Paclitaxel With Inhibitor of Apoptosis Antagonist, LCL161, for Localized Triple-Negative Breast Cancer, Prospectively Stratified by Gene Signature in a Biomarker-Driven Neoadjuvant Trial
Mené sur 209 patientes atteintes d'un cancer du sein triple négatif de stade localisé, cet essai randomisé évalue l'efficacité, du point de vue du taux de réponse pathologique complète, et la toxicité de l'ajout du LCL161, un inhibiteur d'antagonistes des protéines apoptotiques, au paclitaxel dispensé en traitement néoadjuvant, en fonction de la signature d'expression génique basée sur le facteur de nécrose tumorale alpha (TNF alpha)
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/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.