柳叶刀·肿瘤学：曲妥珠单抗治疗后进展，阿法替尼＋长春瑞滨并不优于曲妥珠单抗＋长春瑞滨

　　2016年1月25日，复旦大学附属肿瘤医院邵志敏、上海交通大学医学院附属瑞金医院沈坤炜、哈尔滨医科大学附属肿瘤医院张清媛、中国医学科学院北京协和医院孙强、中国医学科学院肿瘤医院徐兵河（通讯作者）以及德国、中国台湾、美国、韩国、波兰、比利时学者在《柳叶刀·肿瘤学》（Lancet Oncololy）联合发表了一项国际、多中心、非盲、随机3期临床研究（LUX-Breast1）的结果，同时配发了美国哈佛医学院、达纳法伯癌症研究所Ian E. Krop教授的评论，讨论了酪氨酸激酶抑制剂（TKI）一次次失败的可能原因以及未来在临床上可能的方向。

　　该研究从2010年8月26日至2013年4月26日比较了508例HER2阳性乳腺癌患者在辅助或一线曲妥珠单抗治疗进展后阿法替尼＋长春瑞滨（339例）对比曲妥珠单抗＋长春瑞滨（169例）的疗效，中位随访9.3个月（IQR：3.7～16.0）。结果显示，阿法替尼治疗组患者的中位无进展生存（PFS）与曲妥珠单抗组相似（5.5个月比5.6个月，HR=1.10，95%CI：0.86～1.41，P=0.43），但中位总生存（OS）显著少于曲妥珠单抗（HR=1.48，95%CI：1.13～1.95，P=0.0048），提示曲妥珠单抗治疗后进展的患者，继续使用曲妥珠单抗联合长春瑞滨的疗效反而优于改用阿法替尼联合长春瑞滨的疗效。

　　HER2特异性单克隆抗体曲妥珠单抗在临床上的应用进展在肿瘤界是一个相当成功的故事。曲妥珠单抗是治疗HER2阳性乳腺癌最有效的靶向治疗药物之一，无论是早期还是进展期HER2阳性乳腺癌患者，与单纯化疗相比，曲妥珠单抗联合化疗都能显著改善生存。尽管如此，曲妥珠单抗也并非对所有患者都有效。即使有效的患者，也可能最终出现治疗失败或肿瘤进展。在转移性乳腺癌患者中，进展是必然的。然而曲妥珠单抗甚至在进展后也存在获益。最初报道这个现象的研究，是一项比较一线接受曲妥珠单抗为主方案并发生进展的患者，随机给予卡培他滨单药或卡培他滨＋曲妥珠单抗效果的研究。与卡培他滨单药相比，继续联合曲妥珠单抗显著改善了进展时间。

　　HER2靶向治疗的一种替代方案是使用小分子TKI，一旦出现肿瘤复发或进展，目前常用的是使用小分子TKI如拉帕替尼（已获FDA批准），还有一些正在研究阶段的TKI如阿法替尼、来那替尼、ONT-380等。

　　拉帕替尼获批的依据是一项比较拉帕替尼联合卡培他滨对比单用卡培他滨二线治疗曲妥珠单抗进展后进展期乳腺癌的III期临床试验的结果。与卡培他滨相比，拉帕替尼＋卡培他滨方案能够显著改善患者的PFS。

　　在MA.31研究中，拉帕替尼也直接与曲妥珠单抗进行了比较。该研究比较了大部分（82%）未曾接受曲妥珠单抗治疗的患者中，一线紫杉类药物＋曲妥珠单抗/拉帕替尼的疗效，与曲妥珠单抗组相比，拉帕替尼组PFS数据更差，同时毒性反应更多。

　　然而，目前并不清楚在曲妥珠单抗治疗后发生进展的患者中，拉帕替尼或其他TKI方案与继续曲妥珠单抗方案哪种疗效更好。LUX-Breast1研究是第一个试图解决这一问题的研究。由于中期分析时显示阿法替尼能够改善PFS的可能性很低，同时曲妥珠单抗组的OS显著高于阿法替尼组，且阿法替尼方案相关毒性更大，所以数据监查委员会建议中止该研究。

