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Clinical Trial
. 2023 Apr 3;6(4):e235822.
doi: 10.1001/jamanetworkopen.2023.5822.

Cardiac Safety and Efficacy of SB3 Trastuzumab Biosimilar for ERBB2-Positive Early Breast Cancer: Secondary Analysis of a Randomized Clinical Trial

Xavier Pivot  1 , Javier Cortés  2   3   4 , Diana Lüftner  5 , Gary H Lyman  6 , Giuseppe Curigliano  7 , Igor M Bondarenko  8 , Jin-Hee Ahn  9 , Seock-Ah Im  10 , Maria Litwiniuk  11 , Yaroslav V Shparyk  12 , Gwo Fuang Ho  13 , Nikolay V Kislov  14 , Marek Wojtukiewicz  15 , Tomasz Sarosiek  16 , Yee Soo Chae  17 , Jin Seok Ahn  18 , Hyerin Jang  19 , Sujung Kim  19 , Jiwon Lee  19 , YeChan Yoon  19
Affiliations
Clinical Trial

Cardiac Safety and Efficacy of SB3 Trastuzumab Biosimilar for ERBB2-Positive Early Breast Cancer: Secondary Analysis of a Randomized Clinical Trial

Xavier Pivot et al. JAMA Netw Open. .

Abstract

Importance: Trastuzumab has been the standard of care for the treatment of patients with ERBB2-positive breast cancer; however, cardiac events have been reported. This long-term follow-up study provides clinical evidence supporting the similarity of a trastuzumab biosimilar (SB3) to reference trastuzumab (TRZ).

Objective: To compare cardiac safety and efficacy between SB3 and TRZ for patients with ERBB2-positive early or locally advanced breast cancer after up to 6 years of follow-up.

Design, setting, and participants: This prespecified secondary analysis of a randomized clinical trial, conducted from April 2016 to January 2021, included patients with ERBB2-positive early or locally advanced breast cancer from a multicenter double-blind, parallel-group, equivalence phase 3 randomized clinical trial of SB3 vs TRZ with concomitant neoadjuvant chemotherapy who completed neoadjuvant and adjuvant treatment.

Interventions: In the original trial, patients were randomized to either SB3 or TRZ with concomitant neoadjuvant chemotherapy for 8 cycles (4 cycles of docetaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide). After surgery, patients continued SB3 or TRZ monotherapy for 10 cycles of adjuvant treatment per previous treatment allocation. Following neoadjuvant and adjuvant treatment, patients were monitored for up to 5 years.

Main outcomes and measures: The primary outcomes were the incidence of symptomatic congestive heart failure and asymptomatic, significant decrease in left ventricular ejection fraction (LVEF). The secondary outcomes were event-free survival (EFS) and overall survival (OS).

Results: A total of 538 female patients were included (median age, 51 years [range, 22-65 years]). Baseline characteristics were comparable between the SB3 and TRZ groups. Cardiac safety was monitored for 367 patients (SB3, n = 186; TRZ, n = 181). Median follow-up was 68 months (range, 8.5-78.1 months). Asymptomatic, clinically significant LVEF decreases were rarely reported (SB3, 1 patient [0.4%]; TRZ, 2 [0.7%]). No patient experienced symptomatic cardiac failure or death due to a cardiovascular event. Survival was evaluated for the 367 patients in the cardiac safety cohort and an additional 171 patients enrolled after a protocol amendment (538 patients [SB3, n = 267; TRZ, n = 271]). No difference was observed in EFS or OS between treatment groups (EFS: hazard ratio [HR], 0.84; 95% CI, 0.58-1.20; P = .34; OS: HR, 0.61; 95% CI, 0.36-1.05; P = .07). Five-year EFS rates were 79.8% (95% CI, 74.8%-84.9%) in the SB3 group and 75.0% (95% CI, 69.7%-80.3%) in the TRZ group, and OS rates were 92.5% (95% CI, 89.2%-95.7%) in the SB3 group and 85.4% (95% CI, 81.0%-89.7%) in the TRZ group.

Conclusions and relevance: In this secondary analysis of a randomized clinical trial, SB3 demonstrated cardiac safety and survival comparable to those of TRZ after up to 6 years of follow-up in patients with ERBB2-positive early or locally advanced breast cancer.

