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

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.