Neoadjuvant Paclitaxel With LCL161 in Localized Triple-Negative Breast Cancer
In a phase II study reported in the Journal of Clinical Oncology, Bardia et al evaluated the effects of adding an antagonist of inhibitor of apoptosis proteins (LCL161) to paclitaxel as neoadjuvant therapy in patients with localized triple-negative breast cancer who did or did not have a tumor necrosis factor α–based gene expression signature (GS) predictive of sensitivity to LCL161. Results indicated a higher likelihood of pathologic complete response (pCR) with the combination in GS-positive disease.
In the study, 207 women with localized disease (T2, N0–2, M0) from 47 sites in 11 countries were stratified by GS status and randomly assigned between August 2012 and September 2014 to receive oral LCL161 (1,800 mg once per week) and intravenous paclitaxel (80 mg/m2 once per week) or paclitaxel alone for 12 weeks followed by surgery. Among 63 patients with GS-positive disease, 34 received the combination and 29 received paclitaxel. Among 144 patients with GS-negative disease, 71 received the combination and 73 received paclitaxel. The primary objective was to determine whether LCL161 increased the efficacy of paclitaxel, with improvement defined as > 7.5% increase in pCR in the breast.
pCR Rates and Adverse Events
In the GS-positive group, pCR was observed in 38.2% of the combination group vs 17.2% of the paclitaxel group (88.8% posterior probability of > 7.5% increase in rate). In the GS-negative group, pCR was observed in 5.6% of the combination group vs 16.4% of the paclitaxel group (0% posterior probability of > 7.5% increase in rate).
Grade 3 or 4 adverse events occurred in 58.5% of the combination group vs 23.3% of the control group, including a higher incidence of neutropenia (24.5% vs 3.9%) and diarrhea (5.7% vs 1.0%) with the combination. Serious adverse events of pyrexia (17.9% vs 1.0%), pneumonitis (9.4% vs 0%), and Pneumocystis pneumonia (3.7% vs 0%) were more common with the combination. Adverse events led to discontinuation of treatment in 18.1% vs 4.9% of patients.
The investigators concluded, “This neoadjuvant trial provides evidence supporting a biomarker-driven targeted therapy approach for selected patients with GS-positive [triple-negative breast cancer] 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 [triple-negative breast cancer].”
Financial support for the work was provided by Scott Cameron, MD, PhD, of the Novartis Institutes for BioMedical Research, an author of the Journal of Clinical Oncology article. Aditya Bardia, MD, MPH, of the Massachusetts General Hospital Cancer Center, Harvard Medical School, is the corresponding author for the Journal of Clinical Oncology article.
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