Academician Xu Binghe: The road to advancement of biosimilar drugs - Hanquyou International Multi-center Phase III Clinical Trial HLX02-BC01 announced the 3-year OS results.

Academician Xu Binghe: The road to advancement of biosimilars - Hanquyou (trastuzumab) international multi-center phase III clinical trial HLX02-BC01 announced the 3-year OS outcome

Editor's note: For applied biosimilars The long-term survival benefit and safety of drugs are always the most concerned issues for most patients and clinicians. The international multi-center phase III clinical trial of Hanquyou® (trastuzumab) HLX02-BC01 (Clinical Trial No. : NCT03084237; European Clinical Trial Number: 2016-000206-10) The final analysis results-3-year overall survival rate (OS) were officially announced recently. Prior to this, the interim analysis results of the study had been published in Biodrugs, an established and authoritative journal in the field of biopharmaceuticals. This time, "Tumor Outlook" specially invited to interview Academician Xu Binghe, the leader of this international multi-center clinical trial. I hope that through this interview, I can not only introduce the Phase III clinical trial and final results of Hanquyou® to everyone, but also provide more clinicians and patients with more confidence in the use of trastuzumab biosimilars, and give more confidence to Hanquyou®. The clinical application prospects of Quyou® describe a clear path.

01

"Tumor Outlook": Hanquyou® is the first "Chinese and European double batch" Chinese trastuzumab biosimilar drug. As the leading expert in the phase III clinical trial of this drug, can you learn from the protocol design of this study? Let me introduce from an angle why it has been approved for marketing by the two major drug regulatory authorities of China's NMPA and Europe's EMA at the same time?

Academician Xu Binghe: Trastuzumab has always attracted much attention in the industry due to its significant anti-tumor effect and high initial price. With the improvement of my country's industrial innovation capabilities and technological levels, the national drug regulatory authorities have vigorously supported the research and development of biosimilars, with a focus on trastuzumab biosimilars, in an effort to improve drug accessibility and ultimately achieve affordable prices. medicine to benefit patients. In fact, there are many domestic companies planning to develop trastuzumab biosimilars, but only Hanquyou® Phase III clinical trial HLX02-BC01 is designed as a randomized, double-blind, international multi-center study, which fully illustrates The applicant company targeted the international market and benchmarked against international standards at the beginning of research and development.

HLX02-BC01 participating research centers are located in 89 medical centers in China, the Philippines, Poland, and Ukraine, among which 57 centers are located in China. This study aims to evaluate Hanquyou® and trastuzumab commercially available in Europe (EU- Efficacy, safety, and immunogenicity of trastuzumab in patients with HER2-positive recurrent or metastatic breast cancer who have not received systemic therapy. Since biosimilars need to be compared with reference drugs to see if they are similar, the study was designed for equivalence. After screening, a total of 649 subjects were enrolled. This is also the largest clinical study of biosimilar drugs in HER2-positive breast cancer in China. The subjects were randomly divided into two groups according to the ratio of 1:1, and were given intravenous injection of Hanquyou® combined with docetaxel or EU-trastuzumab combined with docetaxel (initial dose: 8 mg/kg, Subsequent injections of 6 mg/kg every three weeks until 12 months). The primary endpoint of the study was overall response rate (ORR24w) at 24 weeks, and other indicators were evaluated as secondary study endpoints (Figure 1).

▵ Figure 1. Trial design of the Phase III clinical study of Hanquyou® (HLX02)

Many experts have been confused in the early days about why EU-trastuzumab was chosen as the reference drug and why ORR24w was chosen as the main research endpoint. But this is precisely the finishing touch of this research in laying out the international market. Regarding the selection of the primary endpoint, since the purpose of biosimilar clinical trials is to identify the difference in clinical efficacy between the candidate drug and the reference drug, it is necessary to select the most sensitive indicator as the primary endpoint.After joint consultation with the two major drug regulatory authorities of China's NMPA and Europe's EMA, it was unanimously recommended to use the objective response rate (ORR), which directly reflects the activity of the drug, as the most sensitive indicator of late-stage first-line research design, that is, the primary research endpoint, and tumor The commonly used efficacy endpoints in clinical trials of new drugs, such as progression-free survival (PFS) and overall survival (OS), are not the most sensitive indicators and are evaluated as secondary endpoints.

