preface
On January 25, 2022, Beijing time, the full text of the research results of pirolactinib 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 (IF=41.32). The results of this study show that pirrolidinib combined with capecitabine is well tolerated and effectively inhibits both intracranial and extraterrestrial lesions, particularly in patients with previously untreated brain metastases [1]. Professor Yan Min was invited to share the PERMEATE study.
This study is the first prospective study to report the efficacy and safety of pyrrolotinib combined capecitabine in all PATIENTS WITH HER2-positive breast cancer brain metastases, and the first prospective clinical study in Chinese patients divided into two independent cohorts for analysis and comparison based on 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, brain metastases still occur in approximately 30 to 50 percent of patients with HER2-positive metastatic breast cancer [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: "The study can be recognized by the international top journals, mainly answering the practical problems that need to be solved urgently in the clinic, and bringing a glimmer of light to breast cancer brain metastase patients in the treatment dilemma, which is also the significance of initiating this clinical study." "The findings suggest that for brain metastases in HER2-positive breast cancer, pirroltinib plus capecitabine regimens are effective in controlling both intracranial and extracranial lesions, especially in patients who have not previously received local brain radiotherapy." Pyrrolidinib is expected to be the preferred treatment option for people with HER2-positive brain metastases in China, and is expected to provide a systematic treatment option for patients who need to postpone topical therapy. ”
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.
Pirrolidinib is the first original EGFR/HER2/HER4-targeted drug in China. In 2018, pirlotinib was conditionally approved for listing by the State Food and Drug Administration (NMPA) with phase II clinical research data, which is the first innovative drug in China in the field of solid tumors to be 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.
Brain metastases from breast cancer are the second most common cause of brain metastases, and their incidence is second only to non-small cell lung cancer. Can you please talk about the characteristics of breast cancer brain metastases and the current diagnosis and treatment status? What are the urgent problems to be solved in clinical practice?
Professor Yan Min
Henan Provincial Cancer Hospital
The available data show that the incidence of brain metastasis in breast cancer is second only to non-small cell lung cancer, among which the incidence of brain metastasis in breast cancer patients with different molecular subtypes is different, and the incidence of brain metastasis in HER2-positive and triple-negative breast cancers is relatively higher.
At present, the treatment of breast cancer brain metastases includes brain surgery, brain radiotherapy, drug therapy and symptomatic supportive therapy, and the standard treatment of new brain metastases recommended by major guidelines is still the priority local treatment (including surgery and/or radiation therapy for brain lesions), and only her2 small molecule TKI drugs can be given priority for her2 small molecule TKI in patients with a limited number of brain metastases and asymptomatic HER2 positive patients.
In recent years, the treatment of HER2-positive advanced breast cancer has made great progress, and the survival time of patients with recurrent metastatic breast cancer has been significantly prolonged, but due to the existence of the blood-brain barrier, the efficacy of drug therapy on breast cancer brain metastases is far less than that of extracranial lesions, and the intracranial objective response rate (ORR) of most regimens is limited. It is also for this reason that it has become clinical practice to give priority to local treatment for patients with new brain metastases.
Brain radiotherapy is efficient for brain metastasis, local control is fast, and has a pivotal position in brain metastases treatment, but radiotherapy also has limitations, that is, exceeding the standard dose, may bring irreversible trauma to the patient's brain, so the lifelong dose of brain radiotherapy is limited, on the other hand, conventional dose radiotherapy also has different degrees of cognitive and memory loss and other side effects, so it can delay the progression of brain lesions and delay the timing of whole brain radiotherapy Drug treatment programs have become the expectations of clinical experts; the advantages of head surgery, It is that it can quickly relieve the symptoms of tumor compression and the risk of cerebral edema and cerebral herniation, but also due to the limitations of invasiveness, non-reproducibility and multi-lesion lesions, and lesions that are too risky for surgery, it cannot meet the treatment needs of all patients with brain metastases.
Therefore, more effective treatment methods are needed to break through the bottleneck of "further prolonging survival under the premise of ensuring quality of life". Continuous exploration of effective drug treatment options for brain metastases has become a feasible research direction. The drug can only achieve the desired efficacy if it meets two conditions at the same time: on the one hand, it is highly effective for breast cancer, and on the other hand, it is highly permeable to the blood-brain barrier.
