The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer.
The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer.
复制标题
DOI：
10.1158/1078-0432.ccr-14-1760
复制
发表时间：
2015-07-01
期刊：
影响因子：
--
通讯作者：
Esserman LJ
中科院分区：
文献类型：
--
作者：
DeMichele A;Yee D;Berry DA;Albain KS;Benz CC;Boughey J;Buxton M;Chia SK;Chien AJ;Chui SY;Clark A;Edmiston K;Elias AD;Forero-Torres A;Haddad TC;Haley B;Haluska P;Hylton NM;Isaacs C;Kaplan H;Korde L;Leyland-Jones B;Liu MC;Melisko M;Minton SE;Moulder SL;Nanda R;Olopade OI;Paoloni M;Park JW;Parker BA;Perlmutter J;Petricoin EF;Rugo H;Symmans F;Tripathy D;van't Veer LJ;Viscusi RK;Wallace A;Wolf D;Yau C;Esserman LJ
近年来，乳腺癌治疗的许多改进降低了复发率，以至于现在很难或不可能进行足够强大的辅助临床试验。考虑到许多新药和潜在的协同作用组合，新辅助方法已被用于在原发性乳腺癌的临床试验中测试药物组合的益处。最近FDA领导的一项荟萃分析显示，病理完全应答(PCR)可以预测特定乳腺癌亚型患者的无病生存率(DFS)。这一荟萃分析激发了FDA关于在加速药物审批中使用PCR作为替代终点的指南草案。在ASCO 2014年会上，使用聚合酶链式反应作为登记终点受到了挑战，因为ALTTO的介绍，这是一项针对HER2阳性乳腺癌的辅助试验，显示在曲妥珠单抗和化疗中加入HER家族酪氨酸激酶抑制剂拉帕替尼对DFS风险没有显著降低。这一结论似乎与NeoALTTO的结果不一致，NeoALTTO是一项新辅助试验，发现含有相同拉帕替尼的方案的PCR率在统计上有所改善。我们解决了两个试验中可能导致不一致结论的不同之处。然而，我们使用FDA的荟萃分析表明，在观察到的NeoALTTO的PCR差异和观察到的ALTTO的HR之间根本没有不一致。这强调了在设计临床试验时对两个端点进行适当建模的重要性。I-SPY 2/3新佐剂试验就是这种方法的例证。
The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.