Prof. Igor Bondarenko: Metastatic breast cancer is a global cause of death in women. There are an estimated 2 million people diagnosed with breast cancer yearly with the mortality of about 71，300 people due to its pathology. High expression or amplification of the human epidermal growth factor receptor 2 (HER2) defines a distinct group of breast cancers， accounting for approximately 20% worldwide and resulting in more aggressive disease associated with poor prognosis. However， the tumour dependence on HER2 has also provided a target treatment. Thanks to the modern medications like trastuzumab， a humanised monoclonal antibody binding to a portion of the HER2， which became a real breakthrough over the last 15 years. While trastuzumab therapy has converted the unfavourable natural history of HER2-positive breast cancer into favourable clinical outcomes， the metastatic disease still remains incurable for most patients and approximately 50% of patients experience disease progression within 1 year of therapy for their advanced disease.

 

Although trastuzumab was initially evaluated and used in the first-line metastatic setting， it has become a common practice to continue trastuzumab therapy at progression， which improves patient outcomes. However， the use of trastuzumab has significant cost implications for patients and health care systems. That is why we participated in this HLX02-BC01 study， as well as other studies evaluating biosimilars with the potential of 3~5 times lower treatment price of cost savings. Personally， I’ve seen this Phase 3 blinded results of the investigator evaluation on the overall response rate for the two treatment groups (docetaxel in combination with either the standard treatment or the Henlius investigational product， HLX02) which were considerably similar. I would like to say my congratulations to our partners in China， and great achievement with positive results from this trial. 

 

Prof. Xu: The introduction of trastuzumab in combination with chemotherapy has significantly improved clinical outcomes for patients with HER2-positve breast cancer; however， its high manufacturing cost has driven up prices resulting in limited access to this effective therapy. HLX02 was developed as a biosimilar of Herceptin® in consultation with China NMPA and EMA to support global development. Following the stepwise clinical approach for the development of biosimilar， we previously reported the clinical PK and safety bioequivalence between HLX02， EU-sourced trastuzumab and CN-sourced trastuzumab. 

 

At this ESMO conference， we report the multi-national， randomised， double-blind Phase 3 study investigating the efficacy and safety profiles of HLX02 and EU-sourced trastuzumab in combination with docetaxel in HER2-overexpressing recurrent or previously-untreated metastatic breast cancer has met the primary endpoint of best overall response rate (ORR) after eight cycles of therapy (Week 24， ORR₂₄). We also report the results of the interim analysis including secondary efficacy endpoints of CBR， DCR， DoR， PFS， OS， and safety outcome 

 

 

 

Prof. Xu: Sure. The use of HLX02 compared with EU-sourced trastuzumab results in an equivalent ORR at week 24. The primary outcome was ORR， which was 71.0% (HLX02) and 71.4% (EU-sourced trastuzumab) with no statistical difference observed (p=0.952) between the groups， and the ORR difference (-0.4; 95% CI: -7.4% to 6.6%) was also within the predefined margin (13.5% and -13.5%). With no new safety signals in comparison with EU-sourced trastuzumab， all secondary efficacy and safety analyses supported the biosimilarity of HLX02 and reference trastuzumab. 

 

The positive results of the interim analysis supported the NDA and MAA submissions to China NMPA and EMA， respectively. HLX02 is the first China-manufactured trastuzumab biosimilar which developed in accordance with NMPA and EMA guidelines and maybe the first potential Chinese biosimilar being approved outside of China.

Prof. Igor Bondarenko: I think it is important to mention that this Phase 3 trial has employed the randomised and double-blind study design with high international good clinical practice (GCP) - International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) standards for evidence-based medicine. We know the primary outcome was ORR at week 24， which was approximately 71.0% in both treatment groups. The primary efficacy results from this study are quite similar to the ORR at week 25 (62.5% for PF-05280014 group; 66.5% for Herceptin group) in the Trazimera’s Pfizer study and the ORR at week 24 (69.6% for MYL-1401O group; 64.0% for Herceptin group) in the Ogivri’s Mylan study， which are the two recent trastuzumab biosimilar studies in metastatic breast cancer. At my clinic， I enrolled 22 patients into the study and we do not observe any differences between the two treatment groups in general.

 

It is my understanding that the submission of the marketing authorisation application (MAA) with the results from this interim analysis has been accepted by the European Medicines Agency (EMA) for review. And maybe I don’t know the details， but I know that Henlius has also filed new drug application of HLX02 in China and received priority review by the NMPA. Therefore， the results from this study are good news to many patients and countries， not only China， because access to trastuzumab might be limited for various reasons in different country， such as lack of drug funding or treatment costs. 

 

 

Prof. Xu: We know that great progress has been made in the treatment of HER2-positive breast cancer， but there are still many patients who are unable to get adequate treatment because of the high drug prices. During the development of NCCN guidelines， the committee was asked to develop them in a cost-insensitive manner. The committee was supposed to come up with what they thought to be the best clinical care. But if the same exact high-quality clinical care could be delivered at a lower cost， it’s going to allow for continued innovation and improvement in the marketplace. The extremely high prices of most biological products have forced to look for alternative options such as the development of biosimilar products. 

