Efficacy and Safety of EG12014 (Biosimilar Trastuzumab) Compared to Reference Trastuzumab in HER2-Positive Early Breast Cancer: A Phase III Randomized Study

Trastuzumab biosimilar EG12014 (Herwenda ® ; EirGenix/Sandoz) was approved by the European Medicines Agency (EMA) in 2023. We aim to demonstrate equivalent efficacy, and to compare safety, immunogenicity, and pharmacokinetic (PK) profiles, of EG12014 and reference trastuzumab (ref-TRA) in early breast cancer (EBC). This Phase III, randomized, multicenter, double-blind study included adult patients with EBC. In the neoadjuvant phase, patients received epirubicin and cyclophosphamide for four cycles, then were randomized (1:1) to four cycles of EG12014 or ref-TRA (loading/maintenance dose: 8/6 mg/kg) with paclitaxel. Following surgery, patients continued adjuvant EG12014, or were rerandomized (1:1) from ref-TRA to ref-TRA or EG12014. Patients completed 12 months of treatment. The primary endpoint was centrally-assessed pathological complete response (pCR; defined as ypT0/is ypN0) at the time of surgery. Additional efficacy, safety, immunogenicity, and PK endpoints were evaluated. In the neoadjuvant phase, 405 and 402 patients were randomized to EG12014 and ref-TRA, respectively. In the adjuvant phase, 386 patients continued EG12014, 188 continued ref-TRA, and 188 switched from ref-TRA to EG12014. The primary objective, to demonstrate equivalent efficacy between EG12014 and ref-TRA, was achieved: the risk difference between treatment arms in pCR rate was − 0.004 (95% CI − 0.072 to 0.065), with the 95% CI entirely within the predefined equivalence margin of − 0.13 to 0.13 (EMA requirement). Equivalence was also demonstrated regarding the risk ratio, with a relative risk of 0.992 (90% CI 0.880–1.118) and the 90% CI completely within the predefined equivalence margin of 0.741–1.349 (US Food and Drug Administration requirement). Secondary efficacy endpoints, including overall response prior to surgery and overall survival, were also comparable between treatments. Safety, immunogenicity and PK profiles were comparable between treatments and were not impacted by switching. Trastuzumab biosimilar EG12014 and ref-TRA have equivalent efficacy, and comparable safety, immunogenicity, and PK profiles, in patients with EBC. Clinical trial registration NCT03433313; EudraCT Number 2017-003973-33.