Three patients with mesothelioma had stable disease on treatment for more than 6 months.
  • No consistent changes in tumor-infiltrating CD8+ T-cells or PD-L1+ cells were seen in paired tumor biopsies taken during dose expansion.
  • Baseline mesothelin levels correlated with progression-free survival in the expansion cohort of 14 patients (7 ovarian cancer, 7 mesothelioma), with a Spearman correlation of 0.606 and p=0.021. Among all 36 evaluated patients, the correlation was 0.284 (p=0.098).
• The authors' conclusion: The authors concluded that ABBV-428 alone had an acceptable safety profile but minimal clinical activity, including in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. They suggested that higher doses or selecting patients by mesothelin expression may be required.
• Limitations the authors state:
  • Patients were not selected for the study based on their tumor's mesothelin expression.
  • Enrollment in the expansion cohorts was stopped early because of a lack of preliminary clinical activity. 24 patients per cohort had been planned.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Immunotherapy, Macrophage, Biomarker, Tumor Microenvironment, Ovarian Cancer, Mesothelioma, Pericardial Effusion.

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