Paclitaxel with inhibitor of apoptosis antagonist, LCL161, for localized triple-negative breast cancer, prospectively stratified by gene signature in a biomarker-driven neoadjuvant trial Journal Article


Authors: Bardia, A.; Parton, M.; Kümmel, S.; Estévez, L. G.; Huang, C. S.; Cortés, J.; Ruiz-Borrego, M.; Telli, M. L.; Martin-Martorell, P.; López, R.; Beck, J. T.; Ismail-Khan, R.; Chen, S. C.; Hurvitz, S. A.; Mayer, I. A.; Carreon, D.; Cameron, S.; Liao, S.; Baselga, J.; Kim, S. B.
Article Title: Paclitaxel with inhibitor of apoptosis antagonist, LCL161, for localized triple-negative breast cancer, prospectively stratified by gene signature in a biomarker-driven neoadjuvant trial
Abstract: Purpose There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor a (TNFa)-based gene expression signature (GS) predictive of sensitivity to LCL161, inhibitor of apoptosis antagonist,was translated into a clinical assay and evaluated in a neoadjuvant trial. Patients and Methods Women with localized TNBC (T2/N0-2/M0) were prospectively stratified by GS status and randomly assigned (1:1) to receive oral LCL161 (1,800mg once per week) and intravenous paclitaxel (80mg/m2 once per week; combination arm) or paclitaxel alone (control arm) for 12 weeks, followed by surgery. The primary objective was to determine whether neoadjuvant LCL161 enhances efficacy of paclitaxel, defined by . 7.5% increase in the pathologic complete response (PCR, breast) rate, stratified by GS. Results Of 209 patients enrolled (207 with valid GS scores), 30.4% had GS-positive TNBC. In the GS-positive group, PCR was higher in the combination versus the control arm (38.2% v 17.2%), with 88.8% posterior probability of . 7.5% increase in PCR. However, in the GS-negative group, the PCR was lower in the combination group (5.6% v 16.4%), with 0% posterior probability of . 7.5% increase in PCR. A higher incidence of grade 3 or 4 adverse events in the combination arm included neutropenia (24.5%) and diarrhea (5.7%). Overall, 19 patients (18.1%) in the combination arm discontinued treatment because of adverse events, including pyrexia (n = 5), pneumonia (n = 4), and pneumonitis (n = 4), versus five patients (4.9%) in the control arm. Conclusion This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive TNBC and demonstrates the utility of a neoadjuvant trial for biomarker validation and drug development, but also highlights toxicity risk. Future neoadjuvant clinical trials should carefully weigh these considerations for targeted therapy development in biomarker-defined TNBC. © 2018 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 36
Issue: 31
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2018-11-01
Start Page: 3126
End Page: 3133
Language: English
DOI: 10.1200/jco.2017.74.8392
PROVIDER: scopus
PUBMED: 30235087
DOI/URL:
Notes: Article -- Export Date: 3 December 2018 -- Source: Scopus
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MSK Authors
  1. Jose T Baselga
    389 Baselga