Trastuzumab Biosimilar vs Reference Trastuzumab in HER2-Positive Early Breast Cancer
In the phase III LILAC equivalence trial reported in The Lancet Oncology, von Minckwitz et al found similar efficacy and safety with the trastuzumab biosimilar ABP 980 vs reference trastuzumab (Herceptin) in HER2-positive early breast cancer. On local review, the risk difference and risk ratio (RR) for pathologic complete response between the groups—the primary endpoints—exceeded the upper statistical margins for equivalence.
Study Details
In the double-blind trial, 725 patients from 97 sites in 20 countries (mainly in Europe and South America) were randomized to receive ABP 980 (n = 364) or trastuzumab (n = 361). The co-primary efficacy endpoints were risk difference and risk ratio of pathologic complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. The primary endpoint was assessable in 358 patients who received ABP 980 and 338 who received trastuzumab.
After four cycles of run-in anthracycline-based neoadjuvant chemotherapy, patients received neoadjuvant ABP 980 or trastuzumab with paclitaxel in a loading dose followed by 3 cycles along with paclitaxel every 3 weeks. Surgery was completed 3 to 7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year. Patients were randomized at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as adjuvant treatment.
Pathologic Complete Response Rates
Pathologic complete response was observed in 48% of the ABP 980 group vs 41% of the trastuzumab group (risk difference = 7.3%, 90% confidence interval [CI] = 1.2–13.4; RR = 1.188, 90% CI = 1.033–1.366); the upper bounds of the confidence intervals exceeded the predefined equivalence margins of 13% and 1.318 for the endpoints. On central laboratory assessment, pathologic complete response was observed in 48% vs 42% (risk difference = 5.8%, 90% CI = -0.5–12.0; RR = 1.142, 90% CI = 0.993–1.312).
Adverse Events
Grade ≥ 3 adverse events during neoadjuvant treatment occurred in 15% of the ABP 980 group vs 14% of the trastuzumab group, with neutropenia occurring in 6% of patients in both groups. In the adjuvant phase, grade ≥ 3 adverse events occurred in 9% of 349 patients continuing ABP 980, 6% of 171 continuing trastuzumab, and 8% of 171 who switched from trastuzumab to ABP 980, with similar incidence of infections and infestations (1%, 1%, and 1%), neutropenia (1%, 1%, and 1%), and infusion reactions (1%, 1%, and 2%) among groups.
Two patients died from adverse events considered unrelated to the investigational products. One died from pneumonia while receiving neoadjuvant ABP 980, and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab.
The investigators concluded, “Although the lower bounds of the 90% CIs for RR and risk difference showed noninferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that nonsuperiority was nonconclusive. In our sensitivity analyses based on central laboratory evaluation of tumor samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study.”
The study was funded by Amgen.
Gunter von Minckwitz, MD, of the German Breast Group, Neu-Isenburg, is the corresponding author for The Lancet Oncology article.
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