Study Design

This was a multinational, randomized, double-blind, phase III study conducted across 143 sites in 25 countries between February 2014 and June 2020 (Last Subject Last Visit: 27 June 2020). The study was conducted in accordance with the Declaration of Helsinki, as well as following all relevant local requirements. The protocol, its amendments, and informed consent documentation were reviewed and approved by the institutional review board(s) or independent ethics committee(s) at each site. Patients gave informed consent prior to undergoing any study-specific procedure.

Data were analyzed firstly when all patients had completed week 33 (the primary efficacy analysis) and secondly when all patients had completed week 53 (the secondary analysis) visit assessments. After the data cutoff date (11 January 2017) for the week 53 analysis, the study protocol was amended to delineate two treatment periods (treatment period 1 [TP1] and treatment period 2 [TP2]). TP1 for a patient began with the first dose of study treatment on cycle 1, day 1 and ended with the completion of the week 53 visit assessments and upon providing written, signed, and dated informed consent for the protocol amendment. The study elements required to achieve study objectives and endpoints (i.e., through week 53 visit assessments) were contained within TP1. TP2 was intended solely to provide access to study treatment for patients who continued to receive clinical benefit beyond TP1. Patients who received study treatment beyond week 53 at the time of the protocol amendment and provided written informed consent for the protocol amendment, entered TP2 as soon as possible and no later than 28 days following the approval of the protocol amendment. During TP2, minimal protocol-required assessments and procedures were undertaken, and all other routine patient care assessments were at the discretion of the investigator based on local practice/standard of care (SoC). Patients were treated in TP2 in a blinded manner with the trastuzumab treatment to which they were initially randomized (PF-05280014 or trastuzumab-EU) until discontinuation. Continued treatment in the study was based on documented evidence of clinical benefit. The study design is shown in Supplementary Fig. 1 in the electronic supplementary material (ESM).

The study ended after marketing authorization for PF-05280014 was granted in several countries globally. Patients who continued to show clinical benefit were transferred to access programs as per regional regulations. The last dose of study treatment was administered on 30 May 2020.