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

Paul Baverel, Lorin Roskos, Manasa Tatipalli, Nancy Lee, Paul Stockman, Maria Taboada, Paolo Vicini, Kevin Horgan, Rajesh Narwal, Paul Baverel, Lorin Roskos, Manasa Tatipalli, Nancy Lee, Paul Stockman, Maria Taboada, Paolo Vicini, Kevin Horgan, Rajesh Narwal

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.

Conflict of interest statement

P.B., L.R., N.L., Paolo Vicini and R.N. are employees of MedImmune, a wholly owned subsidiary of AstraZeneca. P.S. and M. Taboada are employees of AstraZeneca. M. Tatipalli and P.V. are former employees of MedImmune, and K.H. is a former employee of AstraZeneca.

© 2019 MedImmnue. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
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
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
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
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.

References

    1. Tarhini, A.A. & Kirkwood, J.M. Tremelimumab (CP‐675,206): a fully human anticytotoxic T lymphocyte‐associated antigen 4 monoclonal antibody for treatment of patients with advanced cancers. Expert Opin. Biol. Ther. 8, 1583–1593 (2008).
    1. Ribas, A. et al Antitumor activity in melanoma and anti‐self responses in a phase I trial with the anti‐cytotoxic T lymphocyte‐associated antigen 4 monoclonal antibody CP‐675,206. J. Clin. Oncol. 23, 8968–8977 (2005).
    1. Kirkwood, J.M. et al Phase II trial of tremelimumab (CP‐675,206) in patients with advanced refractory or relapsed melanoma. Clin. Cancer Res. 16, 1042–1048 (2010).
    1. Ribas, A. et al Phase III randomized clinical trial comparing tremelimumab with standard‐of‐care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31, 616–622 (2013).
    1. Calabrò, L. et al Tremelimumab for patients with chemotherapy‐resistant advanced malignant mesothelioma: an open‐label, single‐arm, phase 2 trial. Lancet Oncol. 14, 1104–1111 (2013).
    1. Calabrò, L. et al Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy‐resistant malignant mesothelioma: an open‐label, single‐arm, phase 2 study. Lancet Respir. Med. 3, 301–309 (2015).
    1. Edwards, J.G. , Abrams, K.R. , Leverment, J.N. , Spyt, T.J. , Waller, D.A. & O'Byrne, K.J. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax 55, 731–735 (2000).
    1. Vogelzang, N.J. et al Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 21, 2636–2644 (2003).
    1. Ceresoli, G.L. et al Phase II study of pemetrexed and carboplatin plus bevacizumab as first‐line therapy in malignant pleural mesothelioma. Br. J. Cancer 109, 552–558 (2013).
    1. Wang, E. , Kang, D. , Bae, K.‐S. , Marshall, M.A. , Pavlov, D. & Parivar, K. Population pharmacokinetic and pharmacodynamic analysis of tremelimumab in patients with metastatic melanoma. J. Clin. Pharmacol. 54, 1108–1116 (2014).
    1. Narwal, R. et al Tremelimumab, a fully human anti‐CTLA‐4 monoclonal antibody, optimal dosing regimen for patients with unresectable malignant mesothelioma (MM). ASCO. (2015) Abstract 3042.
    1. Kindler, H.L. , Scherpereel, A. , Calabrò, L. , Aerts, J. , Cedres Perez, S. & Bearz, A. Tremelimumab as second‐ or third‐line treatment of unresectable malignant mesothelioma (MM): results from the global, double‐blind, placebo‐controlled DETERMINE study. ASCO. (2016) Abstract 8502.
    1. Maio, M. et al Tremelimumab as second‐line or third‐line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double‐blind, placebo‐controlled phase 2b trial. Lancet Oncol. 18, 1261–1273 (2017).
    1. Dirks, N.L. & Meibohm, B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 49, 633–659 (2010).
    1. Calabro, L et al Pharmacokinetics of tremelimumab, a fully human anti‐CTLA‐4 monoclonal antibody, in subjects with unresectable malignant mesothelioma. AACR. 2014, Abstract 228.
    1. Beal, S.L. , Sheiner, L.B. , Boeckmann, A.J. & Bauer, R.J. NONMEM Users Guides (Icon Development Solutions, Ellicott City, MD, 1989).
    1. R Development Core Team . R: A Language and Environment for Statistical Computing, Vol. 3.3.1. (R Foundation for Statistical Computing, Vienna, Austria, 2013).
    1. Shavelle, R. , Vavra‐Musser, K. , Lee, J. & Brooks, J. Life expectancy in pleural and peritoneal mesothelioma. Lung Cancer Int. 2017;(2):1–8.
    1. Skelly, A. , Dettori, J. & Brodt, E. Assessing bias: the importance of considering confounding. Evid. Based Spine Care J. 3, 9–12 (2012).
    1. Wang, Y. , Booth, B. , Rahman, A. , Kim, G. , Huang, S.M. & Zineh, I. Toward greater insights on pharmacokinetics and exposure–response relationships for therapeutic biologics in oncology drug development. Clin. Pharmacol. Ther. 101, 582–584 (2017).
    1. Ryman, J.T. & Meibohm, B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacometrics Syst. Pharmacol. 6, 576–588 (2017).
    1. Baverel, P. et al Population pharmacokinetics of durvalumab in cancer patients and association with longitudinal biomarkers of disease status. Clin. Pharmacol. Ther. 103, 631–642 (2018).
    1. Liu, C. et al Association of time‐varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin. Pharmacol. Ther. 101, 657–666 (2017).
    1. Bang, Y.J. et al Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2‐positive advanced gastric or gastro‐oesophageal junction cancer (ToGA): a phase 3, open‐label, randomised controlled trial. Lancet 376, 687–697 (2010).
    1. Verma, S. et al Trastuzumab emtansine for HER2‐positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2016).
    1. Yang, J. et al The combination of exposure‐response and case‐control analyses in regulatory decision making. J. Clin. Pharmacol. 53, 160–166 (2013).
    1. Wang, J. et al Exposure‐response relationship of T‐DM1: insight into dose optimization for patients with HER2‐positive metastatic breast cancer. Clin. Pharmacol. Ther. 95, 558–564 (2014).
    1. Shah, M.A. et al HELOISE: phase IIIb randomized multicenter study comparing standard‐of‐care and higher‐dose trastuzumab regimens combined with chemotherapy as first‐line therapy in patients with human epidermal growth factor receptor 2‐positive metastatic gastric or gastroesophageal junction adenocarcinoma. J. Clin. Oncol. 35, 2558–2567 (2017).
    1. Krop, I.E. et al Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2‐positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open‐label phase 3 trial. Lancet Oncol. 18, 743–754 (2017).

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