编者按：在2023年SABCS大会上，HER2CLIMB-02研究结果公布，研究结果显示，与T-DM1联合安慰剂相比，T-DM1联合图卡替尼可显著改善既往接受过治疗的HER2阳性转移性乳腺癌患者的无进展生存期（PFS），在脑转移患者中也是如此。肿瘤瞭望特邀采访了HER2CLIMB-02研究PI——弗雷德·哈钦森癌症中心/华盛顿大学洛杉矶分校Sara Hurvitz教授，请她就该研究相关数据进行介绍。

 

Sara Hurvitz教授：HER2CLIMB-02是一项随机3期临床试验，评估了tucatinib（图卡替尼）联合Trastuzumab emtansine（T-DM1）治疗HER2阳性转移性乳腺癌的效果。该试验允许入组既往接受过曲妥珠单抗和紫杉烷治疗的患者，以及有脑转移病史的患者，包括未经治疗的活动性转移患者。

 

 

在这项研究中，约一半患者（228例）接受图卡替尼+T-DM1治疗，另一半患者（235例）接受安慰剂+T-DM1治疗。患者既往治疗线的中位数为1，约90%的患者之前接受过帕妥珠单抗治疗。

 

 

研究结果显示，与安慰剂+T-DM1相比，接受图卡替尼+T-DM1治疗的患者无疾病进展生存期（PFS）显著提高（9.5个月vs 7.4个月，HR 0.76，95%CI：0.61～0.95，P=0.0163）。

 

 

发现这种统计学显著性后，我们进行了第一次中期总生存分析，研究过程中总共进行两次。此时，总生存分析尚不成熟，只有53%（134/253）的事件数据可用，结果并不理想，没有显示出两种治疗方案之间的差异。

 

 

然而，在具有脑转移HER2阳性乳腺癌患者中，与安慰剂+T-DM1组相比，图卡替尼+T-DM1治疗组的PFS获益更好（7.8个月vs 5.7个月，HR 0.64，95%CI：0.46～0.89），但我们并没有对此进行统计学分析。

 

 

在副作用方面，接受图卡替尼+T-DM1治疗的患者发生3-4级不良事件的风险更高，同时出现了更多的因不良事件导致的治疗中断。肝转氨酶升高、腹泻、恶心、呕吐和疲劳的发生率较高，但这些通常是可以通过停药和剂量减少来管理和逆转。总体来说，这些数据提供了第二个涉及图卡替尼的大型随机试验，展示了图卡替尼在HER2阳性乳腺癌中的获益，包括那些具有活动性、进展性脑转移的患者。

 

 

Oncology Frontier：Congratulations on the success of the HER2CLIMB-02 study.Could you please introduce the main results and clinical significance of this study?

 

Professor Sara Hurvitz：HER2CLIMB-02 was a randomized phase 3 clinical trial that evaluated tucatinib when added to T-DM1 in HER2-positive metastatic breast cancer.Patients who’d previously received trastuzumab and a taxane were allowed，and patients who had a history of brain metastases，including active，untreated brain metastases，were also allowed.In this study，half of the patients received trastuzumab emtansine with tucatinib and half received it with placebo.Patients had had a median of one prior line of therapies and 99%of patients had received prior pertuzumab.

 

The study showed that progression-free survival was significantly improved in the tucatinib treated patients by about two months with a hazard ratio of 0.76.This statistical significance prompted the first of two interim overall survival analyses.At this time，the survival analysis was immature with only 53%of events，but it was not positive.It did not demonstrate a difference between the two treatment arms.

 

The progression-free survival in patients with brain metastases however，did look very compelling.There was a hazard ratio of about 0.64 in favor of tucatinib，but this was not statistically tested.In terms of side effects，patients treated with tucatinib added to T-DM1 had a higher rate of grade 3-4 events as well as discontinuations.There were higher rates of liver transaminase elevation，diarrhea，nausea，vomiting，and fatigue，but these tended to be very manageable and reversible with dose holds and dose reductions.In summary，these data provide the second large randomized trial involving tucatinib showing the benefits of tucatinib in HER2 positive breast cancer including in patients who have active，progressing brain metastases.

