Background: Traditionally, most monoclonal antibodies (mAbs) have been dosed based on body weight because of perceived contribution of body size in pharmacokinetic variability. The same approach was used in the initial pembrolizumab studies; however, following availability of PK data, the need for weight-based dosing for pembrolizumab was reassessed. Methods: A previously established population PK (popPK) model as well as exposure-response results from patients with advanced melanoma or non-small cell lung cancer (NSCLC) were used to evaluate the potential application of a fixed dosing regimen with the aim of maintaining pembrolizumab exposures within the range demonstrated to provide near maximal efficacy and acceptable safety. Individual PK exposures for the selected fixed dosing regimen from recently completed trials with head and neck cancer, NSCLC, microsatellite instability high (MSI-H) in colorectal cancer (CRC) and urothelial cancer were used to confirm acceptability. To determine whether fixed dosing would maintain exposures within the range of clinical experience, the individual AUC distributions with fixed dosing were compared with the range of exposures from the pembrolizumab doses that were evaluated in early studies (2 mg/kg Q3W, 10 mg/kg Q3W/Q2W). Results: Body-weight dependence of clearance was characterized by a power relationship with an exponent of 0.578, a value consistent with fixed-and weight-based dosing providing similar control of PK variability. A fixed dose of 200 mg Q3W was investigated in trials based on predicted exposures maintained within the established exposure range in all patients. Mean (% CV, n) AUC ss, 6-weeks was 1.87 (37%, 830), 1.38 (38%, 760) and 7.63 (35%, 1405) mg*day/mL in patients receiving 200 mg, 2 mg/kg and 10 mg/kg Q3W pembrolizumab. High-weight patients had the lowest exposures with 200 mg Q3W; however, exposures in this group (>90 kg) were within the range of prior clinical experience at 2 mg/kg Q3W associated with near maximal efficacy. Conclusions: Doses of 200 mg and 2 mg/kg provide similar exposure distributions with no advantage to either dosing approach with respect to controlling PK variability. These findings suggest that weight-based and fixed-dose regimens are appropriate for pembrolizumab.

Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL. Overall results indicate that CL decreases over the treatment period of a typical patient in a pattern well described by a sigmoidal function of time with three parameters: the maximum proportion change in CL from baseline (approximately I or exactly e - 1), the time to reach I/2 (TI), and a Hill coefficient. Best overall response per response evaluation criteria in solid tumor category was found to be associated with the magnitude of I.

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.

PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.

Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose‐escalation design revealed several critical uncertainties, a model‐based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow‐up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low‐dose range by 200‐fold. Modeling of the resulting data demonstrated that pembrolizumab PKs are nonlinear at <0.3 mg/kg every 3 weeks, but linear in the clinical dose range. Saturation of ex vivo target engagement in blood began at ≥1 mg/kg every 3 weeks, and a steady‐state dose of 2 mg/kg every 3 weeks was needed to reach 95% target engagement, supporting examination of 2 mg/kg every 3 weeks in ongoing trials in melanoma and other advanced cancers.