Exposure-Response Analysis of Overall Survival for Tremelimumab in Unresectable Malignant Mesothelioma: The Confounding Effect of Disease Status

Abstract

Tremelimumab, an anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that enhances T-cell activation, was evaluated in a randomized, double-blind, placebo-controlled, phase IIb study (NCT01843374) in patients with unresectable malignant mesothelioma. The study demonstrated no clinically meaningful differences in overall survival (OS). The objective of this analysis was to evaluate the relationship of exposure with OS. A population pharmacokinetic (PK) model adequately described the PK data. Three factors (sex, C-reactive protein, and baseline tumor size) were identified as statistically significant PK predictors (P < 0.05 on clearance). A positive association between exposure and OS was observed. However, an association between key baseline factors with OS (regardless of treatment) and imbalances in prognostic factors favoring patients with higher exposure (upper vs. lower PK quartile) was seen. Taken together, these results suggest that the exposure OS relationship observed for tremelimumab in mesothelioma is likely spurious rather than a true association of exposure with efficacy.

Figure 1

Left panel: Kaplan–Meier analysis of overall survival (OS) by treatment group (intention‐to‐treat population). Right panel: Kaplan–Meier analysis of OS by quartiles of exposure at area under the exposure time‐course curve at steady‐state (AUC _ss) for the tremelimumab‐treated group with overlaid placebo group OS profile.

Figure 2

Kaplan–Meier analyses of overall survival (OS) split by baseline patient factors in each treatment arm. Kaplan–Meier plots of the key factors indicating differentiation in OS are presented for reference. All other Kaplan–Meier plots showed little difference (data on file). CRP, C‐reactive protein; ECOG, Eastern Cooperative Oncology Group ; EORTC, European Organisation for Research and Treatment of Cancer.

Figure 3

Proportion of patients with each baseline risk factor indicating differentiation in overall survival in the overall population (all‐comers) and in each extreme exposure quartile of area under the exposure time‐course curve at steady‐state (AUC _ss) or clearance (CL; Q1 and Q4). Continuous covariates (serum albumin, C‐reactive protein (CRP), and tumor burden) were dichotomized into high and low levels based on their respective median cutoff. Tremelimumab predicted exposure at steady‐state (AUC _ss) was used for all comparison apart for SEX for which CL was used instead to prevent body weight confounding due to the tremelimumab weight‐based dosing scheme (AUC _ss = dose/CL). Q1, lowest quartile; Q4, highest quartile. ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer.

Figure 4

Deductive map of the putative relationships among overall survival (OS), pharmacokinetics (PK) of tremelimumab, and patients’ baseline characteristics in second‐line unresectable malignant mesothelioma. The key variables (OS and PK) for exposure–response (E‐R) analysis are coded in blue, whereas variables impacting OS and/or PK are coded in yellow. Single direction arrow (→) represents a putative causal path, based on either clinical judgment or observed correlation between risk factors and key variables. Correlations among risk factors were ignored for simplicity. Sex (SEX), tumor burden (TUMSIZE), and C‐reactive protein (CRP) appear as confounders of tremelimumab E‐R analysis, because these factors simultaneously affect both the dependent and independent variables (OS and PK, respectively), thus preventing the direct application of standard approaches to E‐R analysis. These relationships have variable strength, with the longer length of the line linkers of TUMSIZE and SEX with OS representing weaker link than the relationship of CRP with OS as well as the positioning of variables in the map; CRP relationship with PK and OS is further reinforced by placing it in the middle of the diagram, to reflect its relative larger effect on PK and OS compared with TUMSIZE and SEX. ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer.