Clinical Trial Simulations From a Model‐Based Meta‐Analysis of Studies in Patients With Advanced Hepatocellular Carcinoma Receiving Antiangiogenic Therapy

Abstract

A mixed effect model describing median overall survival (mOS) in patients with advanced hepatocellular carcinoma (aHCC) treated with antiangiogenic therapy (AAT) was developed from literature data. Data were extracted from 59 studies, representing 4,813 patients. The final model included estimates of mOS after AAT (8.5 months) or placebo (7.1 months) administration. The mOS increased 21% when the AAT was sorafenib (SOR) or 42% when locoregional therapy was coadministered. The mOS decreased when patients received prior systemic therapy (↓7%) or concomitant chemotherapy (↓4%) or the percentage of patients with hepatitis B increased (↓∼0.4%/%). Clinical trial simulations of a phase II comparative trial predicted an mOS ratio (placebo:AAT) of 0.687 or 0.831, with a 65% or 22% probability of demonstrating superiority, for SOR or other AATs, respectively. Additionally, the 95% confidence interval (CI) of the simulated median mOS ratio for non‐SOR AATs was similar to the 95% CI of the hazard ratio (HR) observed in the trial.

Model‐Based Meta‐Analysis for Multiple Myeloma: A Quantitative Drug‐Independent Framework for Efficient Decisions in Oncology Drug Development

“…MBMA is acknowledged as a valuable tool in the drug development process that is widely used for integrating data to enable informed and efficient development decisions, for example in dose–response analyses . The approach has been successfully used in other cancer types and in other therapeutic areas to assist in the development of new agents and, in combination with network meta‐analysis, to model the findings of head‐to‐head trials . For example, an MBMA was recently reported on median OS among patients with advanced hepatocellular carcinoma receiving antiangiogenic therapy that identified predictors of median OS and enabled clinical trial simulations of phase II comparative studies .…”

“…[33][34][35] For example, an MBMA was recently reported on median OS among patients with advanced hepatocellular carcinoma receiving antiangiogenic therapy that identified predictors of median OS and enabled clinical trial simulations of phase II comparative studies. 35 Similarly, in rheumatoid arthritis, this approach was used to assess the relationship between short-term and long-term treatment effects measured by the American College of Rheumatology (ACR) 50 responses and to assess the feasibility of predicting 6-month efficacy from short-term data. 34 In this study, the findings quantitatively supported the empirical clinical development paradigm of using 3-month efficacy data to predict long-term efficacy and to inform the probability of clinical success based on an early efficacy readout.…”

Micro RNA‐4651 Serves as a Potential Biomarker for Prognosis When Selecting Hepatocellular Carcinoma Patients for Postoperative Adjuvant Transarterial Chemoembolization Therapy

“…The incidence and mortality of this tumor is increasing because of high incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and/or high exposure of aflatoxin B1 . Although advances in curative treatments, such as surgical resection and liver transplantation, significantly improve life expectancy for these patients with early‐stage hepatocellular carcinoma, this type of therapies are not beneficial for most tumor cases because they are diagnosed at advanced stages . In the past decades, transarterial chemoembolization (TACE) has become an increasingly important palliative treatment for hepatocellular carcinoma.…”

Model‐Based Meta‐Analysis: Optimizing Research, Development, and Utilization of Therapeutics Using the Totality of Evidence

“…For example, to improve the efficiency of the drug development program, MBMA was utilized in real time for axitinib, an antiangiogenic agent for the new indication advanced hepatocellular carcinoma (aHCC) . MBMA helped gain insight on the overall benefit of all antiangiogenic therapies (AATs) in aHCC to inform development decisions for axitinib as a therapeutic option for aHCC.…”

“…For example, to improve the efficiency of the drug development program, MBMA was utilized in real time for axitinib, an antiangiogenic agent for the new indication advanced hepatocellular carcinoma (aHCC). 25 MBMA helped gain insight on the overall benefit of all antiangiogenic therapies (AATs) in aHCC to inform development decisions for axitinib as a therapeutic option for aHCC. Specifically, MBMA quantified the determinants of median overall survival (mOS) observed across 59 clinical trials with a range of treatments (e.g., placebo with best supportive care, locoregional therapy, chemotherapy, sorafenib, nonsorafenib AATs) in 4,813 patients with aHCC.…”