Population PK/PD Analysis of Necitumumab: Dose justification for Squamous Cell Lung Cancer (SqCLC) Patients in Japan

Abstract

Abstract Background Necitumumab (NEC) in combination with gemcitabine+cisplatin (GC) demonstrated significant improvement in overall survival (OS) compared to GC in advanced SqCLC patients (pts) in Global Ph3 study JFCC. In Study JFCM Ph2 part, NEC in combination with GC improved OS compared to GC in SqCLC pts in Japan. Population PK/PD analysis including Study JFCM was conducted to determine the adequacy of the dose in pts in Japan based on NEC PK, and relationship between exposure and efficacy and safety. Methods Two studies, one of which Study JFCM, were added into the analysis previously performed with five Ph 1, 2, and 3 studies. The effect of Japan/non-Japan origin on NEC PK was assessed. Simulations were performed to compare predicted NEC serum concentrations after flat 800 mg and body weight based dosing. The relationship between exposure and OS in Studies JFCC and JFCM Ph2 part was explored. The relationship between exposure and safety measurements (hypomagnesemia, rash and thromboembolic events) in Studies JFCC and JFCM Ph2 part was explored. Results Population PK analysis included blood samples collected from 967 pts (including 114 pts in Japan) treated with NEC. PK parameters were similar between Japanese and non-Japanese pts. NEC PK is dependent on body weight; however, simulations indicated weight-based dosing would not significantly decrease PK variability. Exposure-response analysis included 1195 pts, including 181 pts in Japan. Exposure-efficacy analysis suggested that pts with higher NEC concentration had longer OS, however, majority of pts in both studies had steady state exposure greater than EC80. No correlation was observed between NEC serum exposure and severity of hypomagnesemia or rash. No correlation was observed between NEC serum exposure and risk of treatment emergent thromboembolic events. Conclusion Population PK/PD analysis supports the administration of 800 mg NEC on Day 1 and 8 of a 21-day cycle as an appropriate dose in SqCLC pts in Japan.