Results from the phase 3 REFLECTIONS B327-02 study in patients with HER2-positive metastatic breast cancer (MBC) were first presented in abstract form, but have now been reported in detail.
In July 2018, the European Commission authorized the Pfizer’s PF-05280014, a trastuzumab biosimilar referencing Herceptin, under the brand name Trazimera. The marketing approval followed a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use, which relied on Pfizer’s data package that included results from the phase 3 REFLECTIONS B327-02 study. The study’s results were first presented in abstract form at the European Society for Medical Oncology conference in 2017 but have now been reported in detail the British Journal of Cancer.
In the ongoing, international, randomized, double-blind, parallel-group study, 707 female patients with HER2-positive metastatic breast cancer (MBC) were randomized at 143 sites in 24 countries. Exclusion criteria include prior systemic therapy, except for endocrine therapy.
Patients received either the biosimilar (n = 352) or the EU-licensed reference trastuzumab (n = 355) together with paclitaxel. Upon completion of the paclitaxel administration period, no earlier than week 33, the trastuzumab regimen could be changed at the investigators’ discretion, though dose reductions were not allowed, and treatment could continue until disease progression.
The study’s primary endpoint was objective response rate (ORR), which regulators considered sufficiently sensitive to detect any clinically meaningful differences in efficacy between the biosimilar and the reference. ORR was measured as the percentage of patients in each group with complete or partial response at week 25 that was confirmed at week 33. The investigators prespecified that equivalence would be determined if the 95% CI of the risk ratio for ORR fell within the margin of 0.80 to 1.25.
The risk ratio for ORR by week 25, confirmed by week 33, in the intention-to-treat (ITT) population was 0.940, with a 95% CI of 0.842-1.049, which fell within the prespecified equivalence margin. ORR in the biosimilar group was 62.5% (95% CI, 57.2%-67.6%) versus 66.5% (95% CI, 61.3%-71.4%) in the reference group. The risk difference for ORR was −4.0% (95% CI, −11.0% to 3.1%).
At week 53, disease progression or death in the ITT population was reported for 40.9% of the patients in the biosimilar group and 41.7% of patients in the reference group. The respective estimated 1-year progression-free survival (PFS) rates were 54% (95% CI, 48%-60%) and 51% (95% CI, 45%-57%). Median respective times to PFS were 12.16 (95% CI, 11.93-12.48) months and 12.06 (95% CI, 11.79-not estimable) months.
Estimated 1-year overall survival rates were 89.31% (95% CI, 85.48%-92.17%) in the biosimilar group versus 87.36% (95% CI, 83.27%-90.51%) in the reference group.
At week 53, most patients (96.6% in the biosimilar arm and 96.0% in the reference arm) in the safety population had experienced at least 1 treatment-emergent adverse event (AE). The incidence for all AEs was similar between groups, with alopecia, anemia, neutropenia, and peripheral sensory neuropathy being the most commonly reported. Serious AEs were reported in 20.1% of patients in the biosimilar arm and 20.7% of patients in the reference arm, with disease progression, pulmonary embolism, and pneumonia being the most common serious AEs.
In total, 2 patients, 1 from each group, tested positive for antidrug antibodies (ADAs) and neutralizing antibodies (NABs) at the end-of-treatment visit. One of the 2 patients was also positive for both ADAs and NABs at baseline.
The investigators concluded that, when used as a first-line treatment for HER2-positive MBC, the biosimilar, used together with paclitaxel, demonstrated equivalence to the EU-licensed Herceptin plus paclitaxel in terms of ORR. The investigators noted that the study is ongoing, and the database lock will take place when long-term follow-up is complete.
While Pfizer’s biosimilar has demonstrated equivalence to the EU reference, the product is not yet authorized in the United States; in April 2018, Pfizer received a Complete Response Letter from the FDA for the drug. Pfizer indicated at the time that the FDA had highlighted the need for additional technical information, but it clarified that the FDA did not request any additional safety or clinical data. The company stated that it would work closely with the FDA to address the agency’s questions and remained committed to developing the biosimilar.
Pegram MD, Bondarenko I, Zorzetto MMC, et al. PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomized, double-blind study. Brit J Cancer. 2019;120:172-182. doi: 10.1038/s41416-018-0340-2.