 

A biosimilar is highly similar to and has no clinically meaningful differences in safety and efficacy from the reference product. The availability of safe and effective trastuzumab biosimilar HLX02 may improve access to this critical therapy. Furthermore， HLX02 may generate savings for healthcare systems， particularly because HER2-targeted drugs may be administered for extended periods of time and in combination with other systemic therapies. The availability of HLX02 may address the unmet needs of patients and clinicians.

 

Prof. Igor Bondarenko: You know there’s no need for all of the patients to be treated with either biosimilar or originator. Physicians might decide not to prescribe the originators in situations where such medications have regulatory approval but they are not funded or reimbursed. Reimbursement of anti-HER2 therapy also varies across Europe， which might create disparities in accessing trastuzumab. That’s why NCCN presented their position on biosimilars couple years ago， not only for Chinese but for patients worldwide. I had participated in eight biosimilar studies in breast cancer， lung cancer， lymphoma. To date， results from some of these trials have only been disclosed at international oncology congresses and these biosimilars are highly similar to the reference products. The regulatory framework for biosimilars provides a more tailored pathway for approval compared with the originators that relies on a rigorous assessment of similarity. I believe that HLX02 will bring positive impact on clinical practice based on the results from this study that both HLX02 and the reference trastuzumab are highly similar. As a result， HLX02 might provide a lower-cost alternative to the reference trastuzumab and has the potential to generate cost savings.

 

 

Prof. Xu: HLX02 is the first and only potential Chinese trastuzumab biosimilar being approved by EMA. Clinicians need to understand what are biosimilars and how to incorporate HLX02 in a way that continues to add value to their patients and provide optimum care. Initiating treatment with an approved trastuzumab biosimilar is as safe and effective as initiating treatment with the reference product. However， questions have been raised about switching between a reference product and its biosimilar or between biosimilars of the same reference product， although no issues have been identified thus far with switching from a reference product to its biosimilar. Henlius plans to conduct post-marketing surveillance study addressing the impact of switching between reference product to HLX02.

 

Prof. Igor Bondarenko: Over the last few years， biosimilars have generated great interest worldwide as effective alternatives to the reference biologics. Biosimilars have been integral to clinical practice in the European Union for almost a decade. Several trastuzumab biosimilars have also recently approved in Europe. In Ukraine， we may not be at the front lines in research but we assist in the development of biosimilars for other companies and we paid attention to the many companies from Korean， China and so on. These biosimilars are highly similar to the originator products “notwithstanding minor differences in clinically inactive components and have no clinically meaningful differences in safety， purity or efficacy compared with the reference products”. The introduction of a lower-cost biosimilar such as HLX02 to my country could make trastuzumab cost-effective and support decisions for drug funding and reimbursement， thereby improving patient access to HER2 therapy for treatment of HER2-positive breast cancer.

 

So， what can I also remember about this study (HLX02-BC01) - the important note is that Henlius is really reaching very high international standards. This is a study involving many centres in China， Ukraine， Philippines and Poland. Our research staff have done excellent job strictly adhering to high international standards in the design and implementation of the study. I believe that this study carried out at such high GCP/ICH standards may also meet the market approval requirements from European and other countries.

 

 

 

专家简介

 

徐兵河

主任医师、教授、博士后/博士生导师

国家癌症中心/中国医学科学院肿瘤医院内科

国家新物（抗肿瘤药）临床研究中心主任

中国抗癌协会乳腺癌专业委员会前任主任委员

中国抗癌协会肿瘤药物临床研究专业委员会主任委员

国家肿瘤质控中心乳腺癌专家委员会主任委员

国家癌症中心“中国乳腺癌筛查与早诊早治指南”专家委员会主任委员

中国医师协会内科医师分会副会长

中国老年医学学会老年肿瘤分会副会长

北京乳腺病防治学会理事长

北京肿瘤学会副理事长兼秘书长 

St.Gallen早期乳腺癌治疗国际共识专家团成员

晚期乳腺癌（ABC）治疗国际共识指南专家团成员

 

Igor Bondarenko

乌克兰DNIPropetrovsk医学科学院肿瘤科主任

Bondarenko教授是乌克兰最大的肿瘤研究机构DNIPropetrovsk医学科学院的PI，并担任该院肿瘤学和医学放射学系主任。Bondarenko教授及其领导的研究团队已参与了355项临床试验，所在的研究中心曾17次入选全球最佳研究机构。Bondarenko教授及团队的主要研究旨在评估实体瘤个体化治疗方法的疗效，以及生物标记物指导的靶向药物使用，尤其关注免疫治疗、免疫相关并发症的预防和治疗。Bondarenko教授在众多国际知名期刊杂志发表315篇论文及专著。H指数为42。作为乌克兰被引频次最高的科学家，Bondarenko教授于2016年被汤森路透授予科学网络奖“乌克兰科学家”。Bondarenko教授是ASCO、ESMO、皇家医学会（英国）、USSO（乌克兰）的成员