Aditya Bardia1, Marina Parton1, Sherko Kümmel1, Laura G Estévez1, Chiun-Sheng Huang1, Javier Cortés1, Manuel Ruiz-Borrego1, Melinda L Telli1, Paloma Martin-Martorell1, Rafael López1, J Thaddeus Beck1, Roohi Ismail-Khan1, Shin-Cheh Chen1, Sara A Hurvitz1, Ingrid A Mayer1, Daniel Carreon1, Scott Cameron1, Serena Liao1, José Baselga1, Sung-Bae Kim1. 1. 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, Hospital Universitario Virgen del Rocío, Seville; Paloma Martin-Martorell, Hospital Clínico Universitario de Valencia, Valencia; Rafael López, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain; Chiun-Sheng Huang, National Taiwan University Hospital, National Taiwan University College of Medicine; Shin-Cheh Chen, Chang Gung Memorial Hospital, Taipei, Republic of China; Melinda L. Telli, Stanford University School of Medicine, Stanford; Sara A. Hurvitz, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Roohi Ismail-Khan, Moffitt Cancer Center, Tampa, FL; Ingrid A. Mayer, Vanderbilt-Ingram Cancer Center, Nashville, TN; Daniel Carreon, Novartis Pharmaceuticals Corporation, East Hanover, NJ; José Baselga, Memorial Sloan Kettering Cancer Center, New York, NY; and Sung-Bae Kim, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Abstract
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.
RCT Entities:
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.
Authors: Peter D Koch; Christopher B Rodell; Rainer H Kohler; Mikael J Pittet; Ralph Weissleder Journal: Cell Chem Biol Date: 2020-01-02 Impact factor: 8.116
Authors: María Paz Saldías; Diego Maureira; Octavio Orellana-Serradell; Ian Silva; Boris Lavanderos; Pablo Cruz; Camila Torres; Mónica Cáceres; Oscar Cerda Journal: Front Oncol Date: 2021-06-10 Impact factor: 6.244