{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:11:15Z","timestamp":1789049475480,"version":"build-2803163510"},"reference-count":31,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>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).<\/jats:p><\/jats:sec>Objective<\/jats:title>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.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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.<\/jats:p><\/jats:sec>Interventions<\/jats:title>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.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>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).<\/jats:p><\/jats:sec>Results<\/jats:title>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\u2009=\u2009186; TRZ, n\u2009=\u2009181). 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\u2009=\u2009267; TRZ, n\u2009=\u2009271]). No difference was observed in EFS or OS between treatment groups (EFS: hazard ratio [HR], 0.84; 95% CI, 0.58-1.20; P<\/jats:italic>\u2009=\u2009.34; OS: HR, 0.61; 95% CI, 0.36-1.05; P<\/jats:italic>\u2009=\u2009.07). 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.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT02771795<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.5822","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T15:03:45Z","timestamp":1680793425000},"page":"e235822","source":"Crossref","is-referenced-by-count":13,"title":["Cardiac Safety and Efficacy of SB3 Trastuzumab Biosimilar for ERBB2-Positive Early Breast Cancer"],"prefix":"10.1001","volume":"6","author":[{"given":"Xavier","family":"Pivot","sequence":"first","affiliation":[{"name":"Institut de Canc\u00e9rologie Strasbourg Europe, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Cort\u00e9s","sequence":"additional","affiliation":[{"name":"International Breast Cancer Center, Pangaea Oncology, Quir\u00f3nsalud Group, Barcelona, Spain"},{"name":"Scientific Department, Medica Scientia Innovation Research, Valencia, Spain"},{"name":"Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"L\u00fcftner","sequence":"additional","affiliation":[{"name":"Campus R\u00fcdersdorf, Immanuel Hospital M\u00e4rkische Schweiz and Medical University of Brandenburg Theodor Fontane, R\u00fcdersdorf bei Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary H.","family":"Lyman","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Research Center, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Curigliano","sequence":"additional","affiliation":[{"name":"European Institute of Oncology, IRCCS, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor M.","family":"Bondarenko","sequence":"additional","affiliation":[{"name":"Dnipropetrovsk City Multi-Field Clinical Hospital #4, Dnipropetrovsk, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hee","family":"Ahn","sequence":"additional","affiliation":[{"name":"Asan Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seock-Ah","family":"Im","sequence":"additional","affiliation":[{"name":"Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Litwiniuk","sequence":"additional","affiliation":[{"name":"Greater Poland Cancer Centre and Poznan University of Medical Sciences, Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaroslav V.","family":"Shparyk","sequence":"additional","affiliation":[{"name":"Lviv State Oncological Regional Therapeutical and Diagnostic Center, Lviv, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwo Fuang","family":"Ho","sequence":"additional","affiliation":[{"name":"University Malaya Medical Centre, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay V.","family":"Kislov","sequence":"additional","affiliation":[{"name":"State Budgetary Healthcare Institution of Yaroslavl Region, Regional Clinical Oncology Hospital, Yaroslavl, Russian Federation"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Wojtukiewicz","sequence":"additional","affiliation":[{"name":"Bialostockie Centrum Onkologii im. Marii Sk\u0142odowskiej-Curie, Bialystok, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Sarosiek","sequence":"additional","affiliation":[{"name":"LUX MED Onkologia, Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yee Soo","family":"Chae","sequence":"additional","affiliation":[{"name":"Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Seok","family":"Ahn","sequence":"additional","affiliation":[{"name":"Samsung Medical Center, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyerin","family":"Jang","sequence":"additional","affiliation":[{"name":"Samsung Bioepis, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujung","family":"Kim","sequence":"additional","affiliation":[{"name":"Samsung Bioepis, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwon","family":"Lee","sequence":"additional","affiliation":[{"name":"Samsung Bioepis, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YeChan","family":"Yoon","sequence":"additional","affiliation":[{"name":"Samsung Bioepis, Incheon, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"issue":"13","key":"zoi230196r1","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1056\/NEJMcibr1909386","article-title":"HER2 and breast cancer\u2014a phenomenal success story.","volume":"381","author":"Hayes","year":"2019","journal-title":"N Engl J Med"},{"issue":"20","key":"zoi230196r2","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.1200\/JCO.2013.53.9288","article-title":"Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01).","volume":"32","author":"de Azambuja","year":"2014","journal-title":"J Clin Oncol"},{"issue":"13","key":"zoi230196r3","doi-asserted-by":"publisher","first-page":"1660","DOI":"10.1016\/j.ejca.2015.05.028","article-title":"Cardiac toxicity events in the PHARE trial, an adjuvant trastuzumab randomised phase III study.","volume":"51","author":"Pivot","year":"2015","journal-title":"Eur J Cancer"},{"issue":"25","key":"zoi230196r4","doi-asserted-by":"publisher","first-page":"3859","DOI":"10.1200\/JCO.2006.09.1611","article-title":"Trastuzumab-associated cardiac adverse effects in the Herceptin Adjuvant trial.","volume":"25","author":"Suter","year":"2007","journal-title":"J Clin Oncol"},{"issue":"19","key":"zoi230196r5","doi-asserted-by":"publisher","first-page":"4265","DOI":"10.1200\/JCO.2005.04.173","article-title":"Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 Study Group.","volume":"23","author":"Marty","year":"2005","journal-title":"J Clin Oncol"},{"issue":"21","key":"zoi230196r6","doi-asserted-by":"publisher","first-page":"3422","DOI":"10.1200\/JCO.2009.26.0463","article-title":"Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial.","volume":"28","author":"Procter","year":"2010","journal-title":"J Clin