Paclitaxel With Inhibitor of Apoptosis Antagonist, LCL161, for Localized Triple-Negative Breast Cancer, Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial
Open accessAbstract
Purpose: There are currently no targeted therapies approved for triple-negative breast cancer (TNBC). A tumor necrosis factor α ( TNFα)–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 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m 2 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.
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Researchers have developed related drugs, including GDC-0152, GDC-0917 (CUDC-427), LCL-161, AT-406 (Xevinapant, Debio1143), Birinapant (TL32711), ASTX-660.
“Researchers have developed related drugs, including GDC-0152 (184),459 GDC-0917 (CUDC-427) (185),460 LCL-161 (186),461 AT-406 (Xevinapant, Debio1143) (187),462 Birinapant (TL32711) (188),463 ASTX-660 (189).464”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [461]
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- 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.
- Affiliations
- Harvard University (US)
- Aditya Bardia, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston; Scott Cameron and Serena Liao, Novartis Institutes for BioMedical Research, Cambridge, MA; Marina Parton, The Royal Marsden Hospital, London, United Kingdom; Sherko Kümmel, Kliniken Essen-Mitte, Essen, Germany; Laura G. Estévez, Centro Integral Oncológico Clara Campal; Javier Cortés, University Hospital Ramón y Cajal, Madrid; Javier Cortés,Vall d’Hebron Institute of Oncology, Barcelona; Manuel Ruiz-Borrego,...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-11-01
- Volume
- 36
- Issue
- 31
- Pages
- 3126-3133
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2891818168
- Cited by
- 72
- References
- 20
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 10 · 2021: 13 · 2020: 17 · 2019: 7
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
- Keywords
- triple-negative breast cancer, paclitaxel, LCL161, neoadjuvant therapy, pathological complete response, biomarker validation, drug toxicity, neutropenia
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