Use of Real‐World Evidence in a Virtual Bridging Analysis for a Human Epidermal Growth Factor Receptor 2–Targeted Antibody–Drug Conjugate in Gastric Cancer

Abstract

This study bridged pharmacokinetic, efficacy, and safety clinical trial data from Japan to a Western population using real‐world evidence (RWE) to investigate the antibody–drug conjugate trastuzumab deruxtecan (T‐DXd) in the treatment of human epidermal growth factor receptor 2 (HER2)‐positive advanced gastric cancer. Using population pharmacokinetic and exposure–response (efficacy/safety) models, exposure–efficacy data from 117 patients and exposure–safety data from 158 patients in Japan who received T‐DXd 6.4 mg/kg as second‐line or later treatment were bridged to RWE including covariate information from 25 Western patients with HER2‐positive gastric cancer who received second‐line or later T‐DXd treatment. Pharmacokinetic simulations indicated that intact T‐DXd and released drug (DXd) steady‐state exposures were comparable between Western patients and patients from Japan; the Western/Japan ratio of exposure medians ranged from 0.82 (T‐DXd steady‐state minimum concentration) to 1.18 (DXd steady‐state maximum concentration). Exposure–efficacy simulations estimated a confirmed objective response rate of 28.6% (90% confidence interval, 20.8‐38.4) in real‐world Western patients versus 40.1% (90% confidence interval, 33.5‐47.0) in patients from Japan, possibly because of checkpoint inhibitor use in 4% versus 30% of patients, respectively. Western patients had a higher estimated rate of serious adverse events than patients from Japan (42.2% vs 34.6%); however, the rate of interstitial lung disease was lower (less than 10%) in Western patients. Overall, T‐DXd was predicted to have meaningful clinical activity and a manageable safety profile in Western patients with HER2‐positive gastric cancer. Using RWE, bridging analysis supported US approval of T‐DXd 6.4 mg/kg in advanced gastric cancer before a clinical trial was completed in Western patients.