HER2治疗后获得病理完全应答者结局更佳

圣安东尼奥——圣安东尼奥乳腺癌研讨会上公布的对随机NeoALTTO研究455例患者的分析结果显示，在接受新辅助HER2靶向治疗的HER2阳性早期乳腺癌女性中，病理完全应答(pCR)是强烈的预后因素。

中位随访近4年发现，获得pCR(意即手术时乳腺和腋窝均检测不出浸润性病变)的患者发生复发或第二原发癌等事件的风险比未获得pCR的患者低62%，并且死亡的风险比未获得pCR的患者低65%。在激素受体阴性乳腺癌患者中观察到的pCR获益比在激素受体阳性乳腺癌患者中观察到的pCR获益更明显。


Martine J. Piccart医生

在这项由布鲁塞尔乳腺国际组(BIG)主任Martine Piccart-Gebhart医生及其同事进行的NeoALTTO研究(又称为BIG 1-06)中，直径≥2 cm的HER2阳性早期乳腺癌女性被随机分入以下3组接受18周的新辅助治疗：拉帕替尼(Tykerb)+曲妥珠单抗(Herceptin)联合治疗组、拉帕替尼单药治疗组和曲妥珠单抗单药治疗组。这些患者还同时接受紫杉醇治疗。手术后，患者接受联合化疗，然后接受相同的新辅助治疗至52周，如需要，还接受激素治疗。

既往报道的初始结果显示，拉帕替尼单药治疗组、曲妥珠单抗单药治疗组和联合治疗组的pCR发生率(主要终点)分别为24.7%、29.5%和51.3%。

最新结果显示，各个治疗组在校正的3年无事件生存率(分别为78%、76%和84%)和总生存率(分别为93%、90%和95%)方面无显著差异。但在激素受体阴性亚组患者中观察到的曲线分离度更大，表明存在可能的治疗作用。

以随机分组后30周为起点，对所有治疗组进行综合分析发现，与未获得pCR的患者相比，获得pCR的患者发生事件(术后复发、第二次原发癌或死亡，或见于未进行手术的患者的进展)[风险比(HR) 0.38；P=0.0003]和死亡(HR 0.35；P=0.005)的风险显著更低。

所观察到的不良事件均为拉帕替尼和曲妥珠单抗的已知不良事件。在整个研究期间，与曲妥珠单抗单药治疗组相比，拉帕替尼+曲妥珠单抗联合治疗组的重度腹泻、肝胆管不良事件和皮疹发生率更高，心脏事件发生率也更高。

研究者表示，上述最新研究结果应该不会改变曲妥珠单抗+化疗这一标准治疗方案。但该研究表明，对于激素受体阴性、HER2阳性的乳腺癌亚组患者，有可能使用新辅助模型来加快新药的批准。这具有重要意义，因为乳腺癌辅助研究既费时间又费钱，而且需要数以千计的患者。因此，研究结果支持美国食品药品管理局使用pCR作为加快批准用于治疗该患者亚组的新药的标准。

该研究获葛兰素史克公司资助。Piccart-Gebhart医生声明从罗氏公司获得咨询费，其所在的机构从葛兰素史克和罗氏公司获得研究资金。

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By: SUSAN LONDON, Internal Medicine News Digital Network

SAN ANTONIO – Pathologic complete response is a strong prognostic factor in women with HER2-positive early breast cancer who receive neoadjuvant HER2-targeted therapy, investigators reported at the annual San Antonio Breast Cancer Symposium.

A team led by Dr. Martine Piccart-Gebhart, chair of the Breast International Group (BIG) in Brussels, analyzed data from 455 patients in the randomized NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, who received one or both HER2 therapies, along with chemotherapy.
 
With a median follow-up of almost 4 years, those who experienced a pathologic complete response (pCR) – meaning no detectable invasive disease in either the breast or axilla at surgery – were 62% less likely to have had events such as recurrences or second primaries, and 65% less likely to have died, she reported in a session and related press briefing.

The benefit of pCR was more pronounced among patients whose tumors were negative for hormone receptors than among their counterparts whose tumors were positive.

The new data should not change the standard of care, trastuzumab and chemotherapy, she cautioned. "But what this trial indicates to us is that it is possible that for this particular subgroup – hormone receptor–negative, HER2-positive – we could potentially use a neoadjuvant model to speed up approval of new agents. And that’s important because we know that adjuvant trials in breast cancer take forever and are very time- and money-consuming, and require thousands of patients."

