In a recent study published in the BMJ Journal, a team of scientists from China investigated the safety and efficacy of treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with pyrotinib, a pan-HER inhibitor, in combination with docetaxel and trastuzumab, and compared it to that of a variety of a placebo, docetaxel, and trastuzumab.
Study: Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial. Image Credit: Sai Thaw Kyar/Shutterstock.com
Approximately 20% of all breast cancers are characterized by the over-expression of HER-2, which results in a more aggressive form of disease, a higher probability of metastasis, and an overall poor prognosis.
Recent research has been focused on developing agents that target HER-2 through various mechanisms, which has brought about significant improvements in many of the clinical outcomes in breast cancer patients who are HER-2 positive.
Evidence from various studies also indicates that using two agents targeting HER-2 through differing mechanisms of action has proven more effective than using just one anti-HER-2 agent.
Previous studies have shown that using monoclonal antibodies that target HER-2, such as trastuzumab and pertuzumab, combined with docetaxel, had significantly improved the progression-free survival rate.
Pyrotinib is a tyrosine kinase inhibitor that irreversibly targets HER-2, HER-4, and epidermal growth factor receptors, and the irreversible nature of its mechanism of action could result in sustained HER-2 inhibition.
About the study
The present study conducted a double-blinded, randomized, multicenter phase 3 clinical trial to assess the safety and efficacy of using pyrotinib with docetaxel and trastuzumab to treat metastatic HER-2 breast cancer. They compared it against a combination of a placebo, trastuzumab, and docetaxel.
Females between the ages of 18 and 75 with metastatic or recurrent breast cancer that was HER-2 positive, confirmed through histological tests such as immunohistochemistry or in situ hybridization, were eligible for the trial.
The participants had to be naive to any systemic anti-tumor medication for metastatic or recurrent breast cancer and have a minimum of one lesion that was measurable based on the Response Evaluation Criteria in Solid Tumors classification.
The patients were randomly assigned to the treatment or placebo groups and received 400 mg of pyrotinib or placebo, respectively, along with intravenous docetaxel and trastuzumab.
Loperamide hydrochloride was prescribed for the intervention or prevention of diarrhea during the treatment. The treatment was discontinued in cases of unacceptable toxicity, disease progression, mortality, consent withdrawal, or based on the investigator’s decision.
Computed tomography (CT) or magnetic resonance imaging (MRI) was used to assess the tumors at baseline, every nine weeks during the first 18 months, and after that every 12 weeks.
Additionally, laboratory assessments, vital sign monitoring, 12 lead electrocardiographs, and echocardiography were conducted during the evaluations. Adverse reactions to the treatment were also recorded and graded.
Progression-free survival assessed by the investigator was the primary examined outcome. In contrast, the secondary endpoints were evaluated by an independent review committee of progression-free survival, objective response date, clinical benefit rate, duration of response, safety, and overall survival.
The treatment efficacy was examined in all the randomized patients. In contrast, the safety profile of the treatment was evaluated in all the patients who received at least one dose of the treatment.
The results indicated that pyrotinib, in combination with docetaxel and trastuzumab, was effective in increasing the progression-free survival rate of patients with untreated, HER-2-positive breast cancer.
The safety assessments indicated that the toxicity of the drug was manageable. The median value for progression-free survival for the pyrotinib treatment group was significantly longer than that of the placebo group.
The current standard of care treatment for HER-2-positive breast cancer is pertuzumab with docetaxel and trastuzumab, for which the progression-free survival is 18.7 months. The primary and secondary endpoints reported a two-year increase in progression-free survival for treatment with a combination of pyrotinib with docetaxel and trastuzumab.
Using a small molecule intracellular HER-2 inhibition mechanism, such as pyrotinib, along with the extracellular antibody trastuzumab, showed strong HER-2 inhibition ability.
The safety profile indicated that diarrhea was the most common adverse reaction to the drug, and most of the events were in grades one or two. Furthermore, the use of loperamide hydrochloride was effective in controlling the diarrhea.
The grade three adverse events in the study were attributed to the hematological adverse reactions due to docetaxel use, which were controlled with leukopoietic agents.
Overall, the findings from this grade three clinical trial indicated that the use of pyrotinib, in combination with docetaxel and trastuzumab, improved the progression-free survival for HER-2 positive breast cancer patients significantly, as compared to the placebo, with trastuzumab and docetaxel.
The toxicity of the treatment also appeared to be manageable, with grade one or two diarrhea being the most reported adverse reaction.