HLX02, a trastuzumab biosimilar developed and manufactured by Shanghai Henlius Biotech, a Chinese biotech company, achieved similar overall response rate (ORR) to reference trastuzumab (Herceptin®; Roche) in women with human epidermal growth factor receptor 2-positive (HER2+) recurrent or previously untreated metastatic breast cancer.
This conclusion is based on study results of a large, randomized, phase III clinical trial presented during the European Society for Medical Oncology (ESMO) Asia Congress 2019, held November 22 – 24, 2019 in Singapore. 
The investigational agent was also the first fully-humanized anti-HER2 monoclonal antibody, manufactured in China, accepted for Marketing Authorization Application (MAA) review by the European Medicines Agency (EMA).
Following the MAA acceptance by the EMA earlier this year, Scott Liu, co-Founder, President and Chief Executive Office at Henlius Biotech, noted: “[This milestone] shows that our clinical, medical, regulatory affairs and quality system capabilities have been internationally recognized.”
“Trastuzumab is not widely accessible around the world due to its high cost. The entry of more affordable versions of trastuzumab such as HLX02 could open up treatment access,” said study first author, Professor Binghe Xu, MD, Ph.D, Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China.
The anti-HER2 antibody trastuzumab given in combination with chemotherapy has significantly improved overall survival in patients with HER2-positive breast cancer and become the standard of care over the past decade. However, the cost can limit patient access to this treatment in regions with limited financial resources for healthcare. 
The development of biosimilars, which are medicinal products containing a similar version of the active substance of their biological originator or reference product and are derived from living organisms, offers a way of improving access to cancer treatments by increasing treatment options and reducing cost. 
The new study randomized women with HER2-positive breast cancer to HLX02, a fully humanised anti-HER2 that was developed in China as a trastuzumab biosimilar, or to reference trastuzumab sourced from the European Union.
“Overall response rate at week 24 was similar for HLX02 and reference trastuzumab with no statistical difference observed between the two treatment groups,” reported Xu. The rates of adverse events and treatment emergent adverse events were similar for HLX02 and reference trastuzumab and there were no differences in safety profiles or immunogenicity.
“HLX02 is equally safe and effective as the reference trastuzumab and has been rigorously evaluated by regulatory authorities such as the European Medicines Agency (EMA), based on sound scientific principles,” said Xu. He added, “HLX02 has a clear potential to drive down spending on HER2+ cancer treatment,” although he said, “…the price has not yet been agreed.”
“The development of biosimilars is important both for patients, by improving access to cancer drugs, and for health systems, allowing cost savings that can be re-invested in patient care and support the sustainability of healthcare systems,” said Rosa Giuliani, Consultant Medical Oncologist, Clatterbridge Cancer Centre, in Liverpool, United Kingdom.
Giuliani further noted that other trastuzumab biosimilars have been approved in Europe. “The potential approval of China-produced HLX02 would add a further option,” she added.
“[However] access to cancer medicines is a huge problem throughout the world, applying to relatively inexpensive medicines but even more to more expensive drugs such as monclonal antibodies,” Giuliani warned.
“A survey carried out by ESMO in 2016 and the subsequent follow-up study showed that many patients in different countries, including Europe, have difficulty in accessing cancer medicines. What is even more astonishing is that this includes medicines listed in the World Health Organization’s (WHO) Essential Medicines List, such as trastuzumab,” she said.
“It is not acceptable that medicines which have shown to have a major impact on patients survival are not given to patients in need. Biosimilars are safe and effective drugs which can finally allow those patients to receive an appropriate standard of care,” Giuliani concluded.
“The development of biosimilars means that more women will have access to potentially life-saving HER2-targeted therapies because of the cost-savings they provide,” noted Rebecca Dent, Head of Medical Oncology at the National Cancer Center Singapore.
“Development of biosimilars introduces competition and potentially lowers the price of drugs,” Dent said.
“As more biosimilar therapies are being developed there is also a need for vertical integration of the biomarkers that identify patients who will benefit,” she added.
“For trastuzumab biosimilars this means ensuring access to HER2 status testing,” Dent observed.
Reviewing the quality of the study design, Dent considered it important that the clinical program with HLX02 was developed in consultation with the EMA and the China National Medical Products Administration (NMPA). The interim results of the study have been submitted to the NMPA and EMA to support approval of HLX02 in China and Europe.
The phase III study randomized 649 women with HER2+ recurrent or previously untreated metastatic breast cancer to the investigational trastuzumab biosimilar HLX02 or to the reference drug, trastuzumab (Herceptin®) sourced in the European Union (dose of 8mg/kg for both drugs) with docetaxel on day 1. Cycle 1 was followed by a dose of 6mg/kg in three-weekly cycles for up to 12 months.
The women were recruited from 89 centers in China, the Philippines, Poland and Ukraine.
Result showed similar overall response rate at 24 weeks with HLX02 (71.0%) as with EU sourced trastuzumab (71.4%, p=0.952). The risk difference in overall response rates between the two groups was -0.4% (95% confidence interval [CI] -7.4, 6.6), which was within the predefined margin (+13.5%).
All secondary endpoints, including overall response rates at weeks 6, 12 and 18, clinical benefit rate, disease control rate, duration of response, progression-free survival and overall survival at week 24 were similar for HLX02 and EU-sourced trastuzumab. The disease control rate was 83.0% in the HLX02 group and 84.3% in the reference trastuzumab group (p=0.646). The median progression-free survival with HLX02 was 11.7 months compared to 9.69 months with trastuzumab (p=0.079).
In each treatment group 98.8% of the patients reported at least one adverse event or treatment emergent adverse event and a similar number of adverse events were reported in the two treatment groups. There were no differences in safety profiles or immunogenicity between HLX02 and reference trastuzumab.
The overall study conclusion is that the phase III trial of HLX02 met primary endpoint in the treatment of patients with breast cancer.
The clinical trial program for HLX02 was developed in consultation with China National Medical Products Administration (NMPA) and European Medicines Agency (EMA) for global development. Previously, the researchers reported clinical pharmacokinetic (PK) equivalence of HLX02 at the ESMO-ASIA 2018 meeting.
- Compare Efficacy, Safety and Immunogenicity of HLX02 and Herceptin in Previously Untreated HER2 +Overexpressing Metastatic Breast Cancer – NCT03084237
- A Safety and Pharmacokinetic Study Between HLX02 and Herceptin® (U.S. and German) in Healthy Chinese Male Subjects – NCT02581748
 Xu B, Zhang Q, Sun T, Li W, Teng Y, Hu X, Bondarenko I, Adamchuk H, et al. ‘First China-manufactured ’ will be presented will be presented during the Proffered paper session – Breast cancer, Saturday 23 November 2019, 09:00-10:30 SGT, Hall 405. Annals of Oncology, Volume 30, 2019 Supplement 9. Abstract LBA6
 Lammers P, Criscitiello C, Curigliano G, Jacobs I. Barriers to the use of trastuzumab for HER2+ breast cancer and the potential impact of biosimilars: a physician survey in the United States and emerging markets. Pharmaceuticals 2014; 7: 943-953.
 ESMO Biosimilar Portal. European Society for Medical Oncology (ESMO). Online. Last accessed November 22, 2019.
 ESMO Understanding biosimilars for cancer patients. European Society for Medical Oncology (ESMO). Online. Last accessed November 22, 2019.
 Cherny N, Sullivan R, Torode J, Saar M, Eniu A. ESMO European Consortium Study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in Europe. Ann Oncol. 2016;27(8):1423–1443. doi:10.1093/annonc/mdw213 [Pubmed]