Thus, the findings would lend support to the Food and Drug Administration’s use of pCR as the bar for accelerated approval of new drugs for this patient subgroup, she said.

Event-free and overall survival did not differ significantly according to the specific HER2 therapy received, although dual therapy tended to have an edge in patients with hormone receptor–negative tumors. However, the trial was not powered to detect moderate differences in these outcomes, according to Dr. Piccart-Gebhart.

"It is the very large ALTTO trial, with the recruitment of 8,300 women, that will provide a robust answer on the effect of dual HER2 blockade on long-term outcomes, and we expect to report these results at ASCO [American Society of Clinical Oncology] next year," she commented.

Analyses of NeoALTTO will be repeated after another 2.5 years, Dr. Piccart-Gebhart added. "It is possible that with longer follow-up, we will also see a bigger treatment effect in the hormone receptor–positive subgroup. But clearly, this trial provides further evidence that HER2-positive, hormone receptor–negative and HER2-positive, hormone receptor–positive groups are two different diseases."

Press briefing moderator Dr. Jennifer Litton of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center, Houston, noted that pCR was used to gain initial approval of pertuzumab (Perjeta), another targeted therapy, in the neoadjuvant setting.

The reported data "in my opinion, show that it continues to be a very valid surrogate endpoint, and continues to [address the issue] of how we can develop new drugs, get them to patients quicker, with a smaller number of patients involved and less cost," she said.

Session attendee Dr. Steven E. Vogl, an oncologist in New York, asked whether pCR should be abandoned as a surrogate marker for the hormone receptor–positive subset. "It looks like the benefit of pCR was, at best, tiny in your study for those women, and probably we should think twice about using pCR in deciding which therapy is better – we should wait for event-free and overall survival. What do you think?"

Dr. Piccart-Gebhart replied that a meta-analysis of HER2 neoadjuvant therapy performed by the FDA with a much longer follow-up did find a benefit of pCR in the hormone receptor–positive subset. "It was less striking, but it was there. So I think that we have to be cautious because NeoALTTO is still a relatively small study.

"But I would tend to agree with you that the data look a lot stronger in the hormone receptor–negative subgroup, and there, based on the results I showed today, I feel confident that you could use the neoadjuvant model for accelerated approval of new drugs," she added. "For the hormone receptor–positive patients, I’m a little bit more cautious. I think these are slow actors. The events come later; you need a longer follow-up. And then of course the endocrine treatment is important and you give it after surgery in all these trials, which could be a mistake."

In the NeoALTTO study (also known as BIG 1-06), women with HER2-positive early breast cancer measuring at least 2 cm were randomly assigned to 18 weeks of neoadjuvant therapy with dual HER2 blockade using both lapatinib (Tykerb) and trastuzumab (Herceptin), or single HER2 blockade with one of the agents alone – each given along with paclitaxel.

After surgery, they received combination chemotherapy and then more of the same HER2 therapy out to 52 weeks, as well as hormonal therapy if indicated.

Initial results, previously reported, showed that the rate of pCR – the trial’s primary endpoint – was 24.7% with lapatinib alone, 29.5% with trastuzumab alone, and 51.3% with the combination, Dr. Piccart-Gebhart reported.

The new results showed that there were no significant differences between the treatment arms in the adjusted 3-year rates of event-free survival (78%, 76%, and 84%, respectively) or overall survival (93%, 90%, and 95%, respectively). But there was greater separation of the curves in the hormone receptor–negative subset, suggesting a possible treatment effect, according to Dr. Piccart-Gebhart.

In an analysis of all trial arms combined that used a starting point of 30 weeks after randomization, relative to patients who did not have a pCR, those who did were significantly less likely to have events (postoperative recurrence, second primary, or death, or progression in those who did not have surgery) (hazard ratio, 0.38; P = .0003) and to die (HR, 0.35; P = .005).

"There were no surprises" in terms of adverse events, she reported. "The adverse events were consistent with the known safety profiles of lapatinib and trastuzumab."

Over the entire study period, compared with trastuzumab alone, the combination of lapatinib plus trastuzumab led to higher rates of severe diarrhea, hepatobiliary adverse events, and rash, as well as a higher rate of cardiac events.

Dr. Piccart-Gebhart disclosed that she has received consulting fees from Roche, and her institution has received research funding from GlaxoSmithKline PLC and Roche. The trial was sponsored by GlaxoSmithKline.