FDA Approves Fourth Trastuzumab Biosimilar

The FDA has granted an approval to PF-05280014 (Trazimera; trastuzumab-qyyp), a trastuzumab (Herceptin) biosimilar, to treat patients with HER2-overexpressing breast cancer as well as HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.¹ This marks the fourth approval by the FDA for a trastuzumab biosimilar.

The decision was based on findings of a comprehensive data package, including results from the phase III REFLECTIONS B327-02 trial, demonstrating similar efficacy and safety outcomes between PF-05280014 and standard trastuzumab. The European Medicines Agency approved the biosimilar in this setting in July 2018.

"Approximately 15% to 30% of breast cancers and 10% to 30% of gastric cancers are HER2-positive, which is associated with aggressive disease and poor prognoses for patients," said Mark Pegram, MD, associate director for clinical research at the Stanford Comprehensive Cancer Institute, and director of the Breast Oncology Program at the Stanford Women’s Cancer Center, in a press release. "With the availability of biosimilars like Trazimera in the [United States], oncologists will have additional treatment options to choose from, which may help provide patients with greater access to the medicines they need."

In the phase III REFLECTIONS B327-02 trial, 707 patients with HER2-positive metastatic breast cancer were randomized 1:1 to receive paclitaxel plus PF-05280014 or trastuzumab-EU. All patients received weekly trastuzumab for at least 33 weeks at a starting dose of 4 mg/kg and subsequent doses of 2 mg/kg. Additionally, therapy continued until disease progression.

Additional findings showed that PF-05280014 achieved equivalence in ORR compared with trastuzumab. The risk ratio was 0.940 with a 95% CI of 0.842 to 1.049, achieving the equivalence margin of 0.8-1.25 specified in the clinical trial design. Moreover, the 1-year PFS was 56% for PF-05280014 versus 52% for trastuzumab-EU, and the 1-year OS was 88.84% versus 87.96%, respectively.

Regarding safety, investigators did not report any new safety signals; the safety profile was similar in both arms.

Investigators published data from a substudy, REFLECTIONS B327-04 (NCT02187744), in the British Journal of Cancer in July 2018, which demonstrated clinical equivalence for safety and efficacy between PF-05280014 and trastuzumab in 226 women with operable HER2-positive breast cancer.^3,4 Patients were stratified by primary tumor size and hormone receptor status and assigned to PF-05280014 (n = 114) or trastuzumab-EU (n = 112). Both cohorts received an 8 mg/kg loading dose, followed by a 6 mg/kg dose thereafter along with docetaxel and carboplatin every 3 weeks for 6 treatment cycles. A total of 190 patients were included in the per protocol population.

The percentage of patients with trough plasma concentration (Ctrough) >20 μg/ml at cycle 5, cycle 6 predose, was the primary endpoint. Secondary endpoints included ORR as assessed by central radiology review and pathological complete response (pCR). PF-05280014 would be declared noninferior to the referent product if the lower limit of the confidence interval in the percentage of patients with Cycle 5 Ctrough >20 μg/ml exceeded the noninferiority margin of —12.5% for the stratified difference between the 2 groups.

Data from this study, which were also presented at the 2017 ESMO Congress, showed that the cycle 5 Ctrough >20 μg/ml was 92.1% in the PF-05280014 arm compared with 93.3% for trastuzumab-EU patients (95% CI, −8.02% to 6.49%). The stratified estimated difference between the treatment arms was —0.76%, exceeding the prespecified margin for noninferiority.

The pCR (47.0% vs 50.0%, respectively) and ORR (88.1% vs 82.0%, respectively) were similar between the 2 arms.

Regarding safety, 43 (38.1%) patients in the experimental arm and 51 (45.5%) in the referent arm experienced grade 3/4 treatment-related adverse events. There were 7 (6.2%) serious adverse events in the PF-05280014 arm compared with 6 (5.4%) in the trastuzumab arm. One patient in the experimental arm died.

"This is an important milestone in the [United States] which both adds to our growing portfolio of oncology treatments and has the potential to improve access to cancer care," said Andy Schmeltz, global president of Pfizer Oncology, in the press release. "We are proud to be able to offer treatment options that can help address the diverse needs of patients."

In April 2018, the FDA issued a complete response letter to Pfizer, the manufacturer of the biosimilar, regarding a biologics license application for PF-05280014, citing the need for additional technical information. At the time, Pfizer issued a statement noting that it was “working closely with the FDA to address the contents of the letter.”

The FDA previously approved intravenous (IV) trastuzumab for the adjuvant treatment of patients with HER2-overexpressing, node-positive or node-negative breast cancer as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; with docetaxel and carboplatin; and as a single agent following multi-modality anthracycline-based therapy. It is also indicated as a single agent for patients with HER2-overexpressing breast cancer who have received one or more chemotherapy regimens for metastatic disease, or in combination with paclitaxel as a first-line treatment for patients with HER2-overexpressing metastatic breast cancer.

In March 2019, the FDA approved a subcutaneous formulation of trastuzumab and hyaluronidase-oysk injection (Herceptin Hylecta) in combination with chemotherapy for the treatment of select patients with HER2-positive early breast cancer, in combination with paclitaxel in patients with metastatic HER2-positive breast cancer as a frontline treatment, and alone for patients with metastatic disease who have received at least 1 prior chemotherapy regimen.

References

1. Trastuzumab-qyyp prescribing information. FDA. https://bit.ly/2TLnRHy. Accessed March 11, 2019.
2. Pegram M, Tan-Chiu E, Freyman A, et al. Abstract 238PD. A randomized, double-blind study of PF-05280014 (a potential trastuzumab biosimilar) vs trastuzumab, both in combination with paclitaxel, as first-line treatment for HER2-positive metastatic breast cancer. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 238PD.
3. Lammers PE, Dank M, Masetti R, et al. Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer [published online July 13, 2018]. Br J Cancer. 2018;119:266—273. doi.org/10.1038/s41416-018-0147-1.
4. Lammers PE, Dank M, Masetti R, et al. A randomized, double-blind study of PF-05280014 (a potential biosimilar) vs trastuzumab, both given with docetaxel (D) and carboplatin (C), as neoadjuvant treatment for operable human epidermal growth factor receptor 2-positive (HER2+) breast cancer. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 154PD.

Results from the REFLECTIONS B327-02 study (NCT01989676), which were presented at the 2017 ESMO Congress, PF-05280014 met its primary endpoint for equivalent objective response rate (ORR) versus trastuzumab as a frontline treatment for patients with HER2-positive metastatic breast cancer. At 1 year, progression-free survival (PFS) and overall survival (OS) were similar between the two arms.²