SAN ANTONIO (EGMN) –Dual HER2-targeted therapy with lapatinib and trastuzumab yielded an impressive 4.5-month improvement in overall survival compared to lapatinib alone in heavily pretreated patients with HER2-positive metastatic breast cancer that had progressed on trastuzumab, a phase III trial shows.

At 12 months followup in the 296-patient EGF104900 study, the overall survival rate was 56% in patients randomized to lapatinib (Tykerb) at 1,000 mg/day plus trastuzumab (Herceptin) compared to 41% in those assigned to 1,500 mg/day of lapatinib alone. Median overall survival was 14 months with dual therapy and 9.5 months with lapatinib alone.

That’s a highly significant—and unprecedented—26% reduction (P =.026) in the risk of death with dual HER2-blockade compared to single-agent therapy in the setting of metastatic disease that has progressed on trastuzumab, Dr. Kimberly Blackwell announced at the San Antonio Breast Cancer Symposium.

“It means 15 more women out of 100 were alive at a year, because they were randomized to the combination therapy,” observed Dr. Blackwell of Duke University, Durham, North Carolina.

Moreover, that 26% figure considerably underestimates the true mortality benefit, since 77 patients assigned to single-agent lapatinib underwent a prespecified crossover to dual therapy when they experienced disease progression. One-half of the crossovers occurred at week 8 of the trial or earlier. Counting only the non-crossovers in the lapatinib arm, the overall survival advantage with combination therapy increased from 26% to 35%, she continued.

One-third of study participants had received at least six prior chemotherapy regimens before enrollment. Patients had a median of three prior trastuzumab-containing regimens for metastatic breast cancer, with disease progression on the most recent one. Three-quarters of participants had visceral disease, and one-fifth had known stable brain metastases.

There was no signal of a cardiac safety issue with combination therapy. The sole cardiac death in the study was due to pulmonary embolism in a patient on dual therapy. Most adverse events in both study arms were grade 1/2. Only one grade 3/4 adverse event occurred in 5% or more of subjects; that was diarrhea, occurring in 8% of the dual therapy group and 7% with lapatinib alone.

“As a practicing clinician I think it’s really amazing that there was not a significant safety signal. In considering the heavily pretreated nature of these patients, the fact that we really did not see any significant side effects is remarkable for this combination of agents,” Dr. Blackwell said.

Lapatinib and trastuzumab target HER2 through different mechanisms. Preclinical and animal studies have suggested synergistic benefits for the combination of agents, including enhanced apoptosis and antiproliferative effects and downregulation of survivin, she continued.

Asked how she’ll interpret the EGF104900 data in her own practice, Dr. Blackwell said she will now consider using the lapatinib/trastuzumab combination in patients who have previously done well on approved chemotherapy/anti-HER2 regimens before developing disease progression.

Dr. Edith Perez called this a “provocative” study, the first-ever to show a survival improvement for any anti-HER2 agent taken beyond first-line therapy. It validates the concept that trastuzumab is an important drug to maintain through disease progression into second-, third-, and fourth-line therapy.

For now, the oral small-molecule lapatinib is approved for use by the U.S. Food and Drug Administration only in combination with capecitabine (Xeloda) in the setting of metastatic HER2-positive breast cancer previously treated with trastuzumab plus chemotherapy, noted Dr. Perez, director of the breast cancer program at the Mayo Clinic, Jacksonville, Fla.

The new findings from EGF104900 support the ongoing effort to extend the use of lapatinib into the setting of early-stage breast cancer in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO), which has enrolled roughly 6,800 of a planned 8,000 patients. ALTTO is examining the combination of the two agents versus their sequential use versus using one drug or the other. Dr. Perez is a principal investigator in ALLTO.

Also underway is NeoALLTO, looking at combination therapy versus sequential versus either agent alone as neoadjuvant therapy. That trial should report results within the next 18 months.

