Pembrolizumab: Role of Modeling and Simulation in Bringing a Novel Immunotherapy to Patients With Melanoma.

Recently, immunotherapy has yielded promising results in several cancer types. Contrary to the established classical chemotherapy-dosing paradigm, a maximum tolerated dose approach does not always produce better clinical outcomes for novel targeted therapies, as their efficacy is frequently robust at pharmacologically active doses below the maximum tolerated dose. Integrated safety and efficacy assessments are needed to inform clinical dose and trial design, and to support an early identification of potentially safe and efficacious combination treatments.

Population Pharmacokinetic/Pharmacodynamic Modeling of Tumor Size Dynamics in Pembrolizumab-Treated Advanced Melanoma.

Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response.

Model-Based Characterization of the Pharmacokinetics of Pembrolizumab: A Humanized Anti-PD-1 Monoclonal Antibody in Advanced Solid Tumors.

Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies. Identified effects of sex, baseline Eastern Cooperative Oncology Group performance status, measures of renal and hepatic function, tumor type and burden, and prior ipilimumab treatment on pembrolizumab exposure were modest and lacked clinical significance. Furthermore, simulations demonstrated the model has robust power to detect clinically relevant covariate effects on clearance. These results support the use of the approved pembrolizumab dose of 2 mg/kg every 3 weeks without dose adjustment in a variety of patient subpopulations.

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer.

BACKGROUND: In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. PATIENTS AND METHODS: Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology. RESULTS: Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses. CONCLUSIONS: No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC. CLINICALTRIALSGOV REGISTRY: NCT01295827.