Pembrolizumab exposure–response assessments challenged by association of cancer cachexia and catabolic clearance

Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: 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 ₀ ), 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 ₀ subgroups. Results: 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 ¼ 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR ¼ 0.98; 95% CI, 0.95–1.01); however, a strong CL ₀ –OS association was identified for both cancer types (unadjusted melanoma HR ¼ 2.56; 95% CI, 1.72–3.80 and NSCLC HR ¼ 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL ₀ paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL ₀ –OS association (multivariate-adjusted CL ₀ HR ¼ 1.64; 95% CI, 1.06–2.52 for melanoma and HR ¼ 1.88; 95% CI, 1.22–2.89 for NSCLC). Conclusions: 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 ₀ 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.