编者按：大约有15%～20%的乳腺癌为HER2阳性，对常规治疗效果不佳，对HER2靶向疗法效果较好，例如曲妥珠单抗、T-DM1、帕妥珠单抗等大分子静脉注射药物。不过，这些一线药物治疗失败或发生脑转移后，目前尚无公认有效的治疗药物。近年来，不少口服有效的小分子药物问世，例如拉帕替尼、奈拉替尼，能够可逆或不可逆抑制HER2和EGFR的酪氨酸激酶，被用于一线治疗失败或发生脑转移后的HER2阳性乳腺癌，但是这些药物效果并不显著优于曲妥珠单抗，而且伴有EGFR抑制相关毒性反应，例如皮疹和腹泻。妥卡替尼（ARRY-380、ONT-380）是一种口服有效、高度选择性可逆型HER2酪氨酸激酶抑制剂，已被临床前和1期临床研究证实单药或联合T-DM1对伴或不伴脑转移的HER2阳性转移性乳腺癌有效，EGFR抑制相关毒性反应较少。
2018年5月24日，英国《柳叶刀》肿瘤学分册在线发表美国德克萨斯大学MD安德森癌症中心、科罗拉多大学癌症中心、普罗维登斯癌症中心、西北内科医师协会、卡斯卡迪亚制药、莎拉坎农研究所的研究报告，妥卡替尼联合卡培他滨或曲妥珠单抗治疗HER2阳性乳腺癌伴或不伴脑转移患者的初步活性、药物代谢动力学、安全性、2期研究推荐剂量。
该非随机非盲1b期研究（ONT-380-005）于2014年1月15日～2015年12月15日从美国5个地点入组既往曾经接受曲妥珠单抗、帕妥珠单抗、T-DM1治疗的年龄≥18岁HER2阳性进展期乳腺癌患者60例，由当地根据实体瘤疗效评价标准（RECIST）1.1版对HER2阳性可测量病变进行评定，根据东部肿瘤协作组（ECOG）体力状态评分为0～1。妥卡替尼300→350mg、卡培他滨1000mg/m²，每天口服2次×14天，每21天重复；曲妥珠单抗6mg/kg，每21天静脉注射1次。根据改良3＋3剂量递增设计确定2期研究推荐剂量，首先评估妥卡替尼＋卡培他滨或妥卡替尼＋曲妥珠单抗两药联合，随后评估妥卡替尼＋卡培他滨＋曲妥珠单抗三药联合。主要研究终点：根据毒性反应评定，评估妥卡替尼的最大耐受剂量和2期研究推荐剂量。次要研究终点：安全性、耐受性、初步活性（客观缓解、无病生存）、妥卡替尼＋卡培他滨的药物代谢动力学。2017年6月30日，对所有接受至少一次研究治疗剂量的患者进行分析。该研究在美国政府临床研究网站注册编号：NCT02025192。
患者分组
妥卡替尼300mg＋卡培他滨：7例（脑转移2例）
妥卡替尼300mg＋曲妥珠单抗：18例（脑转移16例）
妥卡替尼350mg＋卡培他滨：4例（脑转移3例）
妥卡替尼350mg＋曲妥珠单抗：4例（脑转移1例）
妥卡替尼300mg＋卡培他滨＋曲妥珠单抗：27例（脑转移11例）
结果，妥卡替尼的2期研究推荐剂量确定为300mg，每天口服2次，相当于单药最大耐受剂量。根据药物代谢动力学分析，妥卡替尼与卡培他滨无药物之间相互影响。无治疗相关死亡。
对于接受妥卡替尼300mg治疗的52例患者，不论治疗相关与否、不论级别的不良事件包括：
腹泻35例（67%）
恶心31例（60%）
手足综合征（掌跖发红麻木）23例（44%）
疲乏20例（38%）
呕吐20例（38%）
对于接受妥卡替尼所有剂量治疗的60例患者，治疗相关、≥3级的毒性反应包括：
疲乏5例（8%）
腹泻4例（7%）
手足综合征（掌跖发红麻木）4例（7%）
对于病变可测量患者，客观缓解比例：
妥卡替尼＋卡培他滨：83%（5/6）
妥卡替尼＋曲妥珠单抗：40%（6/15）
妥卡替尼＋卡培他滨＋曲妥珠单抗：61%（14/23）
因此，该研究结果表明，妥卡替尼＋卡培他滨或曲妥珠单抗的毒性反应可以接受，并且表现出初步抗肿瘤活性。该研究结果将由双盲随机研究HER2CLIMB（ONT-380-206；NCT02614794）进行确定。
对此，意大利米兰圣拉斐尔医院癌症中心肿瘤内科主任、实体瘤新药研发与创新疗法项目负责人、米开朗基罗癌症研究基金会联合创始人卢卡·贾尼（Luca Gianni）教授发表评论：新的HER2靶向药物是否仍有一席之地？
Lancet Oncol. 2018 May 24. [Epub ahead of print]
Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study.
Rashmi Murthy, Virginia F Borges, Alison Conlin, Jorge Chaves, Marc Chamberlain, Todd Gray, Alex Vo, Erika Hamilton.
MD Anderson Cancer Center, Houston, TX, USA; University of Colorado Cancer Center, Aurora, CO, USA; Providence Cancer Center, Portland, OR, USA; Northwest Medical Specialties, Tacoma, WA, USA; Cascadian Therapeutics, Seattle, WA, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
BACKGROUND: Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases.
METHODS: In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3+3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192.
FINDINGS: Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab.
INTERPRETATION: Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794).
FUNDING: Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics.
DOI: 10.1016/S1470-2045(18)30256-0
Lancet Oncol. 2018 May 24. [Epub ahead of print]
Is there room for another HER2-targeting drug?
Luca Gianni.
Ospedale San Raffaele, IRCCS, Milan, Italy.
In The Lancet Oncology, Rashmi Murthy and colleagues report a phase 1b trial of the HER2-selective tyrosine kinase inhibitor (TKI) tucatinib in combination with capecitabine alone or capecitabine and trastuzumab. The wealth of therapeutic options available makes it legitimate to question whether there is both the room and need for yet another HER2-directed drug.
DOI: 10.1016/S1470-2045(18)30405-4
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