Time‐to‐Event Analysis of Polatuzumab Vedotin‐Induced Peripheral Neuropathy to Assist in the Comparison of Clinical Dosing Regimens

• Published in: CPT: pharmacometrics and systems pharmacology Vol. 6; no. 6; pp. 401 - 408
• Main Authors: Lu, D, Gillespie, WR, Girish, S, Agarwal, P, Li, C, Hirata, J, Chu, Y‐W, Kagedal, M, Leon, L, Maiya, V, Jin, JY
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2017; John Wiley and Sons Inc
• Subjects: Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cell division; Clinical trials; Drug dosages; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Immunoconjugates - therapeutic use; Leukemia; Lymphoma; Lymphoma, Non-Hodgkin - blood; Lymphoma, Non-Hodgkin - drug therapy; Models, Biological; Monoclonal antibodies; Original; Patients; Peripheral Nervous System Diseases - blood; Peripheral Nervous System Diseases - chemically induced; Peripheral neuropathy; Regulatory approval; Risk factors; Rituximab - administration & dosage; Rituximab - therapeutic use; Serum Albumin - analysis; Studies; Targeted cancer therapy
• ISSN: 2163-8306; 2163-8306
• DOI: 10.1002/psp4.12192

Polatuzumab vedotin, an antibody‐drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55–72% in patients with indolent non‐Hodgkin lymphoma in a phase II study, when dosed 1.8–2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time‐to‐event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration. When capping the treatment duration to six to eight cycles, the risk ratio of a dose of 2.4 mg/kg vs. 1.8 mg/kg was ≥1.29; the predicted incidence of grade ≥2 PN at 1.8–2.4 mg/kg dose levels was 17.8–37.2%, which is comparable with other antimicrotubule agents for lymphoma treatment.