Recently, a phase II, non-randomized study of brain radiotherapy combined with pyrrolitinib and capecitabine for the treatment of brain metastasis in HER2-positive breast cancer (BROPTIMA study) was published online in JAMA Oncology, an authoritative international oncology journal (IF: 28.4). Prof. Guo Xiaomao and Prof. Yu Xiaoli of the Affiliated Cancer Hospital of Fudan University are the co-corresponding authors of this article, and Prof. Yang Zhaozhi and Prof. Meng Jin are the co-authors. The results of this study showed that the one-year central nervous system-progression-free survival (CNS-PFS) rate for combination therapy reached 74.9%, with a median CNS-PFS of up to 18 months and a central nervous system-objective remission rate (CNS-ORR) of 85%. In terms of safety, with a median follow-up of 17.3 months, the neurological status of most patients remained stable.

This is the first prospective clinical study exploring pyrrolitinib in combination with brain radiotherapy for the treatment of patients with HER2-positive breast cancer brain metastases, which provides informative clinical data for the treatment of patients with breast cancer brain metastases, especially those with neurological-related symptoms who are in urgent need of radiotherapy, and radiotherapy in combination with pyrrolitinib is expected to serve as a new treatment option for such patients.

The incidence of brain metastasis in advanced breast cancer is on the rise, mainly due to the improvement of systemic treatment of breast cancer and the prolongation of patients' survival; in addition, the application of brain magnetic resonance examination has helped to detect more asymptomatic patients with brain metastasis.The risk of brain metastasis for HER2-positive patients with breast cancer is relatively high, with up to 50% of patients developing brain metastasis. The general principle of brain metastasis treatment is to prioritize surgery and/or radiotherapy for brain metastases with adequate assessment of the systemic situation. For HER2-positive patients with manageable local symptoms, radiotherapy can be postponed with close magnetic resonance imaging (MRI) follow-up, prioritizing the use of anti-HER2 therapeutic agents with central activity.

Piratinib, an oral HER1, HER2, HER4 tyrosine kinase inhibitor (TKI) independently developed by Hengrui Pharmaceuticals and with intellectual property rights, is the first self-developed anti-HER1/HER2/HER4 targeting agent in China, and has been shown to have encouraging efficacy in patients with brain metastases that have not been previously treated with local therapy or that have progressed after local therapy in the PERMEATE study. However, there are no clear data on the efficacy of radiotherapy in combination or sequential systemic therapy for a subset of patients who are unable or unsuitable for deferred radiotherapy.

The BROPTIMA study fills this gap and aims to explore the efficacy and safety of local radiotherapy in combination with pyrrolitinib and to confirm whether the combination regimen further reduces the risk of intracranial disease progression. The study has been presented as an oral presentation of key data in October 2023 at the 65th Annual Meeting of the American Society for Radiation Oncology (ASTRO).

A single-center, single-arm, Phase II clinical study, the BROPTIMA study enrolled 40 patients with HER2-positive MRI-confirmed brain metastases from breast cancer. Compared with the PERMEATE study, the patients enrolled in this study had a more severe brain lesion profile: 75% of patients had neurologic symptoms at baseline, 30% had more than four brain lesions, 62.5% had the largest lesion in the brain with a diameter greater than 2 cm; and 52.5% had received prior systemic therapy during metastatic disease.

Enrolled patients were treated with radiotherapy combined with piretinib (400 mg, qd) and capecitabine (1000 mg/m2, bid, d1-14, q3w) according to the protocol. Among the radiotherapy regimens, whole-brain radiotherapy or fractionated stereotactic radiotherapy was selected by the investigators based on the size and number of brain metastases and the location of the parenchymal brain lesions.

The primary study endpoint of one-year CNS-PFS rate of 74.9% was achieved, which exceeded the preset. The median CNS-PFS reached 18.0 months and the CNS-ORR reached 85%, demonstrating a favorable outcome of the combined regimen of local therapy + systemic therapy. Along with effective control of intracranial lesions, piretinib also demonstrated effective remission of extracranial lesions, with an overall median PFS of 17.6 months.

In terms of safety, the combination of radiotherapy did not significantly increase the adverse effects of piretinib and capecitabine, and the overall safety profile was consistent with data from previous studies. Using the Brief Mental Status Examination (MMSE) in order to specifically assess neurocognitive function, the majority of patients' neurocognitive function remained stable during follow-up during treatment. It was shown that this combination regimen does not cause significant impairment of central nervous system function.

The BROPTIMA study represents the industry's recognition of piretinib as a highly rated international journal for its findings in patients with brain metastases from breast cancer, following the PERMEATE study, which was published in Lancet Oncology in 2022, and ASCO 2023, which published a median follow-up of 42 months of overall survival (O months of overall survival (OS) results, with a median OS of up to 36 months for patients with brain metastases from breast cancer previously untreated with localized therapy.

In addition, the efficacy of piretinib in patients with brain metastases has been repeatedly validated in real-world or retrospective data [6-12]. Based on these findings, the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Diagnosis and Treatment Guidelines, the Chinese Anti-Cancer Association (CACA) Breast Cancer Diagnosis and Treatment Guidelines, and the Chinese Guidelines for the Standardized Diagnosis and Treatment of Advanced Breast Cancer have all endorsed pivozitinib as a therapeutic option for patients with brain metastases of HER2-positive breast cancer.The BROPTIMA study has further solidified the clinical evidence, which is an important guideline for clinical practice. important guidance for clinical practice.

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