Up to one third of all breast cancers are classified as the aggressive HER2-positive subtype, which is associated with a higher risk of recurrence compared to HER2-negative breast cancers. The HER2 hyperactivity associated with this subtype drives tumor growth by up-regulation of mechanistic target of rapamycin (mTOR) pathway activity and a metabolic shift to glycolysis. Although inhibitors targeting the HER2 receptor have been successful in treating HER2-positive breast cancer, anti-HER2 therapy is associated with a high risk of recurrence and drug resistance due to stimulation of the PI3K-Akt-mTOR signaling pathway and glycolysis. Combination therapies against HER2 with inhibition of mTOR improve clinical outcomes compared to HER2 inhibition alone. Here, we review the role of the HER2 receptor, mTOR pathway, and glycolysis in HER2-positive breast cancer, along with signaling mechanisms and the efficacy of treatment strategies of HER2-positive breast cancer.

https://www.mdpi.com/2072-6694/13/12/2922/pdf

Targeting mTOR and Glycolysis in HER2-Positive Breast Cancer.

HLX02 is an approved biosimilar of trastuzumab. This study aimed to evaluated the efficacy, safety, and immunogenicity of HLX02 compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. This randomized, double-blind, phase III study was conducted at 89 centers in China, the Philippines, Poland, and Ukraine. Eligible patients were randomized (1:1) to receive HLX02 or European Union (EU)-sourced trastuzumab (initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months) in combination with docetaxel intravenously. The primary endpoint was overall response rate up to week 24 (ORR24). Equivalence was declared if the 95% confidence interval (CI) of difference was within ± 13.5%. Safety and immunogenicity were evaluated in patients who received at least one dose of study medication. Between 11 November 2016 and 10 July 2019, a total of 649 patients were enrolled. The ORR24 was 71.3 and 71.4% in the HLX02 (n = 324) and EU-trastuzumab (n = 325) groups, with a difference of − 0.1% (95% CI − 7 to 6.9), which fell entirely in the predefined equivalence margins. No statistically significant differences were observed in all secondary efficacy analyses. Safety profiles and immunogenicity were comparable in HLX02 and EU-trastuzumab groups. In total, 98.8% of patients in each group experienced at least one treatment-emergent adverse event (TEAE), 23.8 and 24.9% experienced serious TEAEs, and 0.6% in each group had antidrug antibodies. Among patients with HER2-positive recurrent or metastatic breast cancer, HLX02 demonstrated equivalent efficacy and similar safety and immunogenicity to reference trastuzumab. Chinadrugtrials.org CTR20160526 (12 September 2016), ClinicalTrials.gov NCT03084237 (20 March 2017), EudraCT 2016-000206-10 (27 April 2017). Trastuzumab is a biologic drug used to treat patients with certain types of breast cancer and stomach cancer. Biosimilars are medications that are almost identical to and indistinguishable from original biologic drugs but usually less expensive and more accessible. The main purpose of this study was to evaluate the efficacy (treatment effects) of HLX02 (trastuzumab biosimilar) compared with reference trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer. Other objectives were to evaluate the safety of HLX02 by monitoring adverse events and assessing its potential to induce antibody production (which can prevent a drug from being effective). Patients with HER2-positive recurrent or metastatic breast cancer were randomly allocated to receive HLX02 (n = 324) or European Union (EU)-sourced trastuzumab (n = 325). Study drugs (HLX02 or EU-trastuzumab) were given intravenously, with an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for up to 12 months. Statistical analyses showed that HLX02 was equivalent to trastuzumab in efficacy evaluations. Adverse events observed in the HLX02 treatment group were consistent with those seen with trastuzumab in the current and previous clinical studies. Additionally, no statistically significant differences were seen in the tendency to stimulate antibody production between the two study drugs. To conclude, HLX02 and reference trastuzumab had similar efficacy and safety profiles. These data support the approval of HLX02 as a trastuzumab biosimilar.

/pdf/efficacy-safety-and-immunogenicity-of-hlx02-compared-with-2o0h0dqj8v.pdf

Efficacy, Safety, and Immunogenicity of HLX02 Compared with Reference Trastuzumab in Patients with Recurrent or Metastatic HER2-Positive Breast Cancer: A Randomized Phase III Equivalence Trial

ABSTRACT Biosimilars play an important role in reducing the burden on patients and increasing the market competition. Biosimilar monoclonal antibodies are currently one of the hotspots of research and development in China with policies support. With the continuous improvement of policies, the enthusiasm for the research and development of biosimilars has increased year by year. The policy requirements in different periods have different degrees of impact on the patent applications of pharmaceutical companies. This review introduces the biosimilar monoclonal antibodies market status and approval process in China, analyzes the patents in this field, and helps pharmaceutical companies protect their intellectual property rights. Graphical Abstract