　　这个结果很出人意料，这是因为阿法替尼是一种不可逆的高强效TKI抑制剂，且能够阻断HER家族所有的异源二聚体和同源二聚体，特别是可能与曲妥珠单抗耐药相关的HER2-HER-3异源二聚体。因此，预期阿法替尼的疗效应该优于曲妥珠单抗，但很遗憾研究结果是阴性的。

　　对此结果的解释是，曲妥珠单抗除了能够抑制HER2信号通路以外，还能够影响免疫系统，特别是具有激活抗体依赖细胞介导的细胞毒作用的能力，这种免疫相关的机制可能是它在多线治疗后继续使用仍然有效的原因之一。当然，目前的数据并没有排除TKI治疗乳腺癌的作用。一项Ⅲ期随机分组临床试验结果显示，在曲妥珠单抗辅助治疗1年后，与安慰剂相比，序贯1年的奈拉替尼治疗能够改善患者的无病生存。

　　迄今为止，比较TKI和曲妥珠单抗疗效的研究结果均为阴性，表明期望以TKI替代曲妥珠单抗以改善预后的方案很难获得成功。今后的研究应当关注于改变治疗策略，考虑TKI与其他药物联用，或者用于特定适应证，同时需要深入研究HER2阳性乳腺癌的生物学机制和耐药机制。

Lancet Oncol. 2016 Jan 25. [Epub ahead of print]

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial.

Harbeck N, Huang CS, Hurvitz S, Yeh DC, Shao Z, Im SA, Jung KH, Shen K, Ro J, Jassem J, Zhang Q, Im YH, Wojtukiewicz M, Sun Q, Chen SC, Goeldner RG, Uttenreuther-Fischer M, Xu B, Piccart-Gebhart M; LUX-Breast 1 study group.

Brustzentrum der Universitat München and Comprehensive Cancer Center of the Ludwig-Maximilians-Universitat München, Munich, Germany.

National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.

Taiwan Breast Cancer Consortium, Taipei, Taiwan.

University of California, Los Angeles, Los Angeles, CA, USA.

Translational Research in Oncology, Los Angeles, CA, USA.

Taichung Veterans General Hospital, Taichung, Taiwan.

Fudan University Shanghai Cancer Center, Shanghai, China.

Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.

Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Comprehensive Breast Health Center, Rui Jin Hospital, Shanghai, China.

National Cancer Center, Goyang, South Korea.

Medical University, Gdansk, Poland.

Cancer Hospital of Harbin Medical University, Harbin, China.

Samsung Medical Center, Seoul, South Korea.

Comprehensive Cancer Centre, Medical University, Bialystok, Poland.

Peking Union Medical College Hospital, Beijing, China.

Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.

Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Peking Union Medical College, Beijing, China.

Institut Jules Bordet, Brussels, Belgium.

BACKGROUND: Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer.

METHODS: We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m2 per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566.

FINDINGS: Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9.3 months (IQR 3.7-16.0). Median progression-free survival was 5.5 months (95% CI 5.4-5.6) in the afatinib group and 5.6 months (5.3-7.3) in the trastuzumab group (hazard ratio 1.10 95% CI 0.86-1.41; p=0.43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none).

INTERPRETATION: Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab.

FUNDING: Boehringer Ingelheim.

PMID: 26822398

PII: S1470-2045(15)00540-9

DOI: 10.1016/S1470-2045(15)00540-9

Lancet Oncol. 2016 Jan 25. [Epub ahead of print]

Lessons from breast cancer trials of HER2-kinase inhibitors.

Krop IE.

Dana-Farber Cancer Institute, Boston, MA 02215, USA.

The clinical development of the HER2-specific monoclonal antibody trastuzumab is an oncology success story. Adding trastuzumab to chemotherapy markedly improves survival for patients with both early and advanced HER2-positive breast cancer. Despite this success, trastuzumab regimens are not effective in all patients, and in patients with metastatic disease, tumors inevitably progress. However, trastuzumab provides benefit even after progression. This was first shown in a study in which patients with metastatic disease that had progressed with a trastuzumab-based regimen were randomly assigned to receive capecitabine alone or capecitabine plus trastuzumab. Trastuzumab continuation significantly improved time to progression compared with capecitabine alone.