The PERMEATE study, published by you and your team in Lancet Oncology, is the first prospective clinical study of pirrolidinib in patients with brain metastases. Can you give us a brief overview of the context in which you and your team conducted this research?
Research on the treatment of breast cancer brain metastases has been exploring, and the results have been unsatisfactory, until the LANDSCAPE study published at LEMONT ONCOLOGY in 2013, which achieved very impressive results, capecitabine combined with lapatinib in 45 patients with new active brain metastases in HER2-positive breast cancer, and the effective rate of intracranial lesions (CNS-ORR) reached 57.1%, median
Progression-free survival (PFS) 5.5 months. Therefore, in the 2014 ASCO HER2-positive breast cancer and brain metastases guidelines, while local treatment is recommended as the standard recommendation, the recommendation of "for patients with HER2-positive breast cancer brain metastases, capecitabine plus lapatinib treatment can also be preferred", and the ASCO guidelines were updated in 2018, and there is no new progress in brain metastase drug treatment.
The PERMEATE research idea is derived from two clinical studies in which we are participating, one is the Pirroltinib Phase III PHENIX study led by Professor Jiang Zefei (enrollment period is From September 26, 2016 to November 16, 2017), randomized pirlotinib and capecitabine compared to placebo combined with capecitabine; the other is the randomized, controlled, open, Phase III PHEOBE study (enrollment period November 10, 2017 – October 17, 2018), randomized pirratinib plus capecitabine verrapatinib plus capecitabine. Among them, the PHENIX study allowed the enrollment of asymptomatic brain metastase patients, we enrolled 7 patients with brain metastases, and found that pirratinib combined with capecitabine had a significant tumor reduction effect on brain metastases; from the PHHEBE study that was about to end the enrollment, it was seen that pirrotinib was significantly better than the excellent efficacy of lapatinib.
Based on the above background, we analyzed that capecitabine combined with pyrrolidinib is very promising to bring better benefits to patients with brain metastases in HER2-positive breast cancer, so we launched this prospective phase II single-arm clinical study:
After preliminary preparations, the PERMEATE study was successfully registered on the clinicaltrails website on November 5, 2018 (registration number NCT03691051), the first patient enrollment began on January 29, 2019, the enrollment was discontinued on July 10, 2020, and then entered the treatment follow-up phase, the data published this time as of April 16, 2021, reporting the main study endpoint CNS-ORR, Key secondary study endpoints such as PFS and safety are currently underway.
I:Can you briefly tell us about the results of the PERMEATE study? How do you see the difference in efficacy between CohortS and Cohort A and B? What benefits or updates to clinical practice will this study bring to patients with brain metastases with HER2-positive breast cancer?
The study designed two separate cohorts, both using a two-phase SIMMONS design, to observe the efficacy of pironib +capecitabine in the treatment of new brain metastases in HER2-positive breast cancer (CohorT A) and patients with brain metastases who progressed after radiotherapy (Cohor B); all patients were required to have no baseline treatment with anti-HER2-TKI drugs and had measurable lesions intracranial; the primary study endpoint was CNS-ORR, and secondary endpoints included median PFS, disease control rate (DCR), Extracranial lesion ORR, safety, etc., were evaluated according to THE RECIST 1.1 standard.
Cohort A enrolled a total of 59 patients with new brain metastases, and cohort B enrolled a total of 19 patients with progression after brain metastases and radiotherapy, and the efficacy of these two groups of patients was independently evaluated. All patients had intracranial measurable lesions, of which 31 patients (27 in A cohort and 4 in B cohort) had extracranial measurable lesions. Intracranial and extracranial ORRs in Cohort A were 74.6% (44/59) and 70.4% (19/27), respectively, and intracranial ORRs in Cohort B were 42.1% (8/19, with 2 of 4 patients with measurable lesions in extracranial areas achieving partial remission. The median PFS for the two queues was 11.3 months and 5.6 months, respectively. The ORR for extracranial lesions was 67.7% (21/31) and median PFS (11.3 months) in patients with new-onset brain metastases, comparable to data from the PHENIX study (68.6% and 11.1 months) and the PHOEBE study (67.2% and 12.5 months).
