Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses
Taofeek K Owonikoko, Huifeng Niu, Kristiaan Nackaerts, Tibor Csoszi, Gyula Ostoros, Zsuzsanna Mark, Christina Baik, Anil Abraham Joy, Christos Chouaid, Jesus Corral Jaime, Vitezslav Kolek, Margarita Majem, Jaromir Roubec, Edgardo S Santos, Anne C Chiang, Giovanna Speranza, Chandra P Belani, Alberto Chiappori, Manish R Patel, Krisztina Czebe, Lauren Byers, Brittany Bahamon, Cong Li, Emily Sheldon-Waniga, Eric F Kong, Miguel Williams, Sunita Badola, Hyunjin Shin, Lisa Bedford, Jeffrey A Ecsedy, Matthew Bryant, Sian Jones, John Simmons, E Jane Leonard, Claudio Dansky Ullmann, David R Spigel, C14018 study investigators, Taofeek K Owonikoko, Huifeng Niu, Kristiaan Nackaerts, Tibor Csoszi, Gyula Ostoros, Zsuzsanna Mark, Christina Baik, Anil Abraham Joy, Christos Chouaid, Jesus Corral Jaime, Vitezslav Kolek, Margarita Majem, Jaromir Roubec, Edgardo S Santos, Anne C Chiang, Giovanna Speranza, Chandra P Belani, Alberto Chiappori, Manish R Patel, Krisztina Czebe, Lauren Byers, Brittany Bahamon, Cong Li, Emily Sheldon-Waniga, Eric F Kong, Miguel Williams, Sunita Badola, Hyunjin Shin, Lisa Bedford, Jeffrey A Ecsedy, Matthew Bryant, Sian Jones, John Simmons, E Jane Leonard, Claudio Dansky Ullmann, David R Spigel, C14018 study investigators
Abstract
Introduction: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC.
Methods: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated.
Results: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths.
Conclusions: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.
Trial registration: ClinicalTrials.gov NCT02038647.
Keywords: Alisertib; Aurora A kinase; Paclitaxel; Phase II; SCLC.
Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Source: PubMed