Oncol"},{"issue":"10","key":"zoi230196r7","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1200\/JCO.2017.74.0126","article-title":"Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer.","volume":"36","author":"Pivot","year":"2018","journal-title":"J Clin Oncol"},{"issue":"4","key":"zoi230196r9","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1080\/19420862.2017.1305530","article-title":"Drifts in ADCC-related quality attributes of Herceptin: impact on development of a trastuzumab biosimilar.","volume":"9","author":"Kim","year":"2017","journal-title":"MAbs"},{"key":"zoi230196r10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejca.2019.07.015","article-title":"Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer.","volume":"120","author":"Pivot","year":"2019","journal-title":"Eur J Cancer"},{"issue":"20","key":"zoi230196r11","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1001\/jama.2013.281053","article-title":"World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.","volume":"310","author":"World Medical Association","year":"2013","journal-title":"JAMA"},{"key":"zoi230196r12","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.ejca.2018.01.072","article-title":"A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: final safety, immunogenicity and survival results.","volume":"93","author":"Pivot","year":"2018","journal-title":"Eur J Cancer"},{"issue":"13","key":"zoi230196r13","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/S1470-2045(13)70502-3","article-title":"Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.","volume":"14","author":"Buzdar","year":"2013","journal-title":"Lancet Oncol"},{"key":"zoi230196r14","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.ejca.2016.03.087","article-title":"HannaH phase III randomised study: association of total pathological complete response with event-free survival in HER2-positive early breast cancer treated with neoadjuvant-adjuvant trastuzumab after 2 years of treatment-free follow-up.","volume":"62","author":"Jackisch","year":"2016","journal-title":"Eur J Cancer"},{"issue":"4","key":"zoi230196r15","article-title":"Trastuzumab containing regimens for early breast cancer.","volume":"2012","author":"Moja","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"zoi230196r16"},{"key":"zoi230196r17"},{"issue":"5","key":"zoi230196r18","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.0339","article-title":"Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial.","volume":"5","author":"Jackisch","year":"2019","journal-title":"JAMA Oncol"},{"issue":"6","key":"zoi230196r19","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1016\/S1470-2045(14)70080-4","article-title":"Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort.","volume":"15","author":"Gianni","year":"2014","journal-title":"Lancet Oncol"},{"issue":"9938","key":"zoi230196r20","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/S0140-6736(13)62422-8","article-title":"Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.","volume":"384","author":"Cortazar","year":"2014","journal-title":"Lancet"},{"key":"zoi230196r22","doi-asserted-by":"publisher","DOI":"10.1177\/17588359211059587","article-title":"Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects.","author":"Gion","year":"2021","journal-title":"Ther Adv Med Oncol"},{"issue":"2","key":"zoi230196r23","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/S1470-2045(18)30002-0","article-title":"A new era for treatment development in HER2-positive breast cancer.","volume":"19","author":"Pivot","year":"2018","journal-title":"Lancet Oncol"},{"issue":"11","key":"zoi230196r24","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1200\/JCO.2007.14.8957","article-title":"Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2\/neu-positive metastatic breast cancer.","volume":"26","author":"Musolino","year":"2008","journal-title":"J Clin Oncol"},{"issue":"3","key":"zoi230196r25","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1001\/jamaoncol.2016.4884","article-title":"Association of polymorphisms in FCGR2A and FCGR3A with degree of trastuzumab benefit in the adjuvant treatment of ERBB2\/HER2-positive breast cancer: analysis of the NSABP B-31 Trial.","volume":"3","author":"Gavin","year":"2017","journal-title":"JAMA Oncol"},{"key":"zoi230196r26","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003171"},{"issue":"4","key":"zoi230196r29","first-page":"698","article-title":"Biosimilar monoclonal antibodies: preclinical and clinical development aspects.","volume":"34","author":"Gon\u00e7alves","year":"2016","journal-title":"Clin Exp Rheumatol"},{"issue":"4","key":"zoi230196r30","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/s11523-020-00742-w","article-title":"Biologic drug quality assurance to optimize HER2?+?breast cancer treatment: insights from development of the trastuzumab biosimilar SB3.","volume":"15","author":"L\u00fcftner","year":"2020","journal-title":"Target Oncol"},{"issue":"4","key":"zoi230196r31","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1002\/cncr.v128.4","article-title":"Disparities in cardiovascular disease mortality after breast cancer treatment: methodological considerations using real-world data.","volume":"128","author":"Calip","year":"2022","journal-title":"Cancer"},{"key":"zoi230196r27"},{"key":"zoi230196r8","unstructured":"European Medicines Agency. CHMP assessment report: Ontruzant (trastuzumab biosimilar). 2018. Accessed July 22, 2021. https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/ontruzant"},{"key":"zoi230196r21","unstructured":"US Food and Drug Administration. Pathological complete response in neoadjuvant treatment of high-risk early-stage breast cancer: use as an endpoint to support accelerated approval; guidance for industry; availability. Federal Register. October 7, 2014. Accessed June 9, 2022. https:\/\/www.federalregister.gov\/documents\/2014\/10\/07\/2014-23845\/pathological-complete-response-in-neoadjuvant-treatment-of-high-risk-early-stage-breast-cancer-use"},{"key":"zoi230196r28","unstructured":"US Food and Drug Administration. Development of therapeutic protein biosimilars: comparative analytical assessment and other quality-related considerations; draft guidance for industry; availability. Federal Register. May 22, 2019. Accessed June 9, 2022. https:\/\/www.federalregister.gov\/documents\/2019\/05\/22\/2019-10667\/development-of-therapeutic-protein-biosimilars-comparative-analytical-assessment-and-other"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2803254\/pivot_2023_oi_230196_1680032310.39636.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T15:03:51Z","timestamp":1680793431000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2803254"}},"subtitle":["Secondary Analysis of a Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":31,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.5822","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}