A biosimilar to trastuzumab (Herceptin) demonstrated noninferiority versus the branded drug in a randomized trial of patients with metastatic HER2-positive breast cancer.
Treatment with Pfizer’s biosimilar PF-05280014 plus paclitaxel led to objective responses in 62.5% of patients with metastatic HER2-positive breast cancer compared with 66.5% for European-sourced (EU) trastuzumab and the taxane, a difference that met statistical requirements for noninferiority. The two treatment groups had virtually identical progression-free survival (PFS), as reported in the British Journal of Cancer (BJC).
“In the current study … PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in the primary efficacy endpoint of objective response rate (ORR), with no notable differences in safety or immunogenicity profile,” Mark D. Pegram, MD, of Stanford University in California, and coauthors wrote in their conclusion, adding that there were also no statistically significant differences in duration of response (DOR), PFS, and overall survival (OS).
“As part of the totality of the evidence for assessing biosimilarity, these results are consistent with, and build upon, earlier analytical, nonclinical, and clinical comparisons of PF-05280014 and reference trastuzumab,” they wrote.
The totality of evidence included another recently reported randomized trial that demonstrated the noninferiority of PF-05280014 versus trastuzumab-EU in the setting of neoadjuvant therapy for early HER2-positive breast cancer. The two drugs achieved prespecified trough levels (Ctrough) in a similar proportion of patients.
Trastuzumab has attracted considerable interest among biosimilar developers, and the FDA has already approved three agents: Ogivri from Mylan, Herzuma from Celltrion, and most recently Ontruzant from Samsung. The European Medicines Agency has approved four such biosimilars, and several other biosimilar products are under development.
In April 2018, the FDA sent Pfizer a complete response letter for PF-05280014, citing a need for more technical information; it was approved in Europe last summer.
Pegram and coauthors reported findings from a study of first-line systemic therapy for advanced disease. Investigators in 24 countries randomized 707 patients with previously untreated metastatic HER2-positive breast cancer to PF-05280014 or trastuzumab-EU, each in combination with paclitaxel. After completing paclitaxel administration, investigators had the discretion to continue anti-HER2 therapy at the starting dosage or switch to a less frequent administration schedule. Treatment continued until disease progression.
In addition to the primary endpoint of ORR, the trial had secondary endpoints that included DOR, 1-year PFS, and 1-year OS. For the primary endpoint assessment, the trial design specified an equivalence margin of 0.80 to 1.25.
The 4% absolute difference in ORR translated into an odds ratio of 0.94 for the comparison of PF-05280014 versus trastuzumab-EU, falling within the margins for equivalence. The treatment groups also had similar 1-year PFS (54% vs 51%) and 1-year OS (89.31% vs 87.36%). The median PFS was 12.16 months with PF-05280014 and 12.06 months with trastuzumab-EU. Median overall survival had yet to be reached in either group. Safety and immunogenicity analyses yielded similar results for the two treatment groups.
The international neoadjuvant trial, published last summer in BJC, involved 226 patients with resectable newly diagnosed HER2-positive breast cancer, stratified by tumor size and hormone receptor status. Patients received either the biosimilar or branded product in addition to docetaxel and carboplatin. Treatment continued for six 3-week cycles, Philip E. Lammers, MD, and coauthors reported. The trial had a pharmacokinetic primary endpoint: The proportion of patients who had a Ctrough >20 µg/mL during the fifth cycle of treatment.
The data showed that 92.1% of patients assigned to PF-05280014 met the primary endpoint as compared with 93.3% of those allocated to trastuzumab-EU. The 1.3% absolute difference was associated with confidence intervals of -8.02% and 6.49%, exceeding the prespecified lower limit for noninferiority of -12.5%.
Analysis of secondary endpoints showed pathologic complete response rates of 47% and 50.0% for PF-0580014 and trastuzumab-EU, respectively, and ORRs by central radiology review of 88.5% versus 82.0%.
The incidence of grade 3/4 treatment-emergent adverse events (irrespective of cause) was 38.1% for patients treated with the biosimilar and 45.5% for the group that received the branded product. No patient in the PF-05280014 group developed antidrug antibodies as compared with 0.89% in the trastuzumab-EU group.
“These results support similarity of PF-05280014 to trastuzumab-EU as part of the stepwise comparison exercise for demonstrating biosimilarity,” Lammers’s group concluded.
Both trials were supported by Pfizer.
Pegram disclosed relationships with Amgen, Pfizer, Genentech/Roche, and Samsung Bioepis.