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 (Cmin,ss) ± standard deviation was 114 ± 51.8 μg/mL. The target pertuzumab Cmin,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 (Cmin) or Cycle 5 pertuzumab (Cmin,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.

• Authors: Whitney P Kirschbrown, Bei Wang, Ihsan Nijem, Atsushi Ohtsu, Paulo M Hoff, Manish A Shah, Lin Shen, Yoon-Koo Kang, Maria Alsina, Sandhya Girish, Amit Garg
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 84 Issue 3 Pg. 539-550 (09 2019) ISSN: 1432-0843 [Electronic] Germany
• PMID: 31183514 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• ERBB2 protein, human
• Receptor, ErbB-2
• pertuzumab
• Trastuzumab

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Double-Blind Method
• Esophageal Neoplasms (drug therapy, metabolism, pathology)
• Esophagogastric Junction (drug effects, metabolism, pathology)
• Female
• Follow-Up Studies
• Humans
• Male
• Middle Aged
• Prognosis
• Receptor, ErbB-2 (metabolism)
• Stomach Neoplasms (drug therapy, metabolism, pathology)
• Survival Rate
• Tissue Distribution
• Trastuzumab (administration & dosage)
• Young Adult