Dr. Blackwell disclosed receiving honoraria from both Genentech and GlaxoSmithKline and serving as a consultant to Genentech.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

圣安东尼奥(EGMN)——一项Ⅲ期临床研究表明，在已发生转移的HER-2阳性乳腺癌患者中，与拉帕替尼单药治疗相比，应用拉帕替尼加曲妥珠单抗的双重HER-2靶向治疗可延长总体生存4.5个月。

 

EGF104900研究纳入了296例患者，在对患者进行为期12个月的随访后发现，被随机分配接受1,000 mg/d拉帕替尼(泰克博)加曲妥珠单抗(赫赛汀)治疗的患者总体生存率为56%，而仅接受1,500 mg/d拉帕替尼单药治疗的患者为41%。双重治疗患者的中位总体生存时间为14个月，而拉帕替尼单药治疗者为9.5个月。

 

Kimberly Blackwell博士在圣安东尼奥乳腺癌会议上报告，在曲妥珠单抗治疗后疾病进展的转移性乳腺癌患者中，双重HER-2阻滞治疗与单药治疗相比可将患者的死亡风险降低26%，这种降幅很显著(P =0.026)，也是前所未有的。

 

来自美国北卡罗莱那州达勒姆杜克大学的Blackwell博士说：“这意味着每100例女性患者中就会额外有15例存活至1年，这是因为她们接受了联合治疗。”

 

另外，这个数字(26%)大大低估了联合治疗的实际生存益处，这是因为被分配接受拉帕替尼单药治疗的77例患者在疾病进展时转而使用双重治疗(方案预设的)。半数转换治疗发生在研究开始后8周或更早。若仅考虑拉帕替尼单药组未转换治疗的患者，那么联合治疗的总体生存益处则由26%升至35%。

 

研究受试者中有1/3在入组前接受过至少6种方案的化疗。受试者们因乳腺癌转移而接受数次含曲妥珠单抗的化疗方案治疗(中位数为3次)，而最近一次治疗时疾病发生进展。3/4的受试者已有脏器转移，而1/5的受试者发生了已知稳定的脑部转移。

 

联合治疗组未出现任何与心脏安全有关的迹象。研究中仅联合治疗组发生1例心源性死亡，死于肺栓塞。两治疗组中发生的多数不良反应均为1/2级。有5%或更多的受试者仅发生过1次3/4级不良反应；即腹泻，联合治疗组的发生率为8%，而拉帕替尼单药治疗组为7%。

 

Blackwell博士说：“作为一名临床医生，我认为研究中未出现严重安全问题非常令人振奋。考虑到患者们在入组之前接受过过于复杂的治疗，而对于联合治疗来说，研究中未发现任何严重的不良反应真是值得关注。”

 

Blackwell博士说，拉帕替尼与曲妥珠单抗靶向HER-2的机制不同。临床前和动物研究显示了两种制剂的协同效应，包括增强凋亡、抑制增殖和下调生存蛋白(survivin)的表达。

 

当被问及依她的临床经验如何解读EGF104900研究的数据时，Blackwell博士说她将考虑对那些既往在疾病进展前对已获批的化疗/抗HER-2方案反应良好的患者进行拉帕替尼/曲妥珠单抗联合治疗。

 

Edith Perez博士称这是一项“可引起争论”的研究，这是首项显示应用抗HER-2制剂治疗可获得超过一线治疗的生存益处的研究。它证明了以下观点，即在疾病进展过程中曲妥珠单抗是一种重要的维持治疗药物，直至应用到二线、三线和四线治疗。

 

美国弗罗里达州杰克逊维尔Mayo医院乳腺癌项目负责人Perez博士指出，如今，口服小分子的拉帕替尼被美国食品药品管理局批准仅可与卡培他滨(希罗达)联合用于之前应用过曲妥珠单抗加化疗的有转移的HER-2阳性乳腺癌患者。

 

来自EGF104900研究的这项新发现支持了拉帕替尼和(或)曲妥珠单抗辅助治疗优化临床研究(ALTTO)正在进行的将拉帕替尼的应用扩展至早期乳腺癌的努力。ALTTO研究计划入组8,000例患者，而实际入组了近6,800例；这项研究观察比较了两种药物联合、序贯应用与任一药物单用的效果。Perez博士是ALLTO的主要研究者。

 

另一项正在进行的研究为NeoALLTO，其观察比较两种药物联合、序贯应用与任一药物单用作为新辅助疗法的效果。此项研究将在未来18个月内报告结果。

 

Blackwell博士声明接受过来自基因泰克公司和葛兰素史克公司的酬金，并担任基因泰克公司的顾问。

 

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