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 (C_trough) >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 C_trough >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 C_trough >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.

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