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晚期乳腺癌脑转移复旦三联新疗法

01月07日

来源：美国医学会杂志

对于HER2阳性晚期乳腺癌，虽然HER2靶向治疗可显著改善临床结局，但是大约一半患者或早或晚仍然可能发生脑转移。局部放疗或手术是治疗乳腺癌脑转移的标准方法。不过，超过一半患者放疗后1年内仍然出现局部复发或新的脑转移。多项回顾研究表明，HER2阳性乳腺癌与其他乳腺癌相比，脑部放疗后颅内进展率较高。PERMEATE研究已经证实吡咯替尼（中国原创口服HER1、HER2、HER4酪氨酸激酶不可逆抑制剂）联合卡培他滨（口服化疗药物）对脑转移未放疗患者的颅内疗效，中位无进展生存达11.3个月。可是，颅内进展仍是难题，例如HER2 CLIMB研究1年中枢神经系统无进展生存率仅42%、PERMEATE研究颅内进展率达58%。那么，中枢神经系统放疗＋吡咯替尼＋卡培他滨能否改善HER2阳性乳腺癌脑转移患者的中枢神经系统无进展生存？
2024年1月4日，《美国医学会杂志》肿瘤学分册在线发表复旦大学附属肿瘤医院杨昭志、孟晋、梅欣、莫淼、肖琴、韩序、张丽、石薇、陈星星、马金利、邵志敏、章真、俞晓立、郭小毛等学者的BROPTIMA（FDRT-BC010）研究报告，首次探讨了脑部放疗＋吡咯替尼＋卡培他滨治疗HER2阳性晚期乳腺癌脑转移患者的有效性和安全性。该研究得到国家自然科学基金委员会支持，初步结果已于2023年10月4日美国放射肿瘤学会（ASTRO）第65届年会口头报告。

屏幕截图 2024-01-07 230738.jpg

BROPTIMA (FDRT-BC010, NCT04582968) : yrotinib Combined With Brain Radiotherapy in Breast Cancer Patients With Brain Metastases (A Phase Ib/II Pilot Study of Pyrotinib Plus Capecitabine Combined With Brain Radiotherapy in HER2 Positive Breast Cancer Patients With Brain Metastases)

研究方法

该单中心单组非对照非随机Ib＋II期临床研究于2020年1月至2022年8月入组HER2阳性乳腺癌脑转移女性患者40例（中位年龄50.5岁，四分位：46～59，其中3例先参加Ib期安全性研究）接受分次立体定向放疗或全脑放疗，从放疗第1天至放疗完成后第7天口服吡咯替尼（400毫克，每天1次）和卡培他滨（每平方米体表面积1000毫克，每天2次，每21天第1～14天）直至疾病进展或出现无法耐受的毒性反应。主要终点为中枢神经系统一年无进展生存率，根据历史数据大约48%和样本量39例，预设达到70%有统计学意义。次要终点包括中枢神经系统客观缓解率、无进展生存、总生存、安全性和神经认知功能变化。

结果

截至2023年2月1日：

中位随访：17.3个月（四分位：10.3～26.9）
中枢神经系统一年无进展生存率：74.9%（95%置信区间：61.9%～90.7%）
中枢神经系统中位无进展生存期：18.0个月（95%置信区间：15.5～未达）
一年无进展生存率：66.9%（95%置信区间：53.1%～84.2%）
中位无进展生存期：17.6个月（95%置信区间：12.8～34.1）
中枢神经系统客观缓解率：85%（40例其中34例）中位总生存期：未达中位

发生率最高的3或4级治疗相关不良事件为腹泻（7.5%）。接受分次立体定向放疗的67例病灶发生4例（6.0%）无症状放射性坏死。根据不同时间点的精神状态检查简表评分，大多数患者保持神经认知功能。

结论

因此，该研究结果表明，对于HER2阳性晚期乳腺癌脑转移患者，放疗＋吡咯替尼＋卡培他滨三联疗法可能带来长期颅内生存获益，且安全性可接受，为此类难治患者提供了大有希望的新疗法，故有必要对该三联疗法开展大样本随机对照3期临床研究进一步验证。

JAMA Oncol. 2024 Jan 4. IF: 28.4

Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases: A Nonrandomized Phase 2 Trial.

Yang Z, Meng J, Mei X, Mo M, Xiao Q, Han X, Zhang L, Shi W, Chen X, Ma J, Palmer J, Shao Z, Zhang Z, Yu X, Guo X.

Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai, China; The James Cancer Center at The Ohio State University, Columbus.

QUESTION : Can the combination of central nervous system (CNS) radiotherapy with pyrotinib and capecitabine improve CNS progression-free survival (PFS) in patients with ERBB2-positive breast cancer with brain metastases?

FINDINGS : In this phase 2 nonrandomized trial of 40 patients with ERBB2-positive breast cancer, the combination of CNS radiotherapy and pyrotinib plus capecitabine was associated with a 1-year CNS PFS rate of 74.9% and a median CNS PFS of 18.0 months, with an acceptable radiation necrosis rate.

MEANING : The results of this trial suggest that there are potential benefits of combining radiotherapy with pyrotinib and capecitabine for patients with ERBB2-positive breast cancer with brain metastases, suggesting a promising novel treatment approach for this challenging clinical scenario.

IMPORTANCE : The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear.

OBJECTIVE : To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases.

DESIGN, SETTING, AND PARTICIPANTS : This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023.

INTERVENTIONS : Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects.

MAIN OUTCOMES AND MEASURES : The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function.

RESULTS : A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points.

CONCLUSIONS AND RELEVANCE : The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation.

TRIAL REGISTRATION : ClinicalTrials.gov Identifier: NCT04582968

PMID : 38175627

DOI : 10.1001/jamaoncol.2023.5791

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