Pembrolizumab

Pembrolizumab is a humanised monoclonal antibody which binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptor is a negative regulator of T-cell activity that has been shown to be involved in the control of T-cell immune responses. Pembrolizumab potentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be expressed by tumours or other cells in the tumour microenvironment.

The anti-angiogenic effect of lenvatinib (multi-TKI) in combination with the immune-stimulatory effect of pembrolizumab (anti-PD-1) results in a tumour microenvironment with greater T-cell activation to help overcome primary and acquired resistance to immunotherapy and may improve tumour responses compared to either treatment alone. In preclinical murine models, PD-1 plus TKI inhibitors have demonstrated enhanced anti-tumour activity compared to either agent alone.

The pharmacokinetics of pembrolizumab was studied in 2 993 patients with metastatic or unresectable melanoma, NSCLC, or carcinoma who received doses in the range: of 1 to 10 mg/kg bw every 2 weeks, 2 to 10 mg/kg bw every 3 weeks, or 200 mg every 3 weeks.

Absorption

Pembrolizumab is administered via the intravenous route and therefore is immediately and completely bioavailable.

Distribution

Consistent with a limited extravascular distribution, the volume of distribution of pembrolizumab at steady-state is small (~6.0 L; CV: 20%). As expected for an antibody, pembrolizumab does not bind to plasma proteins in a specific manner.

Biotransformation

Pembrolizumab is catabolised through non-specific pathways; metabolism does not contribute to its clearance.

Elimination

Pembrolizumab CL is approximately 23% lower (geometric mean, 195 mL/day [CV%: 40%]) after achieving maximal change at steady-state compared with the first dose (252 mL/day [CV%: 37%]); this decrease in CL with time is not considered clinically meaningful. The geometric mean value (CV%) for the terminal half-life is 22 days (32%) at steady-state.

Linearity/non-linearity

Exposure to pembrolizumab as expressed by peak concentration (C_max) or area under the plasma concentration time curve (AUC) increased dose proportionally within the dose range for efficacy. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3 week regimen and the systemic accumulation was 2.1-fold. The median trough concentrations (C_min) at steady-state were approximately 22 mcg/mL at a dose of 2 mg/kg bw every 3 weeks and 29 mcg/mL at a dose of 200 mg every 3 weeks. The median area under the concentration time curve at steady-state over 3 weeks (AUC_0-3weeks) was 794 mcg•day/mL at a dose of 2 mg/kg bw every 3 weeks and 1 053 mcg•day/mL at a dose of 200 mg every 3 weeks.

Following administration of pembrolizumab 200 mg every 3 weeks in patients with cHL, the observed median C_min at steady-state was up to 40% higher than that in other tumour types treated with the same dosage; however, the range of troug h concentrations is similar. There are no notable differences in median C_max between cHL and other tumour types. Based on available safety data in cHL and other tumour types, these differences are not clinically meaningful.

Special populations

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The following factors had no clinically important effect on the clearance of pembrolizumab: age (range: 15-94 years), gender, race, mild or moderate renal impairment, mild or moderate hepatic impairment and tumour burden. The relationship between body weight and clearance supports the use of either fixed dose or body weight-based dosing to provide adequate and similar control of expos ure. Pembrolizumab exposure with weight-based dosing at 2 mg/kg bw every 3 weeks in paediatric patients (≥3 to 17 years) are comparable to those of adults at the same dose.

Renal impairment

The effect of renal impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate renal impairment and patients with normal renal function. Pembrolizumab has not been studied in patients with severe renal impairment.

Hepatic impairment

The effect of hepatic impairment on the clearance of pembrolizumab was evaluated by population pharmacokinetic analyses in patients with mild and moderate hepatic impairment (as defined using the US National Cancer Institute criteria of hepatic dysfunction) compared to patients with normal hepatic function. No clinically important differences in the clearance of pembrolizumab were found between patients with mild or moderate hepatic impairment and normal hepatic function. Pembrolizumab has not been studied in patients with severe hepatic impairment.

The safety of pembrolizumab was evaluated in a 1-month and a 6-month repeat-dose toxicity study in Cynomolgus monkeys administered intravenous doses of 6, 40 or 200 mg/kg bw once a week in the 1-month study and once every two weeks in the 6-month study, followed by a 4-month treatment-free period. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was ≥200 mg/kg bw, which produced exposure multiples of 19 and 94 times the exposure in humans at doses of 10 and 2 mg/kg bw, respectively. The exposure multiple between the NOAEL and a human dose of 200 mg was 74.

Animal reproduction studies have not been conducted with pembrolizumab. The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.

Animal fertility studies have not been conducted with pembrolizumab. In 1 month and 6 month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, many animals in these studies were not sexually mature.