Model‐Based Population Pharmacokinetic Analysis of Nivolumab in Chinese Patients With Previously Treated Advanced Solid Tumors, Including Non–Small Cell Lung Cancer

Abstract

Nivolumab is the first anti–programmed death‐1 agent approved in China for treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC). Here, we characterize the population pharmacokinetics (PPK) of nivolumab monotherapy in Chinese patients with previously treated advanced/recurrent solid tumors, including NSCLC and nasopharyngeal cancer (NPC), using data from 2 predominantly Chinese (CheckMate 077 and 078), and 5 global (MDX1106‐01, CA209‐003, and CheckMate 017, 057, and 063) studies. The PPK model was developed by reestimating parameters of a prior global population model with Chinese patient data. Model reestimates showed nivolumab pharmacokinetics (PK) to be linear and dose proportional. Race did not have a clinically meaningful effect on nivolumab clearance. Body weight, Asian race, sex, and performance status had significant effects on clearance. Baseline clearance was 9% lower in the Asian versus the global population but not considered clinically relevant. Change in time‐varying clearance and predicted nivolumab exposures with 3 mg/kg every 2 weeks (Q2W) were similar in Chinese, non‐Chinese Asian, and non‐Asian patients. In Chinese patients, the predicted nivolumab exposure with a 240‐mg Q2W regimen was ∼25% higher than with 3 mg/kg Q2W, but ∼62% lower than that of a previously evaluated, well‐tolerated regimen of 10 mg/kg Q2W (global population). Differences in nivolumab baseline clearance and exposures between patients with NPC and NSCLC were not clinically meaningful (<20%). Overall, PPK analysis demonstrated that nivolumab was not sensitive to race when evaluated in Chinese and non‐Asian patients and exhibited similar PK in NSCLC and NPC.

Clinical Benefit‐Risk Assessment of Nivolumab 240 mg Every 2 Weeks in Chinese Patients With Advanced and Metastatic Solid Tumors

“…10,11 Of note, 10 mg/kg every 2 weeks was not administered to Chinese patients in this study. However, our previous PPK analyses demonstrated that race (Chinese or Asian versus non-Asian) was not a clinically meaningful covariate for nivolumab exposures, 19 which is consistent with observations of other immuno-oncology drugs, 27 and there were also similar distributions of PK parameters across different races. 28 Even in studies in which flat dosing in an Asian population may be associated with higher exposure, there may not be a significant impact on safety.…”

“…19 In this model, Asian race and tumor type did not have a clinically meaningful impact on clearance together with other covariates, including baseline body weight, estimated glomerular filtration rate, Eastern Cooperative Oncology Group performance status, and sex. 19 Here, we report the totality of benefit-risk assessment of 240 mg every 2 weeks for Chinese patients, thus providing additional nivolumab treatment options to health care providers and patients. We compared exposures of nivolumab 240 mg and 3 mg/kg every 2 weeks in Chinese patients with advanced and metastatic solid tumors.…”

“…In addition, the overall benefit‐risk analysis demonstrated that exposures, safety, and efficacy of 240 mg relative to 3 mg/kg every 2 weeks were similar across body weights, exposure quartiles, and tumor types in global populations 6 . A PPK analysis developed for Chinese patients demonstrated similar linear and dose‐proportional PK of nivolumab with time‐dependent clearance in both Chinese and non‐Asian patients 19 . In this model, Asian race and tumor type did not have a clinically meaningful impact on clearance together with other covariates, including baseline body weight, estimated glomerular filtration rate, Eastern Cooperative Oncology Group performance status, and sex 19 …”

“…The Chinese National Medical Product Agency (NMPA) approved nivolumab 3 mg/kg every 2 weeks for patients with non‐small cell lung cancer (NSCLC) on June 15, 2018, based on CheckMate 077 and 078 18 . CheckMate 077 investigated nivolumab 3 mg/kg and 240 mg every 2 weeks in Chinese patients with previously treated advanced or recurrent solid tumors 19 . On September 29, 2019, the NMPA announced approval of nivolumab 240 mg every 2 weeks for squamous cell carcinoma of the head and neck 20 .…”

Ongoing Phase I Studies of Immune Checkpoint Inhibitors in China

“…Preliminary results of the first 15 patients were released at the 2017 Chinese Society of Clinical Oncology annual meeting . Based on the released data, the safety and tolerability profiles of nivolumab in Chinese patients were similar to those of white patients.…”