Recently, the Chinese Breast Cancer Society Breast Cancer Diagnosis and Treatment Guidelines (2024 Edition) (hereinafter referred to as the CBCS Guidelines) has been updated and released. As one of the most important and authoritative Chinese diagnosis and treatment norms in the field of breast cancer, the CBCS Guidelines follow the international pace and cutting-edge progress, and comprehensively summarize and elaborate on breast cancer screening, examination, diagnosis and treatment, and reporting. In this guideline recommendation, two new indications for Hengrui Pharmaceuticals' innovative drugs have been added, which are the first-line treatment regimen of piretinib combination for HER2-positive metastatic breast cancer, and the first- and second-line treatment regimen of dalsirib for HR-positive HER2-negative metastatic breast cancer (MBC). Thus, both innovative drugs have been recommended by the 2024 CBCS guidelines for the marketed breast cancer indications.

Breast cancer has become the number one malignant tumor worldwide and is one of the most common malignant tumors in women. Statistics show that there will be approximately 2,261,000 newly diagnosed cases of female breast cancer worldwide in 2020, accounting for 24.5% of all new cases of malignant tumors in women.The HER2 molecule is an independent predictor of poor prognosis in breast cancer, and with HER2-positive breast cancers accounting for approximately 20-25% of all cases and a single drug of choice, there is a huge unmet clinical need for clinical applications.HR positive/HER2-negative breast cancer is the most common subtype, accounting for 65-70% of all breast cancers.

Piratinib is an oral HER1, HER2, HER4 tyrosine kinase inhibitor (TKI) independently developed by Hengrui and with intellectual property rights, and is the first self-developed anti-HER1/HER2/HER4 targeting drug in China.In 2018, Piratinib was conditionally approved for marketing by the State Drug Administration by virtue of its Phase II clinical study, and is the first innovative drug in China in the field of solid tumors to be conditionally approved for marketing by virtue of its Phase II clinical study. It is the first innovative drug in the field of solid tumors in China to be approved for marketing with conditions by virtue of Phase II clinical study. Currently, pivoxil has been approved for marketing in China for three breast cancer indications. Among them, the combination of capecitabine for the treatment of HER2-positive recurrent or metastatic breast cancer treated with trastuzumab, and the combination of trastuzumab and docetaxel for the neoadjuvant treatment of HER2-positive early-stage or locally-advanced breast cancer patients have been recommended by the CBCS guidelines.

This time, pyrrolitinib in combination with trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic breast cancer (MBC) was included as a recommended regimen in the 2024 CBCS guideline based on the results of a randomized controlled, multicenter, double-blind phase III PHILA study: the combination regimen had a significant PFS benefit and manageable safety profile, with a median progression-free survival (mPFS) of 24.3 months, breaking the two-year median progression-free survival. The results of this study were presented as an oral presentation at the European Society of Medical Oncology (ESMO) in 2022[8] and published in October 2023 in the prestigious journal British Medical Journal (BMJ; impact factor: 105.7).

The PHILA study is closer to the current clinical practice in China than the trastuzumab dual-targeted CLEOPATRA study [9]: more trastuzumab-treated patients; and larger Chinese population data from late-stage first-line studies. Based on the excellent results of this study, in April 2023, the National Medicines Control Administration (NMPA) approved piretinib in combination with trastuzumab and docetaxel for the first-line treatment of HER2-positive advanced breast cancer, which is the third indication for which piretinib has been approved in China, and is the first dual-targeted combination of receptor tyrosine kinase inhibitors (TKIs) combined with a large molecule antibody drug approved for the treatment of advanced breast cancer in China. It is also the first dual-target combination of a receptor tyrosine kinase inhibitor (TKI) and a large molecule antibody drug approved in China for the treatment of advanced breast cancer.

In addition, this program has been jointly recommended as a new first-line treatment option by three authoritative domestic guidelines, namely, China Advanced Breast Cancer Standardized Diagnosis and Treatment Guidelines (2022 Edition), China Anti-Cancer Association Diagnosis and Treatment Guidelines (2022 Abstract Edition), and CSCO Breast Cancer Diagnostic and Treatment Guidelines (2023), and has already been included in the 2023 National Health Insurance Catalog.

Dalsiris is a highly selective small molecule CDK4/6 inhibitor independently developed by Hengrui Pharmaceuticals. it was approved for marketing in December 2021 for the treatment of HR-positive, HER2-negative recurrent or metastatic breast cancer that has progressed after endocrine therapy in combination with fulvestrant, bringing a new option to Chinese breast cancer patients. in June 2023, Dalsiris was approved for a second indication, in combination with an aromatase inhibitors as initial treatment for HR-positive, HER2-negative patients with locally advanced or metastatic breast cancer.

This new version of the guideline adds dalsirib to the CDK4/6 inhibitor choices as a recommended regimen for first- and second-line treatment of HR-positive HER2-negative MBC.

The approval of the above indications was based on two late-stage randomized, double-blind phase III clinical studies of dalsirib, DAWNA-1 and DAWNA-2. The DAWNA-1 study [13] enrolled 361 HR-positive HER2-negative locally advanced or metastatic Chinese breast cancer patients who had relapsed or progressed on prior endocrine therapy and who had received ≤1 line of chemotherapy in late-stage, and who were randomized 2:1 to receive dalsirib or placebo combined with fulvestrant treatment. The results showed that the study-assessed PFS, the primary endpoint, was significantly prolonged in patients in the dalsirib group compared with the placebo group, 15.7 months vs. 7.2 months (HR=0.42).The DAWNA-2 study [14] enrolled 456 late-stage, non-systemic-treatment-naïve HR-positive HER2-negative locally advanced or metastatic Chinese breast cancer patients, aiming to validate the efficacy and safety of dalsiris in combination with letrozole or anastrozole. The study results showed a median PFS of up to 30.6 months in the Dalcieli group, compared to 18.2 months in the placebo combination group, reducing the risk of disease progression or death by 49%.

The enrollment population of the DAWNA series of studies is more in line with the clinical practice in China: the peak age of onset of disease is earlier than that in Western countries, the age of patients with advanced disease at the time of first diagnosis is younger, and the majority of patients are not yet menopausal at the time of diagnosis, which brings a suitable and effective new option for Chinese breast cancer patients. The two studies have been published as oral presentations at ASCO 2021 and ESMO 2022, and the full text was published in the top academic journals Nature Medicine (IF:82.9) and Lancet Oncology (IF:51.1).

Domestic innovative drugs have shown good efficacy and safety, and have an irreplaceable role in improving the accessibility of drugs to Chinese patients. Piratinib and Dalcicli were developed with the hope of solving the problem of drug accessibility for Chinese patients.

As an anti-HER2 TKI, piretinib is recommended in the CBCS guidelines across early, late first-line and late second-line. Dalsiris, as the first Chinese self-developed CDK4/6 inhibitor, is also currently the leading CDK4/6 inhibitor in China in terms of late-stage indication coverage. Currently, all indications for which piretinib and dalsirib have been listed are fully covered by health insurance, further reducing the financial burden for breast cancer patients. The two innovative drugs are still continuing to explore new indications, new drug combinations, and new safety optimization solutions, with a view to striving to create a Chinese solution for the whole management of Chinese breast cancer patients.

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