2. Academic Validation
  3. Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma

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

  • AAPS J. 2021 Dec 10;24(1):11. doi: 10.1208/s12248-021-00660-3.
Brian Hess 1,  William Townsend 2,  Weiyun Ai 3,  Anastasios Stathis 4,  Melhem Solh 5,  Juan Pablo Alderuccio 6,  David Ungar 7,  Sam Liao 8,  Lori Liao 8,  Lisa Khouri 8,  Xiaoyan Zhang 7,  Joseph Boni 9
Affiliations

Affiliations

  • 1 Hollings Cancer Center, Charleston, South Carolina, USA.
  • 2 University College London Hospitals NHS Foundation Trust and UCLH National Institute for Health Research Clinical Research Facility, London, UK.
  • 3 Department of Medicine, University of California San Francisco, San Francisco, California, USA.
  • 4 Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
  • 5 Blood and Marrow Transplant Program at Northside Hospital, Atlanta, Georgia, USA.
  • 6 Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
  • 7 ADC Therapeutics Inc, Murray Hill, New Jersy, USA.
  • 8 Pharmax Research Inc, Irvine, California, USA.
  • 9 ADC Therapeutics Inc, Murray Hill, New Jersy, USA. [email protected].
PMID: 34893942 DOI: 10.1208/s12248-021-00660-3
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.

Keywords

Clinical; Drug conjugates; PK/PD Modeling; Pharmacodynamics; Pharmacokinetics.

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