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

Abstract

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.

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

“…Furthermore, as both ADCs and chemotherapeutic agents have narrow therapeutic windows, it is imperative that the effects of conventional drugs on the ADC, as well as the effect of the ADC on conventional drugs, are assessed [44]. A limit of 6-8 cycles of pola 1.8 mg/kg has been determined to be effective reducing the risk of peripheral neuropathy (a known adverse event [AE] with pola as a single agent) [45].…”

Time‐to‐Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine‐Citrulline‐Monomethylauristatin E Antibody–Drug Conjugates

“…The TTE model for grade ≥ 2 PN published previously for polatuzumab vedotin was used as a starting point. The addition of a transit compartment between plasma and the effect compartment provided a slightly better fit to the data with the same number of parameters.…”

“…A time-to-event (TTE) model was previously developed for polatuzumab vedotin, a vc-MMAE-containing ADC, to quantify the relationship between ADC exposure (MMAE conjugated to the mAb) and treatment duration on the incidence of PN, considering the cumulative onset of grade ≥ 2 PN events. 30 Given that the eight in-house vc-MMAE ADCs contain the same antimicrotubule agent (i.e., MMAE), display comparable PK properties, and have consistent exposureresponse trends for grade ≥ 2 PN for the individual ADCs, we have performed a pooled TTE analysis to describe the exposure-safety relationships of grade ≥2 PN. This enabled an informative analysis despite limited data on each separate ADC (except polatuzumab) and also allowed a comparison among ADCs after accounting for other covariate effects.…”

“…For patients not included in the PK analysis, the population PK parameter estimates were used to predict individual exposures accounting for covariate effects. The TTE model for grade ≥ 2 PN published previously for polatuzumab vedotin 30 was used as a starting point. The addition of a transit compartment between plasma and the effect compartment provided a slightly better fit to the data with the same number of parameters.…”

“…On the other hand, consistent with previous reports, no correlation between unconjugated MMAE exposure and grade ≥ 2 PN was seen. A time‐to‐event (TTE) model was previously developed for polatuzumab vedotin, a vc‐MMAE–containing ADC, to quantify the relationship between ADC exposure (MMAE conjugated to the mAb) and treatment duration on the incidence of PN, considering the cumulative onset of grade ≥ 2 PN events . Given that the eight in‐house vc‐MMAE ADCs contain the same antimicrotubule agent (i.e., MMAE), display comparable PK properties, and have consistent exposure–response trends for grade ≥ 2 PN for the individual ADCs, we have performed a pooled TTE analysis to describe the exposure–safety relationships of grade ≥2 PN.…”