奈拉替尼＋卡培他滨治疗乳腺癌脑转移
大约一半的HER2阳性乳腺癌患者可能发生中枢神经系统转移，其循证治疗方法有限。2016年，乳腺癌转化研究联盟（TBCRC）发表的TBCRC022研究结果表明，奈拉替尼（HER1、HER2、HER4不可逆抑制剂）单药疗法对HER2阳性乳腺癌脑转移有效。
2019年5月1日，美国临床肿瘤学会《临床肿瘤学杂志》正式发表哈佛大学达纳法伯癌症研究所、麻省总医院、贝斯以色列女执事医疗中心、北卡罗来纳大学、旧金山加利福尼亚大学、霍普金斯大学、密歇根大学、杜克大学、匹兹堡大学、德克萨斯大学MD安德森癌症中心、梅奥医学中心、贝勒医学院、乔治城大学隆巴迪综合癌症中心的TBCRC022研究其他队列结果报告，探讨了奈拉替尼联合化疗对HER2阳性乳腺癌脑转移的有效性和安全性。
该II期非随机非盲三组平行研究入组病灶可测量、进行性、HER2阳性乳腺癌脑转移患者49例（中枢神经系统手术±放疗后占92%），其中37例未接受过拉帕替尼治疗（3A组）、12例接受过拉帕替尼治疗（3B组），每21天前14天口服奈拉替尼240mg每天1次＋卡培他滨750mg/m²每天2次，随后停药7天。主要研究终点为中枢神经系统综合客观缓解率（中枢神经系统目标病灶大小减少≥50%、非目标病灶无进展、无新病灶、类固醇用药量不增加、无进行性神经系统体征或症状、非中枢神经系统无进展）。如果3A组或3B组的中枢神经系统综合客观缓解率分别≥25.7%或≥12%，那么认为该疗法有希望。
结果，3A组、3B组的中枢神经系统综合客观缓解率分别为49%、33%（95%置信区间：32%～66%、10%～65%），中位无进展生存分别为5.5、3.1个月，中位生存分别为13.3、15.1个月。发生率最高的3级毒性反应为腹泻（29%）。
因此，该研究结果表明，奈拉替尼＋卡培他滨对于难治型HER2阳性乳腺癌脑转移有效，并且进一步证实化疗可以增强HER2靶向疗法对大脑的效果。为了获得最佳耐受性，有必要尽可能预防腹泻。
J Clin Oncol. 2019 May 1;37(13):1081-1089.
TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases.
Freedman RA, Gelman RS, Anders CK, Melisko ME, Parsons HA, Cropp AM, Silvestri K, Cotter CM, Componeschi KP, Marte JM, Connolly RM, Moy B, Van Poznak CH, Blackwell KL, Puhalla SL, Jankowitz RC, Smith KL, Ibrahim N, Moynihan TJ, O'Sullivan CC, Nangia J, Niravath P, Tung N, Pohlmann PR, Burns R, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU; Translational Breast Cancer Research Consortium.
Dana-Farber Cancer Institute, Boston, MA; University of North Carolina at Chapel Hill, Chapel Hill, NC; University of California at San Francisco, San Francisco, CA; Johns Hopkins School of Medicine, Baltimore, MD; Massachusetts General Hospital, Boston, MA; University of Michigan, Ann Arbor, MI; Duke University Medical Center, Durham, NC; University of Pittsburgh Cancer Institute, Pittsburgh, PA; The University of Texas MD Anderson Cancer Center, Houston, TX; Mayo Clinic, Rochester, MN; Baylor College of Medicine, Houston, TX; Beth Israel Deaconess Medical Center, Boston, MA; Lombardi Comprehensive Cancer Center, Washington, DC; The Emmes Corporation, Rockville, MD.
PURPOSE: Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.
PATIENTS AND METHODS: Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m² twice per day for 14 days, then 7 days off. Lapatinib-naive (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.
RESULTS: Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).
CONCLUSION: Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted.
PMID: 30860945
DOI: 10.1200/JCO.18.01511