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2090206?needAccess=true

Biosimilar monoclonal antibodies in China: A patent review

Objectives: Pertuzumab is a monoclonal antibody for the treatment of breast cancer. The aim of this study was to compare the pharmacokinetics, immunogenicity and safety of the test preparation SHR-1309 injecta and the reference preparation Perjeta® in healthy Chinese male subjects. Methods: In this randomized, double-blind, single dose, two-way, parallel bioequivalence trial, a total of 80 qualified Chinese male subjects were selected and randomly divided into two groups. Each subject was intravenously injected with SHR-1309 or Perjeta®. Blood samples were collected at 21 different time points for pharmacokinetic analysis. In addition, immunogenicity was assessed at 5 different time points. The safety of the medication was monitored throughout the whole trial. Results: Cmax and AUC0-t were the primary pharmacokinetic parameters. Under a 90% confidence interval, their geometric mean ratios were 98.30% and 88.41% for SHR-1309 injection and Perjeta®, respectively. The geometric mean ratio of secondary pharmacokinetic parameters AUC0-∞ was 88.58%. These evaluation indexes are in the standard range of 80% - 125%, so SHR-1309 can be considered bioequivalent to Perjeta®. After 1680 h (day 70)c of administration, the two groups had 12 and 13 subjects who produced antidrug antibody (ADA), respectively. The occurrence time and proportion of ADA in SHR-1309 and Perjeta® were similar between subjects, and they had similar immunogenicity. During the entire trial period, there were 71 drug-related adverse reactions in 29 subjects who received SHR-1309 and 61 drug-related adverse reactions in 32 subjects who received Perjeta®. The incidence of adverse reactions between the two drugs was similar. Conclusions: The pharmacokinetic parameters, immunogenicity and safety of the biosimilar SHR-1309 injection produced by Shanghai Hengrui Pharmaceutical Co. Ltd. were similar to the original drug Perjeta® produced by Roche Pharma AG. The two drugs met the bioequivalence evaluation criteria. Therefore, SHR-1309 is bioequivalent to Perjeta®. Clinical trial registration: CTR20200738

/pdf/pharmacokinetics-immunogenicity-and-safety-study-for-shr-1wuqp5ja1t.pdf

Pharmacokinetics, Immunogenicity and Safety Study for SHR-1309 Injection and Perjeta® in Healthy Chinese Male Volunteers

ABSTRACT Background HLX02 is a newly marketed trastuzumab biosimilar in China, but whether its price reflects a potential benefit in terms of its value remains unclear. In addition, the development of biosimilars in China is just beginning, and the state encourages health economic evaluation of newly marketed biosimilars. Methods Based on the previously published randomized controlled trial data, a Markov model was used to perform health economic evaluation of HLX02 and trastuzumab in the treatment of HER2-positive recurrent or metastatic breast cancer, calculate quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER), and evaluate the robustness of the model with sensitivity analysis. Results The model results showed that the 5-year mortality rate was 84.4% in the HLX02 group, while the mortality rate was 91.2% in the trastuzumab group. When without accounting for the cost of second-line treatment, patients treated with HLX02 had an increased life expectancy of 0.138 QALYs and a $421.11 lower cost compared with patients in the trastuzumab group, with an ICER value of -$3,051.52/QALY. Conclusions At the willingness-to-pay threshold of $37,653/QALY in China, HLX02 is more cost-effective than trastuzumab. However, the relevant systems for the regulation of biosimilars still need to be improved. Plain Language Summary Metastatic HER-2 positive breast cancer poses a considerable cost to society due to limitations in health care resources. HLX02 is the first trastuzumab biosimilar produced in China and evaluated worldwide, and its emergence has opened the door to trastuzumab biosimilars in China. Although HLX02 has been shown to be clinically equivalent to the original drug in the treatment of metastatic HER2-positive breast cancer, it remains unclear whether its price reflects the potential benefit in terms of its value. In addition, the development of biosimilars in China is just beginning, and the state encourages health economic evaluation of newly marketed biosimilars. Based on the results of Markov model, at the willingness-to-pay threshold of $37,653/QALY in China, HLX02 is more cost-effective than trastuzumab under the condition of equivalent efficacy and safety. However, it remains challenging to adjust the development of the regulation of biosimilars, such as the price difference between biosimilars and original drugs.

Trastuzumab biosimilar HLX02 versus reference trastuzumab in patients with recurrent or metastatic HER2-positive breast cancer: a model-based economic evaluation for China

This study evaluated the bioequivalence of China-manufactured biosimilar, HLX02, to reference China (CN)- and European Union (EU)-sourced trastuzumab. This was a two-part Phase 1 study conducted in healthy Chinese males. Part 1 evaluated the safety of different doses of HLX02 (2, 4, 6 or 8 mg/kg; intravenous infusion over 90 min, n = 3 per group). Part 2, a randomized, double-blind study, investigated the pharmacokinetics (PK), safety and immunogenicity of study drugs (HLX02 [n = 37], CN-trastuzumab [n = 35] or EU-trastuzumab [n = 37] at the dose suggested by Part 1 results). The primary PK endpoint was the area under the serum concentration–time curve from time 0 to infinity (AUCinf). Equivalence was concluded if the 90% confidence interval (CI) for the geometric least squares mean ratio (GLSMR) fell in the equivalence criteria of 0.80–1.25. In Part 1, all doses of HLX02 were well tolerated and 6 mg/kg was suggested for Part 2. The GLSMRs and 90% CIs for AUCinf were: 0.950 (0.891–1.013), 0.914 (0.858–0.973) and 0.962 (0.902–1.025) for HLX02 versus CN-trastuzumab, HLX02 versus EU-trastuzumab and CN-trastuzumab versus EU-trastuzumab, respectively. Secondary endpoints comparisons also fell in the equivalence criteria. Treatment-emergent adverse events were reported in 75.7, 86.5 and 70.3% of the subjects in HLX02, CN-trastuzumab, and EU-trastuzumab groups, respectively. No serious adverse events or deaths occurred. No treatment-related anti-drug antibodies were detected. This study demonstrated comparable safety profiles and PK bioequivalence among HLX02, CN-trastuzumab and EU-trastuzumab in healthy Chinese male subjects. ClinicalTrials.gov, NCT02581748, registered at October 19, 2015.

A Phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX02 to reference CN- and EU-sourced trastuzumab in healthy subjects

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

S Liu

Author Tools

Chat about Author

Papers

A Phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX02 to reference CN- and EU-sourced trastuzumab in healthy subjects