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 carcinoma (NSCLC). Experimental Design: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200mg or 2-10 mg/kg Q3W. Kaplan-Meier (K-M) plots of OS, stratified by dose, exposure, and baseline clearance 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</SPAN>₀<SPAN style="font-family: Arial, sans-serif;"> subgroups. </SPAN>Results: <SPAN style="font-family: 'Arial','sans-serif';">1453 subjects were included, 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose-independent from 2-10 mg/kg for pembrolizumab-treated melanoma <SPAN style="background: white;">(</SPAN>HR=0.98; 95%CI, 0.94-1.02<SPAN style="background: white;">)</SPAN></SPAN> <SPAN style="font-family: 'Arial','sans-serif'; background: white;">and NSCLC (</SPAN><SPAN style="font-family: 'Arial','sans-serif';">HR=0.98; 95%CI, 0.95-1.01<SPAN style="background: white;">)</SPAN>; however, a strong CL₀-OS association was identified for both cancer types</SPAN> <SPAN style="font-family: 'Arial','sans-serif';">(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 CL₀ paralleled disease severity markers associated with end-stage cancer-anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL₀-OS association (multivariate-adjusted CL₀ HR=1.64; 95%CI, 1.06-2.52 for melanoma; HR=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 2-10 mg/kg. An association of pembrolizumab CL₀ 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 monoclonal antibodies.

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