Pharmacokinetic and exposure-response analysis of pertuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer

Abstract

Purpose: To characterize the pharmacokinetics (PK) of pertuzumab and trastuzumab in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer in the randomized, double-blind, phase III JACOB study (NCT01774786), and to evaluate the appropriateness of the pertuzumab regimen in these patients.

Methods: Patients received 840 mg intravenous pertuzumab or placebo plus trastuzumab q3w and chemotherapy. Pertuzumab and trastuzumab were administered until disease progression or unacceptable toxicity. Chemotherapy was administered for up to six cycles or disease progression or unacceptable toxicity. Serum concentrations of pertuzumab and trastuzumab were measured. Pertuzumab PK was characterized across treatment cycles. The impact of anti-drug antibodies (ADAs) on pertuzumab PK and the impact of pertuzumab on trastuzumab PK were assessed. An exploratory exposure-efficacy analysis was also conducted.

Results: In total, 374 patients in the pertuzumab arm had evaluable PK data. The mean observed pertuzumab steady-state serum trough (minimum) concentration (C_min,ss) ± standard deviation was 114 ± 51.8 μg/mL. The target pertuzumab C_min,ss of ≥ 20 μg/mL was reached in 99.3% of patients at Cycle 5 (steady state) and beyond. Greater than 90% of patients were above the PK target right after the first pertuzumab dose. There was no apparent impact of ADAs on pertuzumab PK nor of pertuzumab on trastuzumab PK. There were no differences in overall survival across Cycle 1 pertuzumab (C_min) or Cycle 5 pertuzumab (C_min,ss) exposure quartiles.

Conclusions: Pertuzumab exposure in JACOB was consistent with prior studies in advanced gastric cancer and breast cancer. The 840 mg q3w dose allowed the majority of patients in JACOB to achieve target pertuzumab concentrations and appears to be an appropriate dose selection.

Keywords: HER2-positive; Metastatic gastric cancer; Metastatic gastroesophageal junction; Pertuzumab; Pharmacokinetics; Trastuzumab.

Fig. 1

Cross-study comparison of PK for a pertuzumab [7, 9, 11] and b trastuzumab [7, 11, 14]. C_max,ss steady-state peak (maximum) serum concentration, C_min,ss steady-state serum trough (minimum) concentration, PK pharmacokinetic. Cycle numbers for C_min,ss and C_max,ss vary between studies. C_min,ss: JACOB, Cycle 3 pre-dose; JOSHUA, Cycle 4 pre-dose; CLEOPATRA, Cycle 9 pre-dose; ToGA, Cycle 9 pre-dose. C_max,ss: JACOB, Cycle 4 post-dose; JOSHUA, Cycle 4 post-dose; CLEOPATRA, Cycle 9 post-dose; ToGA, Cycle 5 post-dose. Red bars = C_min; blue bars = C_max; lower and upper ends of each box plot = 25th and 75th percentile exposure value; horizontal white line = median per group; points = individual PK data. Brackets extending from the ends of the box are drawn to the nearest value, not beyond 1.5 times the interquartile range

Fig. 2

Drug–drug interaction assessment of the potential effects of a chemotherapy on pertuzumab exposure and b pertuzumab on trastuzumab exposure. C Cycle, Chemo chemotherapy, C_max peak (maximum) serum concentration, C_min serum trough (minimum) concentration, PK pharmacokinetic. Red bars = post-dose; blue bars = pre-dose; lower and upper ends of each box plot = 25th and 75th percentile exposure value; horizontal white line = median per group; points = individual PK data. Brackets extending from the ends of the box are drawn to the nearest value, not beyond 1.5-times the interquartile range

Fig. 3

Kaplan–Meier plot of overall survival by pertuzumab exposure quartiles at a Cycle 1 (C_min) and b Cycle 5 (C_min,ss)

Fig. 4

Pertuzumab steady-state exposure vs. HER2 ECD concentrations. C_min serum trough (minimum) concentration, ECD extracellular domain, HER2 human epidermal growth factor receptor 2