T-DM1＋奈拉替尼治疗晚期乳腺癌

　　人类表皮生长因子受体2（HER2）是一种跨越细胞膜内外的酪氨酸激酶，过表达于大约20%的乳腺癌，正常分子量为185，即p185 HER2。曲妥珠单抗、帕妥珠单抗等大分子单克隆抗体通过与HER2细胞膜外结构区结合，可以阻断HER2活性、抑制下游信号传导、引起细胞有丝分裂周期停滞和细胞凋亡、改善HER2阳性乳腺癌患者的结局。曲妥珠单抗恩特星T-DM1将曲妥珠单抗与化疗药物恩特星DM1结合，抗癌作用更为强悍。不过，HER2阳性晚期乳腺癌女性通常对曲妥珠单抗、帕妥珠单抗、T-DM1发生耐药，其原因可能由于部分HER2细胞膜外结构区消失，分子量减少为95，即p95 HER2，无法与曲妥珠单抗、帕妥珠单抗、T-DM1结合，大约30%的HER2阳性晚期乳腺癌存在p95 HER2表达。奈拉替尼（部分蓝方口音学者译为来那替尼、来拿替尼、来拉替尼）是一种可以口服的HER1、HER2、HER4酪氨酸激酶小分子抑制剂，能够不可逆地与HER2细胞膜内结构区结合，对于p95 HER2阳性乳腺癌具有潜在优势，早期II期研究表明，奈拉替尼单药治疗HER2阳性晚期乳腺癌，对于曲妥珠单抗难治患者、曲妥珠单抗无效患者的总缓解率为分别24%，对于的总缓解率为56%。

　　2019年8月23日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表全国乳腺癌大肠癌术后辅助治疗临床研究协作组（NSABP）基金会、克利夫兰医学中心、匹兹堡大学医疗中心、希尔曼癌症中心、陶西格癌症研究中心、佛罗里达大学医疗中心、比利时国际药物开发研究所的NSABP基金会FB-10研究报告，探讨了T-DM1＋奈拉替尼治疗HER2阳性晚期乳腺癌患者的安全性、耐受性和有效性。

NSABP FB-10: A Phase Ib/II Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer (NCT02236000)

　　该多中心非盲3＋3剂量递增Ib期研究于2015年2月～2017年7月从5个医疗中心入组曲妥珠单抗＋帕妥珠单抗＋紫杉类治疗失败的HER2阳性晚期乳腺癌患者27例，每3周静脉注射T-DM1每次每公斤体重3.6毫克，每天口服奈拉替尼剂量递增至120、160、200、240毫克。

　　结果，第1轮治疗限制剂量递增的毒性反应为3级腹泻6例、3级恶心1例；未见4级腹泻或5级毒性反应。其他3～4级毒性反应发生率：恶心11%、脱水11%、电解质异常19%、血小板减少15%、转氨酶升高7%、疲劳7%。

　　有效性可评估患者19例，其中客观缓解12例（63%）。缓解可见于奈拉替尼各个剂量。

　　入组时27例患者血浆的肿瘤细胞游离DNA分析表明，HER2编码基因ERBB2扩增10例，其缓解程度高而持久。完全缓解2例，其入组时肿瘤组织的p185 HER2和p95 HER2均高表达。

　　因此，该Ib期研究为II期研究推荐的联合用药剂量为T-DM1每3周每公斤体重3.6毫克和奈拉替尼每天160毫克。该研究结果表明，HER2抗体耐药机制可能为p185 HER2消失和p95 HER2高表达，这些数据为正在进行的II期研究奠定了基础，可以更好地确定该联合用药方案的有效性。

J Clin Oncol. 2019 Aug 23. [Epub ahead of print]

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10.

Abraham J, Montero AJ, Jankowitz RC, Salkeni MA, Beumer JH, Kiesel BF, Piette F, Adamson LM, Nagy RJ, Lanman RB, Sperinde J, Huang W, Allegra CJ, Srinivasan A, Wang Y, Pogue-Geile KL, Lucas PC, Jacobs SA.

NSABP Foundation, Pittsburgh, PA; Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH; University of Pittsburgh School of Medicine, Pittsburgh, PA; UPMC Hillman Cancer Center, Pittsburgh, PA; International Drug Development Institute, Louvain-la-Neuve, Belgium; Guardant Health, Redwood City, CA; Monogram Biosciences, Laboratory Corporation of America Holdings, South San Francisco, CA; University of Florida Health, Gainesville, FL.

PURPOSE: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab.

PATIENTS AND METHODS: In this 3 + 3 dose-escalation study, patients with metastatic breast cancer who progressed on trastuzumab, pertuzumab, and a taxane were treated with T-DM1 at 3.6 mg/kg intravenously every 3 weeks and dose-escalating neratinib at 120, 160, 200, or 240 mg/d orally.

RESULTS: Twenty-seven patients were treated across four dose-levels of neratinib. Dose-limiting toxicity in cycle 1 was grade 3 diarrhea in six patients and grade 3 nausea in one; no patient experienced grade 4 diarrhea, and there were no grade 5 toxicities. Other grade 3 to 4 toxicities included nausea (11%), dehydration (11%), electrolyte abnormality (19%), thrombocytopenia (15%), elevated transaminase levels (7%), and fatigue (7%). Twelve (63%) of 19 evaluable patients had an objective response. Responses occurred at all neratinib doses. Plasma cell-free DNA at baseline showed ERBB2 (HER2) amplification in 10 of 27 patients. Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification. Two complete responders had high expression of total HER2 and p95HER2 in baseline tissue.

CONCLUSION: We report the recommended phase II dose of T-DM1 3.6 mg/kg and neratinib 160 mg/d for this combination. Possible resistance mechanisms to HER2 antibodies may be loss of the HER2 receptor and high expression of p95HER2. These data provide the basis for an ongoing phase II study to better define the activity of this regimen.

PMID: 31442103

DOI: 10.1200/JCO.19.00858

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