Population Modeling of Tumor Kinetics and Overall Survival to Identify Prognostic and Predictive Biomarkers of Efficacy for Durvalumab in Patients With Urothelial Carcinoma

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Immune checkpoint inhibitors such as antibodies targeting PD‐1 and PD‐L1 have evolved as new treatment options for cancer patients and have demonstrated efficacy in reducing tumor size and prolonging survival in multiple cancer indications.1 An important clinical question in the development of immuno‐oncology (IO) therapies is how to identify patients who are most likely to benefit from these therapies. Pharmacometric modeling provides a quantitative tool to address this question through mathematical modeling of clinical efficacy data with multivariate covariate testing. Although numerous reports of tumor kinetic models have been published for traditional chemotherapy or non‐IO therapies in cancer patients,5 few studies have modeled tumor dynamics after IO therapies.8 Further, no quantitative model has been published to date to link tumor kinetics to overall survival (OS) for IO therapeutics as a tool to identify and characterize prognostic and predictive biomarkers of efficacy outcomes.
Durvalumab is a human immunoglobulin G1 antibody that specifically binds human PD‐L1, blocking its interaction with PD‐1 or CD80 receptors expressed on activated T cells. Durvalumab (10 mg/kg q2w) has recently been approved as a treatment for patients with locally advanced or metastatic urothelial carcinoma (UC) that has progressed after platinum‐containing chemotherapy. Study 1108 (NCT01693562) was a phase I/II, open‐label expansion study of durvalumab in patients with advanced urothelial bladder cancer, in which durvalumab treatment demonstrated favorable clinical activity in objective tumor response and OS.3 The objectives of this analysis were to model survival data and longitudinal changes in target lesion size, to characterize the relationship between tumor kinetics and survival, and to evaluate prognostic and predictive biomarkers for efficacy outcomes in these patients.
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