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. Electronic supplementary material The online version of this article (10.1007/s00280-019-03871-w) contains supplementary material, which is available to authorized users.

Pertuzumab Plus High-Dose Trastuzumab in Patients With Progressive Brain Metastases and HER2-Positive Metastatic Breast Cancer: Primary Analysis of a Phase II Study

“…As expected, observed C max,ss and C min,ss in PATRICIA were higher than modelpredicted exposures in APHINITY (225.5 6 80 and 67.7 6 32 mg/mL, respectively). 22 One patient without a postbaseline assessment was omitted from this analysis because of death within 30 days of last treatment, but was included in the efficacy-evaluable population. One patient was with an unconfirmed PR and was considered to have a confirmed best response of SD in the study.…”

“…As expected, observed C max,ss and C min,ss in PATRICIA were higher than modelpredicted exposures in APHINITY (225.5 6 80 and 67.7 6 32 mg/mL, respectively). 22…”

“…As expected, observed C max,ss and C min,ss in PATRICIA were higher than model-predicted exposures in APHINITY (225.5 ± 80 and 67.7 ± 32 μg/mL, respectively). 22 Observed C max,ss and C min,ss values for pertuzumab in PATRICIA (226 ± 56.2 and 102 ± 41.6 μg/mL, respectively) were also comparable to model-predicted C max,ss and C min,ss values (184.9 [range, 124-260] and 52.1 [range, 16-97] μg/mL, respectively) derived from a population pharmacokinetic model informed by patients with solid tumors, including HER2-positive MBC. 23…”

Genomics and Targeted Therapies in Gastroesophageal Adenocarcinoma

“…The addition of pertuzumab, a monoclonal antibody that blocks ERBB2 heterodimerization with other ERBB family receptors, to trastuzumab plus chemotherapy in the first-line setting did not significantly improve OS for ERBB2+ metastatic gastric or GEJ cancer in the JACOB trial, although trended toward a positive result (62). Importantly, major pharmacokinetic (PK) differences in pertuzumab between ERBB2+ gastric and breast cancer were identified and adequately addressed through a phase 2a dose-finding study (JOSHUA) prior to JACOB and confirmed by PK assessments of JACOB participants (63,64). T-DM1, an antibody-drug conjugate of trastuzumab and a microtubule inhibitor, was not superior to taxane in the second-line setting in the GATSBY trial (65).…”

The role of teratogens in neural crest development

“…Therefore, this evidence shows that any treatment with Trastuzumab of pregnant women should be restricted because of its direct action as a NC teratogen. Similar precautions should be taken for other trastuzumab‐related chemotherapeutic agents such as pertuzumab (Kirschbrown et al, ) and other biosimilars (i.e., SB3, PF‐05280014, CT‐P6, ABP980, BCD‐022, MYL‐1410; (Thill, ).…”