On January 25, 2022, the full text of the research results of pirrotinib combined with capecitabine in the treatment of BRAIN metastases in HER2-positive breast cancer, led by Professor Yan Min of Henan Provincial Cancer Hospital, was officially published online in the international authoritative medical journal Lancet Oncology (Impact Factor 41.32). The results of the study showed that pirrolidinib combined with capecitabine was well tolerated and effectively inhibited both intracranial and external lesions, particularly in patients with previously untreated brain metastases [1].
This study is a prospective study of the efficacy and safety of pyrrolotinib combined with capecitabine in all ENROLLed patients with HER2-positive breast cancer brain metastases, and is also a prospective clinical study in Chinese patients divided into two independent cohorts for analysis and comparison according to the previous local treatment of breast cancer brain metastases, which brings new enlightenment for the clinical treatment of breast cancer brain metastases and individualized decision-making.
In the era of trastuzumab-based therapy, there are still about 30 to 50 percent of people with epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer who develop brain metastases [2-5], resulting in a poor prognosis. At present, the treatment of brain metastases is mainly based on local treatment, including surgical resection, stereotactic radiotherapy and whole brain radiotherapy. However, the recurrence rate remains high within 6 to 12 months after topical therapy, and adverse effects such as cognitive decline [6] pose a huge challenge to clinical treatment.
The PERMEATE study is a multicenter, single-arm, double-cohort, phase II clinical study conducted in 8 centers nationwide to study the efficacy and safety of pirrolidinib combined with capecitabine in the treatment of brain metastasis in HER2-positive breast cancer. Professor Yan Min, the principal investigator of the PERMEATE study, said: "Breast cancer treatment in mainland China must guide clinical practice according to the characteristics of disease development and clinical diagnosis and treatment in the national population. This is also the most important significance of initiating the mainland's independent research and development of innovative drug pirratinib combined with capecitabine in the treatment of HER2-positive breast cancer brain metastasis phase II. The results suggest that pirrolidinib combined with capecitabine regimen is effective in controlling both intracranial and extracranial lesions for brain metastases in HER2-positive breast cancer, especially in patients who have not previously received local brain radiotherapy. Pyrrolidinib is expected to become a new treatment option for her2-positive brain metastases in China, and is expected to provide a systematic treatment option for patients who need to postpone topical treatment. ”
It is understood that the PERMEATA study began in January 2019, enrolling a total of 78 patients with HER2-positive breast cancer brain metastases with intracranial measurable lesions, of which 69 cases had previously received treatment for trastuzumab. According to the previous local treatment of the lesions of the central nervous system, it was divided into - cohort A: brain metastases without local radiotherapy (N =59); cohort B: patients with brain metastases who progressed again after local radiotherapy (N=19). Both received treatment with pirlotinib (400 mg, qd, po) combined with capecitabine (1000 mg/m2, bid, po, d1-14, q3w). The primary endpoint was the objective response rate (CNS ORR) for lesions of the central nervous system. Results Showed that the objective response rate (CNS ORR) of CNS lesions in Cohort A was as high as 74.6% (95% CI: 61.6 to 85.0), of which 7 patients (11.9%) achieved complete response (CR). The objective response rate (CNS ORR) for cns nervous system lesions in cohort B was 42.1% (95% CI: 20.3 to 66.5). Secondary endpoint results showed that in 31 patients with simultaneous extracranial measurable lesions, the objective response rates (Non-CNSORR) of non-central nervous system lesions in both cohorts were 70.4% and 50%, respectively. Median follow-up was 15.7 months, and median disease-free survival (PFS) in cohort A and cohort B was 11.3 months (95% CI: 7.7 to 14.6) and 5.6 months (95% CI: 3.4 to 10.0), respectively [1]. In terms of safety, diarrhea and hand-foot syndrome are the most common adverse events and are generally tolerated and controlled.
Figure: Results of primary endpoint CNS-ORR (cohort A 74.6%, cohort B42.1%) and secondary endpoint PFS (cohort A 11.3 m, cohort B 5.6 m).
The PERMEATA study was presented in the 2020 European Society of Internal Medicine Oncology (ESMO) conference and the 2021 American Society of Clinical Oncology (ASCO) annual meeting, receiving widespread attention from domestic and foreign experts. Today, the clinical research results have been honored in the international authoritative academic journal "Lancet Oncology", showing the affirmation of the international academic community.
Pyrrolidinib is an oral epidermal growth factor receptor (HER1)/human epidermal growth factor receptor 2 (HER2)/human epidermal growth factor receptor 4 (HER4) tyrosine kinase inhibitor independently developed by Hengrui Pharmaceutical and has intellectual property rights, which is the original HER1/HER2/HER4 targeted drug. In 2018, pirroltinib was conditionally approved for listing by the State Food and Drug Administration (NMPA) with Phase II clinical research data, which is an innovative drug in the field of solid tumors that has been conditionally approved for marketing with Phase II clinical research. In 2019, pyrroltinib was included in national health insurance, greatly improving accessibility and affordability. In 2020, pirroltinib was fully approved for marketing by the State Food and Drug Administration with the results of two important Phase III studies (PHENIX and PHOEBE). At present, piroctinib is also conducting a number of clinical studies covering breast cancer, lung cancer, biliary tract cancer and other tumors, and continues to explore treatment options for different stages of different diseases to benefit more Chinese patients.
bibliography:
[1] Yan M, Ouyang Q, Sun T, et al. Pyrotinib pluscapecitabine for patients with human epidermal growth factor receptor2-positive breast cancer and brain metastases (PERMEATE): a multicentre,single-arm, two-cohort,phase 2 trial. Lancet Oncol 2022; published online Jan24. https://doi.org/10.1016/S1470-2045(21)00716-6
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