Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC : Primary and Correlative Biomarker Analyses
Owonikoko, Taofeek K. (Winship Cancer Institute of Emory University)
Niu, Huifeng (Millennium Pharmaceuticals. Inc.)
Nackaerts, Kristiaan (KU Leuven. Universitaire Ziekenhuizen)
Csoszi, Tibor (Hetenyi G Korhaz)
Ostoros, Gyula (Orszagos Koranyi TBC es Pulmonologiai Intezet)
Mark, Zsuzsanna (Tudogyogyintezet Torokbalint)
Baik, Christina (University of Washington Seattle Cancer Care Alliance)
Joy, Anil Abraham (University of Alberta. Cross Cancer Institute)
Chouaid, Christos (CHI de Créteil)
Jaime, Jesus Corral (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Kolek, Vitezslav (Fakultni Nemocnice Olomouc)
Majem, Margarita (Institut d'Investigació Biomèdica Sant Pau)
Roubec, Jaromir (Fakultni Nemocnice Ostrava)
Santos, Edgardo S. (Lynn Cancer Institute/Boca Raton Regional Hospital)
Chiang, Anne C. (Yale University School of Medicine)
Speranza, Giovanna (Université de Sherbrooke)
Belani, Chandra P. (Penn State Cancer Institute)
Chiappori, Alberto (H. Lee Moffitt Cancer Center)
Patel, Manish R. (Florida Cancer Specialists/Sarah Cannon Research Institute)
Czebe, Krisztina (Tudogyogyintezet Torokbalint)
Byers, Lauren (Tudogyogyintezet Torokbalint)
Bahamon, Brittany (Millennium Pharmaceuticals. Inc.)
Li, Cong (Millennium Pharmaceuticals. Inc.)
Sheldon-Waniga, Emily (Millennium Pharmaceuticals. Inc.)
Kong, Eric F. (University of Texas M. D. Anderson Cancer Center)
Williams, Miguel (Millennium Pharmaceuticals. Inc.)
Badola, Sunita (Millennium Pharmaceuticals. Inc.)
Shin, Hyunjin (Millennium Pharmaceuticals. Inc.)
Bedford, Lisa (Millennium Pharmaceuticals. Inc.)
Ecsedy, Jeffrey A. (Millennium Pharmaceuticals. Inc.)
Bryant, Matthew (University of Texas M. D. Anderson Cancer Center)
Jones, Sian (University of Texas M. D. Anderson Cancer Center)
Simmons, John (University of Texas M. D. Anderson Cancer Center)
Leonard, E. Jane (Millennium Pharmaceuticals. Inc.)
Ullmann, Claudio Dansky (Millennium Pharmaceuticals. Inc.)
Spigel, David R. (Personal Genome Diagnostics)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. 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. 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. 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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Alisertib ; Aurora A kinase ; Paclitaxel ; Phase II ; SCLC
Published in:	Journal of Thoracic Oncology, Vol. 15 Núm. 2 (february 2020) , p. 274-287, ISSN 1556-1380

DOI: 10.1016/j.jtho.2019.10.013
PMID: 31655296

14 p, 425.7 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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