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

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.