Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer

Abstract

Background: This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

Methods: Patients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (Ctrough) >20 μg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 Ctrough >20 μg/ml was above the prespecified non-inferiority margin of - 12.5%.

Results: For PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 Ctrough >20 μg/ml; the lower limit of the 95% confidence interval (- 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (- 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%.

Conclusions: PF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.

Trial registration: ClinicalTrials.gov NCT02187744.

Conflict of interest statement

Philip E. Lammers has participated on advisory boards with Pfizer Inc. Magdolna Dank has been a member of Biosimilars Oncology European Advisory Board with Pfizer Inc since 2013. Riccardo Masetti declares no conflicts of interest. Richat Abbas, Fiona Hilton, Jennifer Coppola and Ira Jacobs are full time employees of and declare stock holdings and/or stock options from Pfizer Inc.

Figures

Fig. 1

Overall study design and disposition of patients. a Study design and b patient disposition. aOn Day 1 Cycle 1, patients received a loading dose (8 mg/kg) of PF-05280014 or trastuzumab-EU infused over 90 min followed by docetaxel (75 mg/m2; 60-min intravenous infusion) and carboplatin (target AUC: 6; ≥ 15-min intravenous infusion). Subsequent infusions of PF-05280014 or trastuzumab-EU (6 mg/kg, over 30 to 90 min), docetaxel and carboplatin were administered every 3 weeks for a total of six treatment cycles. bBlood samples were collected predose (−2.5 h to −5 min prior to infusion) on Day 1 of Cycles 1, 2, 4, 5 and 6, and at 1-h post dose on Day 1 of Cycles 1 and 5 for determination of PF-05280014 or trastuzumab-EU serum concentrations. cThe intent-to-treat population consisted of all patients randomised to PF-05280014 or trastuzumab-EU. dThe safety population comprised all patients who received at least one dose of study drug. ePatients in the PF-05280014 group were excluded from the per protocol population for the following reasons: Cycle 5 trough sample taken outside protocol-specified window (n = 6, 46.2%), fewer than six cycles of trastuzumab (n = 5, 38.5%), no Cycle 5 trough pharmacokinetic sample (n = 2, 15.4%), and trastuzumab treatment delay > 1 week (n = 1, 7.7%). A patient may have met multiple criteria for exclusion and may have been counted more than once. fPatients in the trastuzumab-EU group were excluded from the per protocol population for the following reasons: Cycle 5 trough sample taken outside protocol-specified window (n = 13, 56.5%), fewer than six cycles of trastuzumab (n = 5, 21.7%), trastuzumab treatment delay > 1 week (n = 3, 13.0%), Cycle 5 trough sample taken post dose (n = 1, 4.3%), no lesion > 2 cm in breast (n = 1, 4.3%), and missing HER2 sample (n = 1, 4.3%). A patient may have met multiple criteria for exclusion and may have been counted more than once. gThe per protocol population consisted of all randomised patients who received six cycles of PF-05280014 or trastuzumab-EU and had no temporary delays in treatment lasting > 1 week or other significant protocol deviations. AUC = area under the curve; HER2 = human epidermal growth factor receptor 2; trastuzumab-EU = licensed trastuzumab sourced from the European Union