Abstract
PurposeTo 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.MethodsPatients 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.ResultsIn 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.ConclusionsPertuzumab 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.
Highlights
This study showed that the combination of pertuzumab, trastuzumab, and chemotherapy was well tolerated in these patients, with an adverse event (AE) profile similar to that seen in the ToGA trial [8]
Pertuzumab Cmin,ss from JACOB was comparable to the previous studies in metastatic breast cancer (MBC) (CLEOPATRA; 840 mg loading dose followed by 420 mg maintenance dose q3w) [9] and advanced GC (AGC) (JOSHUA; 840 mg q3w arm) [7] (Fig. 1a)
The higher pertuzumab dose in the JACOB study was reflected in higher Cmax concentrations at steady state, compared with CLEOPATRA and consistent with Cmax in JOSHUA
Summary
Hoffmann-La Roche Ltd, Basel, Switzerland) is a monoclonal antibody (mAb) that inhibits human epidermal growth factor receptor 2 (HER2). Extended author information available on the last page of the article dimerization with other HER family receptors, thereby inhibiting mitogen-activated protein kinase and phosphoinositide 3-kinase signaling pathways and promoting cellgrowth arrest and apoptosis [1, 2]. Hoffmann-La Roche Ltd) may provide a more comprehensive HER2 pathway blockade (vs trastuzumab alone) due to the complementary modes of action of the two drugs [3]. The addition of pertuzumab to trastuzumab has been shown to improve survival outcomes in patients with HER2-positive early breast cancer (EBC) and metastatic breast cancer (MBC) [4,5,6]. There are differences in tumor biology between HER2-positive breast cancer
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