Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance

• Published in: Clinical cancer research Vol. 24; no. 23; pp. 5841 - 5849
• Main Authors: Turner, David C., Kondic, Anna G., Anderson, Keaven M., Robinson, Andrew G., Garon, Edward B., Riess, Jonathan Wesley, Jain, Lokesh, Mayawala, Kapil, Kang, Jiannan, Ebbinghaus, Scot W., Sinha, Vikram, de Alwis, Dinesh P., Stone, Julie A.
• Format: Journal Article
• Language: English
• Published: United States 01.12.2018
• Subjects: Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Agents, Immunological - adverse effects; Antineoplastic Agents, Immunological - therapeutic use; Cachexia - etiology; Cachexia - metabolism; Cachexia - mortality; Carcinoma, Non-Small-Cell Lung - complications; Carcinoma, Non-Small-Cell Lung - drug therapy; Case-Control Studies; Humans; Kaplan-Meier Estimate; Melanoma - complications; Melanoma - drug therapy; Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - mortality; Proportional Hazards Models; Randomized Controlled Trials as Topic
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0415

To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non-small cell lung cancer (NSCLC). PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan-Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL ), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL subgroups. A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94-1.02] and NSCLC (HR = 0.98; 95% CI, 0.95-1.01); however, a strong CL -OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72-3.80 and NSCLC HR = 2.64; 95% CI, 1.94-3.57). Decreased OS in subjects with higher pembrolizumab CL paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL -OS association (multivariate-adjusted CL HR = 1.64; 95% CI, 1.06-2.52 for melanoma and HR = 1.88; 95% CI, 1.22-2.89 for NSCLC). These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure-response confounding may be a broader phenomenon generalizable to antineoplastic mAbs. .