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The FDA Approves Fourth Herceptin Biosimilar


The Food and Drug Administration (FDA) has granted an approval to Trazimera (PF-05280014; trastuzumab-qyyp), a Herceptin (trastuzumab) biosimilar, to treat patients with HER2-overexpressing breast cancer as well as HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

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

The decision was based on findings of a comprehensive submission package demonstrating similar efficacy and safety outcomes between Trazimera and standard Herceptin. The European Medicines Agency approved the biosimilar in this setting in July 2018.

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

In the phase 3 REFLECTIONS B327-02 trial, 707 patients with HER2-positive metastatic breast cancer were randomized 1 to 1 to receive paclitaxel plus Trazimera or trastuzumab-EU. All patients received weekly Herceptin 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 Trazimera achieved equivalence in ORR compared with Herceptin.

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 Trazimera and Herceptin in 226 women with operable HER2-positive breast cancer. Patients were stratified by primary tumor size and hormone receptor status and assigned to Trazimera (114 patients) or trastuzumab-EU (112 patients). Both cohorts received an 8 mg/kg loading dose, followed by a 6 mg/kg dose thereafter along with docetaxel and carboplatin every three weeks for six 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 percent for the stratified difference between the two 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 percent in the Trazimera arm compared with 93.3 percent for trastuzumab-EU patients. The stratified estimated difference between the treatment arms was —0.76 percent, exceeding the prespecified margin for noninferiority.

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

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

In April 2018, the FDA issued a complete response letter to Pfizer, the manufacturer of the biosimilar, regarding a biologics license application for Trazimera, 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) Herceptin 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 Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) injection 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 one prior chemotherapy regimen.

This article originally appeared on OncLive as, "FDA Approves Fourth Trastuzumab Biosimilar."

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