Background: SB3 (trastuzumab-dttb) is a biosimilar approved globally based on its similarity with reference trastuzumab (TRZ) demonstrated by thorough comparability exercises in analytical, biological, and clinical studies. In a randomized, double-blind, multicenter Phase 3 study of 875 patients with HER2-positive early or locally advanced breast cancer in the neoadjuvant setting, equivalent efficacy, similar safety, pharmacokinetics, and immunogenicity between SB3 and TRZ were shown. However, when quality attributes of TRZ were examined, downward drifts in antibody-dependent cell-mediated cytotoxicity activities (ADCC) were observed in the TRZ lots with expiry dates ranging from Aug 2018 to Dec 2019. Some of these lots of the reference product were found to be used in the Phase 3 study. After completing the Phase 3 study, patients from select countries were included in a follow-up observational study to monitor cardiac safety and survival. Here, we report the final survival results, including post-hoc subgroup analysis based on ADCC status, at a median follow-up of 68 months. Methods: During the follow-up observational study, the protocol was amended to include additional patients who originally were enrolled in the Phase 3 study but had not been followed in the observational study, in order to collect a larger sample of survival data. For these additional patients, medical records from the last assessment in the Phase 3 study through the date of enrollment in the follow-up study were collected retrospectively. As post-hoc analysis, patients in the TRZ arm were stratified into two subgroups: patients who received during neoadjuvant treatment at least one vial of TRZ with downward drift in ADCC as “Drifted TRZ”, and the others as “Non-drifted TRZ”. Event-free survival (EFS) and overall survival (OS) were assessed. Results: Of 875 patients randomized in the Phase 3 study, 538 patients (SB3, N=267; TRZ, N=271) were enrolled in the follow-up observational study: 367 patients were initially enrolled in the follow-up study, and 171 patients were additionally enrolled following the protocol amendment. The median follow-up duration was 68 months from randomization in the Phase 3 study. 54 events (20.2%) in the SB3 arm, and 67 events (24.7%) in the TRZ arm were reported (HR 0.84 [0.58, 1.20], p=0.335). 22 deaths (8.2%) and 38 deaths (14%) were reported in SB3 and TRZ arms, respectively (HR 0.61 [0.36, 1.05], p=0.073). In post-hoc analysis, of 271 patients in TRZ arm, 107 patients were grouped as “Non-drifted TRZ”, and 164 patients as “Drifted TRZ”. 19 events (17.8%) in the Non-drifted TRZ group and 48 (29.3%) events in the Drifted TRZ group occurred (HR 2.57 [1.28, 5.14], p=0.008). 9 deaths (8.4%) in the Non-drifted TRZ group and 29 deaths (17.7%) in the Drifted TRZ group were reported (HR 3.87 [1.37, 10.93], p=0.011). No difference was observed between SB3 arm and Non-drifted TRZ group in terms of EFS (HR 1.28 [0.73, 2.22], p=0.391) and OS (HR 0.99 [0.42, 2.31], p=0.975). Conclusions: Comparable long-term efficacy results in EFS and OS were shown at 68 months of follow-up, further supporting biosimilarity of SB3 to the reference product. Currently, these follow-up results represent the longest monitoring data of patients treated with a trastuzumab biosimilar for HER2-positive early or locally advanced breast cancer.

Citation Format: Xavier Pivot, Mark D Pegram, Javier Cortes, Diana Lüftner, Gary H Lyman, Giuseppe Curigliano, Igor M Bondarenko, Mikhail Dvorkin, Jin Hee Ahn, Seock-Ah Im, Maria Litwiniuk, Yaroslav V Shparyk, Gwo Fuang Ho, Nikolay V Kislov, Marek Wojtukiewicz, Tomasz Sarosiek, Yee Soo Chae, Jin Seok Ahn, Hyerin Jang, Sujung Kim, Jiwon Lee, Soo Young Lee, Ye Chan Yoon. Final survival analysis of a phase 3 study comparing SB3 (trastuzumab biosimilar) and reference trastuzumab in HER2-positive early or locally advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-04.