EU-Trastuzumab was selected as the reference drug because the European Pharmacopoeia strictly prohibits the addition of antibacterial preservatives to parenteral infusions. Therefore, the trastuzumab used in the European market is different from that in my country. Its specification is 150mg, and It does not contain 1.1% benzyl alcohol diluent, so in order to meet the domestic and foreign clinical trial review requirements at the same time, the more stringent EU-trastuzumab was selected as the reference drug in this study. Therefore, the above experimental design reflects Hanquyou®’s preparations for “going overseas”.

02

"Tumor Outlook": Can you introduce to everyone the research results of HLX02-BC01? Clinical experts are more concerned about long-term survival data. Regarding the 3-year OS rate data released this time, do you think it can eliminate the doubts of clinical experts?

Academician Xu Binghe: The research results have been published or presented at international academic conferences many times. The subgroup analysis results of HLX02-BC01 were presented for the first time at the 2019 CSCO conference, and the efficacy and safety data of the trial drug for 24 weeks were reported at the 2019 ESMO conference and ESMO Asia conference. At the 2020 ESMO Congress, the study's effectiveness, safety data and population pharmacokinetic data with a one-year follow-up were further disclosed. In addition, the study’s clinical benefit rate (CBR), disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS) were also presented at the 12th European Breast Cancer Congress (EBCC) in 2020. ) published on. In April 2021, Biodrugs, an old and authoritative magazine in the field of biopharmaceuticals, published the primary endpoint, secondary endpoint and safety data of the study.

The results showed: The 24-week objective response rates (ORR24w) of the Hanquyou® group (n=324) and the EU-Trastuzumab group (n=325) were 71.3% and 71.4% respectively, and the difference between the groups was -0.1% (95% confidence interval: -7%, 6.9%), completely within the preset equivalent range (±13.5%). No statistically significant differences were observed between the two treatment groups in all secondary efficacy endpoint assessments. At the 24th week of treatment, the proportion of patients in the Hanquyou® group and the EU-trastuzumab group showed CR (5.2% vs. 3.7%) or PR (66% vs. 67.7%) (Table 1). Median DoR (10.61 months vs. 10.22 months: HR=0.79; P=0.103) and median PFS (11.73 months vs. 10.55 months: HR=0.83; P=0.086) were not statistically significant between the two groups. learning differences. After 2 years of follow-up, the median OS of the Hanquyou® group has not been reached, and the median OS of the EU-trastuzumab group is 28.5 months (HR=0.85, P=0.388). The safety and immunogenicity results of Hanquyou® and EU-Trastuzumab were similar, and 0.6% (2 cases) of patients in each group were positive for anti-drug antibodies. The study results fully prove that Hanquyou and the original trastuzumab have similar efficacy and safety in recruited patients with HER2-positive recurrent or metastatic breast cancer from various regions around the world.

Table 1. Objective tumor response rate after 8 cycles of treatment in the Hanquyou® (HLX02) and EU-trastuzumab groups (ITT analysis set)

This time, we used the Tumor Outlook platform to announce the follow-up of HLX02-BC01 3 Final analysis results at year : Median DoR (10.61 months vs. 10.25 months: HR=0.86; P=0.262) and median PFS (11.73 months) in the Hanquyou® group and the EU-Trastuzumab group Month vs. 10.55 months: HR=0.86; P=0.158) is not much different from before, and there is no statistical difference (Figure 2). The 3-year OS rates of Hanquyou® and EU-Trastuzumab were 57.5% vs. 54.0% respectively, P=0.229, with no significant statistical difference (Figure 3, Table 2).

▵ Figure 2. Investigator-assessed progression-free survival (PFS) Kaplan-Meier curve

▵ Figure 3. Investigator-assessed overall survival (OS) Kaplan-Meier curve

Table 2. Hanquyou® (HLX02) Comparison of OS results with the EU-trastuzumab group

Based on the above amazing research results, compared with the EU-trastuzumab group, Hanquyou® has no clinically significant clinical efficacy, safety and immunogenicity. difference in meaning. In July and August 2020, Hanquyou® was approved for marketing in the EU and China, becoming the first domestically produced monoclonal antibody biosimilar in double batches in China and Europe, kicking off China's biopharmaceutical R&D achievements by benchmarking the quality of international standards. A new chapter in internationalization. We believe that both the main efficacy indicators and the long-term survival indicators are sufficient to support Hanquyou® as an affordable and high-quality new treatment option in the field of HER2-positive breast cancer.

