The Neoadjuvant Model Is Still the Future for Drug Development in Breast Cancer

Abstract

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 This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval.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.

Imaging Considerations and Interprofessional Opportunities in the Care of Breast Cancer Patients in the Neoadjuvant Setting

“…1,2 As NAT options for breast cancer continue to expand, it is critical to ensure that imaging can effectively evaluate and direct available treatments. The purpose of NAT is to remove as much of the primary lesion and distant micrometastases as possible in order to improve disease-free and overall survival, while decreasing the initial tumor burden to enable a more limited, breast-conserving, surgery.…”

Neoadjuvant as Future for Drug Development in Breast Cancer—Letter

“…1,2 , Tomasz Burzykowski 2,3 , and Everardo D. Saad 3,4 We agree with DeMichele and colleagues (1) that "the neoadjuvant approach presents the opportunity to speed drug development while simultaneously providing real-time benefits to patients who participate in such trials." Yet, the statistical argument they use to support their claim is flawed and may lead to misleading predictions when an early endpoint, such as pathologic complete response (pCR), is used as a surrogate for a later clinical endpoint, such as event-free survival (EFS).…”

General St. Gallen-2015 guidelines for the treatment of early breast cancer (adapted by the experts of the Russian Society of Breast Oncologists)

“…Хотя неоадъювантное исследование neo-ALTTO показало явно положительные результаты примене-ния двойной HER-2-блокады [87], адъювантное исследование ALTTO [88], напротив, продемонстри-ровало неутешительные результаты применения данного вида лечения. Эти, казалось бы, противоре-чивые результаты могут измениться и исчезнуть при более длительных сроках наблюдения [89]. Отношение рисков (ОР) в исследовании ALTTO, составляющее 0,84, при сравнении двойной блокады с одним трастузумабом [88], как оказалось, было более высоким, чем ожидалось [89].…”

“…Эти, казалось бы, противоре-чивые результаты могут измениться и исчезнуть при более длительных сроках наблюдения [89]. Отношение рисков (ОР) в исследовании ALTTO, составляющее 0,84, при сравнении двойной блокады с одним трастузумабом [88], как оказалось, было более высоким, чем ожидалось [89]. А значение р = 0,048 интерпретировалось как незначимое, потому что в план статистического анализа включа-лось как двойное ингибирование, так и последовательное применение трастузумаба и лапатиниба Лучевая терапия В 2 исследованиях по гипофракционированной лучевой терапии после органосохраняющего лечения были рассмотрены по существу аналогичные схемы [9,10].…”