An alternative approach to HER2-targeting is the use of small molecule tyrosine kinase inhibitors such as lapatinib (which has been approved by the US Food and Drug Administration), and the investigational drugs afatinib, neratinib, and ONT-380. Lapatinib was approved on the basis of a study showing that capecitabine and lapatinib improved progression-free survival compared with capecitabine alone in patients who had previously progressed on trastuzumab. Lapatinib was also directly compared with trastuzumab in MA.31, a trial of predominantly trastuzumab-naive patients (82%) randomly assigned to first-line treatment with a taxane and either lapatinib or trastuzumab; the lapatinib group had inferior progression-free survival and more toxic effects compared with the trastuzumab group.

An unanswered question is how lapatinib or any other tyrosine kinase inhibitor compares with trastuzumab in patients after progression with trastuzumab. Nadia Harbeck and colleagues report the results of the first study that addresses this question. The LUX-Breast 1 trial compared afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients whose cancer had progressed on one line of trastuzumab. The data monitoring committee stopped the study because it had a low likelihood of showing superiority of afatinib for progression-free survival, and overall survival was greater in the trastuzumab group than in the afatinib group (hazard ratio 1.48 [95% CI 1.13-1.95]; p=0.0048). In addition, the afatinib regimen was associated with greater toxic effects.

Superficially, the LUX-Breast 1 trial seems to be just another study showing that a tyrosine kinase inhibitor has inferior outcomes and greater toxic effects compared with trastuzumab. But one could argue that the results of this trial were unexpected. Unlike lapatinib, which reversibly inhibits EGFR and HER2, afatinib is a highly potent and irreversible inhibitor of all kinase-competent HER proteins (EGFR, HER2, and HER4). In addition, afatinib blocks all heterodimers and homodimers of the HER family. Preclinical studies suggest that signalling through heterodimers, most notably HER2-HER3, is an important mechanism of trastuzumab resistance. Thus, the LUX-Breast 1 investigators had a strong rationale for comparing afatinib with trastuzumab. Finally, one could argue that the study design favoured afatinib because the patient population had all previously progressed on trastuzumab. Despite these points favouring afatinib, the study was negative. Faced with these surprising data, it is useful to take a step back and ask what broader lesson can be learned from these results.

One potential explanation for the consistent superiority of trastuzumab over tyrosine kinase inhibitors is trastuzumab's ability to act through mechanisms affecting immunity, rather than solely as a HER2 signalling inhibitor. Evidence to support this contention includes preclinical studies showing that the ability of trastuzumab to activate antibody-dependent cell-mediated cytotoxicity is crucial for its efficacy in vivo. Several clinical studies also suggest an immunomodulatory component to trastuzumab activity. Patients with tumours enriched for gene signatures of immunity benefit more from adjuvant trastuzumab than do patients who have tumors without such signatures. The presence of many tumour-infiltrating lymphocytes also predicts benefit of trastuzumab, although not all studies are concordant. Trastuzumab's ability to act via immune-related mechanisms could explain its unique benefit across multiple lines of treatment.

These data do not rule out a potential role for tyrosine kinase inhibitors for treating breast cancer. Combinations of tyrosine kinase inhibitors with trastuzumab, as well as other targeted drugs, are being explored. In addition, a phase 3 study has shown that 1 year of treatment with the irreversible tyrosine kinase inhibitor neratinib after completion of adjuvant trastuzumab significantly improved invasive disease-free survival compared with placebo.

The consistently negative results from the LUX-Breast 1 trial, and other studies comparing tyrosine kinase inhibitors to trastuzumab, strongly suggest that further attempts to improve outcomes by substituting a tyrosine kinase inhibitor for trastuzumab are unlikely to be successful. Instead, research should focus on alternative strategies to exploit the activity of tyrosine kinase inhibitors in the clinic, either in combination with other drugs, or in specific niche indications. In addition, a better understanding of why trastuzumab repeatedly outperforms even the most potent tyrosine kinase inhibitors might provide important insights into the biology and resistance mechanisms of HER2-positive breast cancer.

PMID: 26822399

PII: S1470-2045(16)00004-8

DOI: 10.1016/S1470-2045(16)00004-8