Abstract
Abstract Purpose: Tremelimumab is a fully human anti-CTLA-4 IgG2 monoclonal antibody that enhances human T-cell activation. Tremelimumab was evaluated in a Phase IIb (DETERMINE), randomised, double-blind, placebo-controlled study in patients with unresectable pleural or peritoneal malignant mesothelioma, randomised (2:1) to receive either tremelimumab (10 mg/kg, seven doses Q4W followed by Q12W) or placebo. The study demonstrated no clinically meaningful differences in overall survival (OS). The primary objectives of this analysis were to evaluate the relationship of exposure with OS, and the impact of potential confounders. Methods: A population PK model was developed to estimate and derive PK exposure metrics (area under the curve at steady state [AUCss] or clearance [CL]) for exposure-OS analysis. Impact of potential confounders was evaluated using graphical and exploratory approaches. Factors including body weight, age, gender, race, ECOG status, anatomical site (pleural or peritoneal), line of therapy, EORTC status, tumour histology, baseline tumour size, LDH, and CRP were evaluated. The analyses were performed using NONMEM 7.2 and R software. Results: The population PK included 376 patients and 1328 post-first dose PK concentrations. PK was consistent with previous knowledge and low incidence of anti-drug antibodies was observed. A 2-compartment linear PK model adequately described the data. Tremelimumab CL and volume of distribution (V1) were 310 mL/day and 3.85 L, with moderate variability of ~38% and ~32%, respectively. There was an apparent exposure-OS relation when stratified by AUCss. However, at least 3 factors (gender, CRP, and baseline tumour size) were statistically significant PK predictors (p<0.05 on CL) indicating multi-dimensional confounding effect. Higher baseline tumor size, higher CRP levels and males were associated with lower PK exposure of tremelimumab. Conclusions: The observed apparent exposure-OS relationship is the result of imbalance in prognostic factors impacting OS rather than a true association of exposure with efficacy. Citation Format: Paul Baverel, Lorin Roskos, Manasa Tatipalli, Nancy Lee, Paul Stockman, Maria Taboada, Paolo Vicini, Kevin Horgan, Rajesh Narwal. Exposure-efficacy (OS) analysis of tremelimumab in unresectable malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5046. doi:10.1158/1538-7445.AM2017-5046
Published Version
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