03

"Tumor Outlook": In an environment where many relevant policies to encourage the research and development of biosimilar drugs have been introduced, more biosimilar drugs will enter clinical use in the future. What do you think of biosimilar drugs today and tomorrow?

Academician Xu Binghe: Biological agents occupy a pivotal position in tumor treatment. However, due to the difficulty of research and development, high technical barriers, and large investment in such drugs, the price of biological agents is high. Therefore, a considerable number of Patients cannot afford the high cost of biologic drugs. In October 2017, the General Office of the State Council issued the "Opinions on Deepening the Reform of the Review and Approval System to Encourage Innovation in Drugs and Medical Devices" which mentioned that in order to improve the accessibility of medicines to the public, it is required to improve relevant research and evaluation technical guidance principles and support biosimilars. Drug research and development. Therefore, the state has been encouraging powerful companies to develop biosimilars for biological drugs whose patents have expired, so as to break the dominance of the original drug from the source, promote drug price reduction, improve drug accessibility, and truly solve the problem of Livelihood issues. After the first true biosimilar drug was approved for sale in China in 2019, 21 monoclonal antibody biosimilar drugs independently developed and produced in China have been approved so far, which fully confirms the country’s strong support for the research and development of biosimilar drugs. .

The rapid development of biosimilar drugs has also promoted the improvement of relevant national regulations. In order to better meet the clinical needs of patients, the State Food and Drug Administration actively absorbs international biosimilar drug research and development experience and refers to the most authoritative European EMA and U.S. FDA drug review standards recognized internationally to provide scientific research and development of biosimilar drugs in my country. The evaluation has also formulated technical guidance suggestions. Since the Center for Drug Evaluation (CDE) of the State Food and Drug Administration issued the "Technical Guiding Principles for R&D and Evaluation of Biosimilar Drugs (Trial)" in 2015, CDE has issued 15 guiding principles, including Including guidance documents such as the "Clinical Trial Guidelines for Trastuzumab Biosimilars for Injection" that are customized based on the characteristics of a single drug, making the research and development of biosimilars more standardized and benchmarking international quality and services. to the majority of patients.

Complete regulations ensure the quality of products, so biosimilars are quickly accepted by major authoritative guidelines after they are approved. Taking trastuzumab biosimilars as an example, Hanquyou® was launched in my country in August 2020. In October of the same year, the National Cancer Center for Quality Control Breast Cancer Expert Committee, the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association and the China The "China Standardized Diagnosis and Treatment Guidelines for Advanced Breast Cancer (2020 Edition)" jointly formulated by the Anti-Cancer Association's Oncology Drug Clinical Research Professional Committee has written biosimilar drugs into the guideline, clearly supporting the use of biosimilar drugs with relevant domestic approved indications and New drug used to treat breast cancer. The following year, whether it was the Breast Cancer Diagnosis and Treatment Guidelines (2021 Edition) and Gastric Cancer Diagnosis and Treatment Guidelines (2021 Edition) formulated by the Chinese Society of Clinical Oncology (CSCO), or the Breast Cancer Diagnosis and Treatment Guidelines and Standards (2021 Edition) formulated by the Chinese Anti-Cancer Association (CACA) 2021 edition), also included trastuzumab biosimilars in the guidelines and standardized their clinical application.The updates of these guidelines are also in line with international trends. Both the American NCCN and the European ESMO have also clarified in the corresponding guidelines that biosimilars and original drugs have the same scope of indications. I believe that the objective recommendations from clinical guidelines will increase the confidence of doctors and patients in their use.

Xu Binghe

Academician of the Chinese Academy of Engineering

Medical oncology expert, permanent professor of Peking Union Medical College, doctoral supervisor

Former director of the Internal Medicine Department of the Cancer Hospital of the Chinese Academy of Medical Sciences

Currently a national new drug (anti-tumor) clinical research Center Director

National Oncology Chairman of the Breast Cancer Expert Committee of the Quality Control Center

Chairman of the National Anti-tumor Drug Clinical Monitoring Expert Committee

Chairman of the Cancer Drug Clinical Research Professional Committee of the Chinese Anti-Cancer Association

Honorary Chairman of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association

China Medical Education Association Chairman of the Oncology Clinical Research Innovation and Development Professional Committee

Vice President of the Physician Branch of the Chinese Medical Doctor Association

Chairman of the Beijing Breast Disease Prevention and Treatment Society