Trial registration: ClinicalTrials.gov Identifier: NCT02771795.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Pivot reported receiving travel fees from Samsung BioEpis during the conduct of the study, travel fees from Prestige Biopharma outside the submitted work, and grants from Publicreation Biennale de Monaco de Cancerologie and Pierre Fabre outside the submitted work. Dr Cortés reported receiving personal fees and/or honoraria from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly and Company, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, HiberCell, BioInvent, GEMoaB, Gilead, Menarini, Zymeworks, Reveal Genomics, Novartis, Eisai, Pfizer, Samsung Bioepis, and Expres2ion Biotechnologies outside the submitted work; receiving grants to the institution from Roche, ARIAD Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai, F. Hoffmann–La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, PIQUR Therapeutics, Puma Biotechnology, and Queen Mary University of London outside the submitted work; and having patents for pharmaceutical combinations of a Pi3k inhibitor and a microtubule destabilizing agent and for ERBB2 as a predictor of response to dual ERBB2 blockade in the absence of cytotoxic therapy. Dr Lüftner reported receiving personal fees from Samsung during the conduct of the study and from AstraZeneca, Novartis, Amgen, Pfizer, Daiichi Sankyo, onkowissen, high5md, Gilead, Eli Lilly and company, Samsung Bioepis, Roche, GSK, and L’oréal outside the submitted work. Dr Lyman reported receiving research grants to the institution from Amgen and personal fees from Sandoz, G1 Therapeutics, BeyondSpring, Samsung Bioepis, ER Squibb, Merck, Jazz Pharma, Teva, Fresenius Kabi, AstraZeneca, Partners Healthcare, and Seattle Genetics outside the submitted work. Dr Curigliano reported receiving grants from Merck and AstraZeneca and personal fees from Roche, Bristol Myers Squibb, Novartis, Eli Lilly and Company, Pfizer, Seagen, AstraZeneca, Ellipsis, Gilead Sciences, Merck, Celcuity, Sanofi, Exact Sciences, and Daiichi Sankyo outside the submitted work. Dr Im reported receiving grants from the Samsung Bioepis SB3 Clinical Trial Fund during the conduct of the study; research funding to the institution from AstraZeneca, Boryung, Daewoong, Daiichi Sankyo, Eisai, Pfizer, and Roche; grants from AstraZeneca, Eisai, Daewoong, Pfizer, Roche, Daiichi-Sankyo, and Boryung; and personal fees from Amgen, Eli Lilly and Company, Hanmi, MSD, Novartis, GSK, AstraZeneca, Bertis, Eisai, Pfizer, Daiichi-Sankyo, and Roche outside the submitted work. Dr Litwiniuk reported receiving personal fees from Samsung Bioepis during the conduct of the study; personal fees from Eli Lilly and Company, Amgen, Novartis, Pfizer, and Gilead Sciences outside the submitted work; and travel grants from Egis and Gilead Science outside the submitted work. Dr Ho reported receiving grants from Eli Lilly and Company, AB Science, Astellas, Tessa Therapeutics, Arcus Biosciences, and Janssen Research & Development; grants and nonfinancial support from Regeneron; grants and personal fees from MSD, Roche, AstraZeneca, Pfizer Novartis, and Boehringer Ingelheim; nonfinancial support and personal fees from Ipsen and Bristol Myers Squibb; nonfinancial support from Taiho; and personal fees from Pfizer outside the submitted work. Dr Kislov reported receiving grants from Samsung during the conduct of the study; grants from AstraZeneca, EMD Serono, Roche, MSD, GlaxoSmithKline, Ipsen, Novartis, Pfizer, Nektar, and Eli Lilly and company; and personal fees from BIOCAD, AstraZeneca, and Janssen. Dr Jin Seok Ahn reported receiving personal fees from Roche Korea, Menarini Korea, Pfizer, Boehringer Ingelheim, Kyowa Kirin, Amgen Korea, Yuhan, AstraZeneca Korea, Bayer Korea, Takeda, Novartis Korea, Hanmi, BC World, ImmuneOncia, Pharmbio Korea, YooYoung, Vifor Pharma, and BIXINK outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
SB3 indicates trastuzumab biosimilar and TRZ, reference trastuzumab.
Figure 2.
Figure 2.. Event-Free Survival and Overall Survival During and After Treatment With Trastuzumab Biosimilar (SB3) or Reference Trastuzumab (TRZ)
Tick marks represent censored patients. Hazard ratios (HRs) with corresponding 95% CIs and P values were estimated using a stratified Cox proportional hazards regression model.
Figure 3.
Figure 3.. Event-Free Survival Among Patients Who Achieved Pathological Complete Response in the Breast (bpCR) Compared With Patients Who Did Not
Tick marks represent censored patients. SB3 indicates trastuzumab biosimilar and TRZ, reference trastuzumab.
Figure 4.
Figure 4.. Event-Free Survival and Overall Survival Among Patients Receiving Reference Trastuzumab (TRZ), by Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Status
Tick marks represent censored patients. Hazard ratios (HRs) with corresponding 95% CIs and P values were estimated using a stratified Cox proportional hazards regression model. ADCC status was assigned based on occurrence of downward drift of TRZ during the neoadjuvant treatment period. SB3 indicates trastuzumab biosimilar.
See this image and copyright information in PMC

Comment in

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