Efficacy and Safety Exposure–Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma

Brian Hess, William Townsend, Weiyun Ai, Anastasios Stathis, Melhem Solh, Juan Pablo Alderuccio, David Ungar, Sam Liao, Lori Liao, Lisa Khouri, Xiaoyan Zhang, Joseph Boni

Research output: Contribution to journalArticlepeer-review

Abstract

We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure–response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan–Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores > 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p < 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p < 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish (US)
Article number11
JournalAAPS Journal
Volume24
Issue number1
DOIs
StatePublished - Feb 2022

Keywords

  • Clinical
  • Drug conjugates
  • Pharmacodynamics
  • Pharmacokinetics
  • PK/PD Modeling

ASJC Scopus subject areas

  • Pharmaceutical Science

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