 

Sara Hurvitz教授：在HER2CLIMB-02研究中，有44%的入组患者有脑转移病灶，其中一半的患者脑转移病灶处于活跃状态。这是继HER2CLIMB之后，第二项评估图卡替尼或评估系统治疗在涉及进展、未治疗或活动性脑转移病灶患者人群中的效果的研究。患者的无疾病进展生存期获益非常有前景。尽管我们尚未报告HER2CLIMB-02的颅内客观缓解率，但从HER2CLIMB研究中，我们确实看到接受基于图卡替尼治疗的患者中有近一半出现脑部病灶缓解。因此，我认为这是一种有前景的治疗方法。基于HER2CLIMB的结果，图卡替尼在全球许多地方已成为脑转移患者的标准治疗方案之一。

 

Oncology Frontier:Based on previous HER2CLIMB and HER2CLIMB-02，what do you think are the advantages of tutorinib?Is there also data on patients with brain metastases in the HER2CLIMB-02 study?

 

Professor Sara Hurvitz：In the HER2CLIMB-02 study，44%of patients enrolled had brain metastases，half of whom had active brain metastases，and this is the second study after HER2CLIMB evaluating tucatinib or evaluating systemic therapy in a patient population involving progressing and untreated or active brain metastases.The progression free survival in the patients were very promising.We haven’t yet reported the intracranial objective response rate from HER2CLIMB-02，but from HER2CLIMB，we did see almost half of patients have a response in the brain with tucatinib-based therapy.So I do think this is a promising treatment.It’s certainly one that is standard of care in many parts of the world now based on the results of HER2CLIMB.

 

Sara Hurvitz教授：多项研究结果表明，HER2双靶向治疗能为患者提供更多获益。HER2CLIMB-02和HER2-CLIMB研究中均使用了图卡替尼，除此之外还使用了另一种HER2靶向药物。我认为这传达了一个强有力的信息。HER2CLIMB-04正在研究图卡替尼与T-DXd的联合应用，这些数据指日可待。我认为我们需要看看这些试验的结果如何。若根据HER2CLIMB-05研究的结果，图卡替尼可在一线治疗中可用，但是如果在DESTINY-Breast09研究中，T-DXd的疗效优于THP，那HER2阳性晚期乳腺癌患者的一线治疗可能会产生不确定性。我们无法进行多个大型随机试验来比较所有的治疗药物，因此我们需要综合药物副作用情况、在特定国家/地区的可及性、患者偏好以及疗效指标，为患者进行治疗决策。

 

Oncology Frontier:We know that there are many combinations in the HER2CLIMB series of studies，such as tucatinib combined with PH dual target therapy in HER2CLIMB-05.And T-DXd has achieved T-DM1 as the new standard.How do you view the prospects of combination therapy based on TKIs?

 

Professor Sara Hurvitz：We have a number of studies indicating that dual HER2 targeting is beneficial.HER2CLIMB-02 and HER2-CLIMB both utilize tucatinib in addition to another HER2-targeted agent.And I think this is something that is very promising.HER2CLIMB-04 is looking at tucatinib plus T-DXd，so we’ll have those data as well.I think we’re going to have to see how all of these trials report out.If we have available tucatinib in the front line setting based on the HER2CLIMB-05，that’s going to create a bit of confusion if T-DXd beats THP and in the Destiny Breast-09.So I think we’re going to have to make very nuanced decisions regarding which therapy to use.It’ll be impossible for us to do multiple large randomized trials comparing all of these agents to one another，so we’ll have to look at the side effect profiles，what’s available in a given country，patient preferences，and the efficacy readouts.

 

Sara Hurvitz

Fred Hutchinson Cancer Center/University of Washington

Los Angeles，California，United States