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

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posted on 2023-03-31, 20:40 authored by David C. Turner, Anna G. Kondic, Keaven M. Anderson, Andrew G. Robinson, Edward B. Garon, Jonathan Wesley Riess, Lokesh Jain, Kapil Mayawala, Jiannan Kang, Scot W. Ebbinghaus, Vikram Sinha, Dinesh P. de Alwis, Julie A. Stone

Fig S1. Kaplan-Meier plots of overall survival, stratified by pembrolizumab dose, demonstrate similarity of efficacy across a 5-fold dose range (2 to 10 mg/kg Q3W) in A) advanced ipilimumab-refractory melanoma, KEYNOTE-002 (Cox HR 0.98; 95% CI 0.94-1.02) and B) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010 (Cox HR 0.98; 95%CI 0.95-1.01). Subjects with at least one available PK measurement were included. Fig S2. Overall pooled exposure-response patterns demonstrate trends incongruent with similarity in dose-response patterns across 2 to 10 mg/kg in A) advanced ipilimumab-refractory melanoma, KEYNOTE-002 and B) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010. Fig S3. Similarity in OS between respective within-dose exposure quartiles at 2 and 10 mg/kg shows E-R patterns from pooled data (Fig S2 above) to be misleading in A-B) advanced ipilimumab-refractory melanoma, KEYNOTE-002 and C-D) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010. Fig S4. Kaplan-Meier plots of OS by all CL0 quartiles in KEYNOTE-002 (melanoma; left) and KEYNOTE-010 (previously-treated NSCLC; right) using the complete case datasets. Fig S5. Kaplan-Meier plots of OS by baseline clearance (CL0) quartiles in advanced, previously-untreated NSCLC with PD-L1 expression at least 50 percent. Pembrolizumab administered at 200 mg Q3W (KEYNOTE-024; n=152). Subjects with at least one available PK measurement were included. Fig S6. Forest plot of Docetaxel-treated NSCLC Cox proportional hazards model-estimated overall survival hazard ratios (n=249). Complete case dataset was used. Supplementary Table S1. Source Profile of PK - Overall Survival Analysis Datasets (KEYNOTE-002 and -010) Used in Multivariate Cox Models. Supplementary Table S2. Demographics and Baseline Characteristics for Subjects with {greater than or equal to} 1 Pembrolizumab PK Measurement (KEYNOTE-010/-024 and -002). Supplementary Table S3. Comparison of Univariate HR Results using Baseline Clearance from Time-dependent PK Model Versus a Steady-state Clearance from a Static PK Model Shows the Choice of Exposure Interval is Not Expected to Impact Rank Order of Exposure Estimates and that a Modest, Time-dependent Change in Pembrolizumab Clearance Does Not Meaningfully Alter Interpretations Described in this Study. Supplementary Table S4. Protocol-specified Pharmacokinetic Sampling Strategy.

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ARTICLE ABSTRACT

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 (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 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 CL0–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 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 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 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 mAbs.See related commentary by Coss et al., p. 5787

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