Figure: Primary endpoints CNS-ORR (cohort A 74.6%, cod., cohort B 42.1%) and secondary endpoint PFS (cohort A 11.3 m, cohort B 5.6 m) results
This study cohort B originally planned to enroll 43 patients, because of the rapid listing of pyrrolidinib and entering medical insurance, most of the brain metastases patients will be treated with pirrolidinib in time, the number of eligible patients is significantly reduced, after half a year without eligible patients, we stopped enrolling, so the evaluation of cohort B is not sufficient. The reason for the difference in efficacy between the two cohorts may lie in the difference in the number of treatment lines on the one hand, and the effect of radiotherapy on the permeability of the blood-brain barrier on the other hand.
The PERMEATE study enrolled patients with active brain metastases and demonstrated that capecitabine plus pirlotinib was equally effective against intracranial and extracranial metastasis in patients with HER2-positive breast cancer (most drugs are significantly less effective than extracranial metastases), making it an important evidence-based evidence to support the preferential choice of capecitabine plus pirrotinib for patients with HER2-positive breast cancer with brain metastases.
As more and more experts recognize that patients with HER2-positive and triple-negative advanced breast cancer regularly undergo brain MRI flat scan + enhanced examination, the proportion of patients with brain metastases who are asymptomatic or symptomatically controllable and do not urgently need local treatment has increased significantly, and they have won the opportunity to give priority to drug therapy, as with extracranial lesions, drug treatment is evaluated every 1-2 months, ineffective patients are timely local treatment, and effective patients can control their condition with long-term drug therapy. Delay the application of local invasive therapy such as radiotherapy or surgery, and after drug treatment is resistant, add local radiotherapy and surgery if necessary, so that patients can survive for a long time under a better quality of life. The "three early" strategies of tumor prevention (early detection, early diagnosis, and early treatment) are also applicable to patients with advanced breast cancer (including brain metastases).
The publication of the PERMEATE study results is expected to enhance the confidence of clinical experts in giving priority to drug therapy for patients with BRAIN metastases in HER2-positive breast cancer, thus further changing the clinical practice of "prioritizing radiotherapy or surgery for patients with brain metastases" in HER2-positive advanced breast cancer. The current clinical study of new drugs for brain metastasis is also expected to add more effective therapeutic drugs to patients with brain metastases, and further consolidate the treatment concept and strategy of "systemic drug treatment is prioritized and local treatment is supplemented".
Expert Profiles
Professor Yan Min
- Department of Breast Medicine, Henan Provincial Cancer Hospital, Deputy Director of Henan Provincial Breast Disease Diagnosis and Treatment Center
- Chief Physician M.D
- Standing Committee Member of Breast Cancer Expert Committee of Chinese Society of Clinical Oncology (CSCO).
- Standing Committee Member of breast disease research center of Chinese Association of Women Physicians
- Standing Committee Member of Breast Cancer Group of oncologist Branch of Chinese Medical Doctor Association
- Standing Committee Member of Tumor Metastasis Professional Committee of China Medical Education Association
- Member of the Expert Committee on Multiple Primary and Unknown Primary Tumors of the Chinese Anti-Cancer Association
- Member of the Expert Committee on Capacity Building and Continuing Education of the National Health Commission
- Vice Chairman of the Breast Science Group of the Precision Medicine and Tumor MDT Professional Committee of the Chinese Society of Research Hospitals
- Vice Chairman of Breast Cancer Expert Committee of Henan Cancer Diagnosis and Treatment Quality Control Center
- Vice Chairman of the Breast Professional Committee of Henan Life Care Association
- Vice Chairman of Breast Disease Management and Innovation Branch of Henan Hospital Association
bibliography:
[1] Yan M, Ouyang Q, Sun T, et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort,phase 2 trial. Lancet Oncol 2022; published online Jan 24. https://doi.org/10.1016/S1470-2045(21)00716-6.
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[6] Tanguturi S, Warren L. The Current and Evolving Role of Radiation Therapy for Central Nervous System Metastases from Breast Cancer. Curr Oncol Rep. 2019. 21(6): 50.