FDA Accepts BLA for Trastuzumab Biosimilar HLX02 in HER2+ Cancers

The FDA has accepted a biologics license application (BLA) for trastuzumab biosimilar HLX02 (Zercepac) for a review as an adjuvant treatment of patients with HER2-overexpressing breast cancer including metastatic disease, and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, according to a press release from Accord BioPharma.¹

"The promise of HLX02’s reference product [trastuzumab] is well documented, and we're thrilled to announce this regulatory milestone as we work to provide patients increased options and access for treatment of serious conditions in oncology, immunology, and critical care," according to the manufacturers of HLX02.

Submission of the BLA was based on data from head-to-head clinical studies evaluating HLX02 and reference trastuzumab (Herceptin), including comparative analytical studies, nonclinical studies, and a global phase 3 trial (NCT03084237) in patients with HER2-positive breast cancer.

In the phase 3 breast cancer trial, the 24-week overall response rate (ORR) was 71.3% with HLX02 and 71.4% with reference trastuzumab, which fulfilled the investigators’ pre-specified difference margin of 13.5% between the treatments.² Additionally, the median duration of response (DOR) in each respective arm was 10.6 months and 10.2 months (HR, 0.79; P = .103), and the median progression-free survival (PFS) was 11.7 months and 10.6 months (HR, 0.83; P = .086). The investigators also reported similarities in terms of disease control rate (DCR) and clinical benefit rate (CBR) between the two treatment arms.

“The promise of HLX02’s reference product [trastuzumab] is well documented, and we're thrilled to announce this regulatory milestone as we work to provide patients increased options and access for treatment of serious conditions in oncology, immunology, and critical care,” Chrys Kokino, president of U.S BioPharma at Accord BioPharma, said in the press release.

Investigators of the global, double-blind, multi-center, phase 3 study assessed HLX02 and trastuzumab in 649 patients with HER2-positive, locally recurrent or previously untreated metastatic breast cancer. Patients were randomly assigned 1:1 to receive either 8 mg/kg of HLX02 or trastuzumab intravenously on day 1 of cycle 1 followed by 6 mg/kg every 3 weeks for subsequent cycles plus 75 mg/m² of docetaxel on day 2 of cycle 1 then every 3 weeks on day 1 of each subsequent cycle.

The primary end point of the trial was ORR at 24 weeks based on RECIST v1.1 criteria. Secondary end points included DOR, DCR, CBR, and PFS.

Patients 18 years or older who had histologically or cytologically confirmed adenocarcinoma of the breast and availability of formalin-fixed paraffin-embedded tissue block from the primary tumor or a metastatic lesion to confirm HER2-positivity were eligible for enrollment on the trial. Additional inclusion criteria included having recurrent disease not amenable to surgery or radiation therapy; measurable disease; adequate hematologic, hepatic, and renal function; and an ECOG performance status of 0 or 1.

Patients who had received previous treatment for metastatic breast cancer or known brain or central nervous system metastases were not eligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had history of another malignancy within the last 5 years, current uncontrolled hypertension, history of chronic heart failure, or known hypersensitivity to any of the study drugs.

Overall, 98.8% of patients had at least 1 adverse effect (AE) in the trial. Grade 3 or higher treatment-emergent AEs (TEAEs) occurred in 85.8% of patients receiving HLX02 and 86.4% of those receiving trastuzumab. Additionally, serious TEAEs occurred in 23.8% vs 24.9% of patients in each respective treatment arm.

Previously, HLX02 received approval from the European Commission in July 2020 and from China’s National Medicines Products Administration in August 2020 for the same indications highlighted in the BLA.

References

1. Accord BioPharma announces U.S. FDA acceptance of biologics license application for proposed biosimilar trastuzumab HLX02. News release. Accord BioPharma. April 5, 2023. Accessed April 7, 2023. bit.ly/3zCPs10
2. Xu B, Zhang Q, Sun T, et al. Efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with recurrent or metastatic HER2-positive breast cancer: a randomized phase III equivalence trial. BioDrugs. 2021;35(3):337-350. doi:10.1007/s40259-021-00475-w