EU Approves Trastuzumab Biosimilar for HER2+ Breast, Gastric Cancers

Diana Lüftner, MD

PF-05280014 (Trazimera), a biosimilar for trastuzumab (Herceptin), has been approved for use in the European Union (EU) to treat patients with HER2 overexpressing metastatic or early breast cancer and HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

The EU’s Committee for Medicinal Products for Human Use issued a positive opinion on PF-05280014 in May. Pfizer, the manufacturer of PF-05280014, issued a release announcing the decision.

In results from the REFLECTIONS B327-02 study (NCT01989676) presented at the 2017 ESMO Congress, PF-05280014 met its primary endpoint for objective response rate (ORR) equivalence compared with trastuzumab in patients receiving first-line treatment for HER2-positive metastatic breast cancer. At 1 year, progression-free survival (PFS) and overall survival (OS) were similar between the treatment groups.¹

“Trazimera has the potential to help many patients with HER2 overexpressing cancers, such as breast and gastric, which can correlate with poor outcomes and aggressive disease,” Diana Lüftner, MD, Charité Campus Benjamin Franklin and member of the presidency of the German Society of Hematology and Medical Oncology, said in a statement. “Today’s approval will help enable greater access for patients and physicians across Europe, without compromising on quality, efficacy, and safety.”

The agent is approved as monotherapy for patients with metastatic breast cancer who have received at least 2 prior chemotherapy regimens, and in combination with paclitaxel or docetaxel for chemotherapy-naïve patients. It is also approved in combination with an aromatase inhibitor for trastuzumab-naïve postmenopausal patients with metastatic disease. For patients with early breast disease, the biosimilar is approved following surgery, chemotherapy, and radiotherapy, and in combination with adjuvant or neoadjuvant chemotherapy.

PF-05280014 is approved in combination with capecitabine or 5-fluorouracil/cisplatin for adults with treatment-naïve, HER2-positive metastatic adenocarcinoma of the stomach or gastroesophageal junction.

In REFLECTIONS B327-02, women with metastatic breast cancer (N = 707) were randomly assigned in a 1:1 ratio to 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. Treatment continued until progression.

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 trial design.

The 1-year PFS was 56% for PF-05280014 versus 52% for trastuzumab-EU. The 1-year OS was 88.84% versus 87.96%, respectively.

Investigators did not identify any new safety signals and the safety profile was similar in both arms.

Investigators published data from a substudy, REFLECTIONS B327-04 (NCT02187744), in the British Journal of Cancer earlier this month demonstrating clinical equivalence for safety and efficacy between PF-05280014 and trastuzumab in 226 women with operable HER2-positive breast cancer. Results from this study were also presented at the 2017 ESMO Congress.^2,3

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.

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.

Forty-three (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.

The FDA in April 2018 issued a complete response letter to Pfizer regarding a biologics license application for PF-05280014, citing the need for additional technical information. The company issued a statement at the time noting that it is “working closely with the FDA to address the contents of the letter.”

References

1. 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.
2. 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.
3. 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.