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

Abstract

Peripheral neuropathy (PN) is a common long‐term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine‐citrulline‐monomethylauristatin E antibody–drug conjugates (ADCs) developed at Genentech. A pooled time‐to‐event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ≥ 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time‐to‐event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ≥ 2 PN.

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

“…Body weight was identified as a positive risk factor for PN after accounting for conjugate exposure. This finding is supported by another analysis in which the TTE model was expanded to include eight MMAE‐containing ADCs . It was reported that height, which is highly correlated with body weight, is an important and independent risk factor for PN .…”

“…This finding is supported by another analysis in which the TTE model was expanded to include eight MMAE-containing ADCs. 26 It was reported that height, which is highly correlated with body weight, is an important and independent risk factor for PN. 27 There is also a trend for higher risk with increasing serum albumin concentrations.…”

Impact of Physiologically Based Pharmacokinetics, Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics in the Development of Antibody‐Drug Conjugates

“…Time-to-event modeling of peripheral neuropathy-platform modeling. 41 (A) Model structure. The hazard in the time-to-event model is driven by individually predicted antibody-drug conjugate plasma concentrations (Cp).…”

“…40 To assess risk factors for developing PN and to evaluate if drug target plays a role, a pooled time-to-event analysis across 8 vc-MMAE antibody-drug conjugates (∼700 patients) was performed to evaluate the relationship between the antibody-drug conjugate exposure and the risk for developing a clinically significant (grade ≥ 2) PN ( Figure 6). 41 The analysis suggested that the risk for developing PN was largely independent of target and cancer type but increased with antibody-drug conjugate exposure and treatment duration. In addition, large body weight and previously reported PN increased the risk for developing PN (Figure 6).…”

Model‐Informed Therapeutic Dose Optimization Strategies for Antibody–Drug Conjugates in Oncology: What Can We Learn From US Food and Drug Administration–Approved Antibody–Drug Conjugates?

“…BW appears to be a PN risk factor independent of drug exposure, as the increased exposure in high BW patients given per mg/kg dose was not sufficient to explain the impact of BW on observed incidence of PN. As a result, the model simulation suggested that capping the dose for patients > 100 kg only had a marginal benefit for these patients in reducing the PN risk (20).…”