Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

Autor:	Owonikoko TK; Winship Cancer Institute of Emory University, Atlanta, Georgia. Electronic address: towonik@emory.edu., Niu H; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Nackaerts K; KU Leuven, Universitaire Ziekenhuizen, Leuven, Belgium., Csoszi T; Hetenyi G Korhaz, Szolnok, Hungary., Ostoros G; Orszagos Koranyi TBC es Pulmonologiai Intezet, Budapest, Hungary., Mark Z; Tudogyogyintezet Torokbalint, Torokbalint, Hungary., Baik C; University of Washington Seattle Cancer Care Alliance, Seattle, Washington., Joy AA; University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada., Chouaid C; CHI de Créteil, Créteil, France., Jaime JC; Hospital Universitario Virgen del Rocio, Seville, Spain., Kolek V; Fakultni Nemocnice Olomouc, Olomouc, Czech Republic., Majem M; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain., Roubec J; Fakultni Nemocnice Ostrava, Ostrava Poruba, Czech Republic., Santos ES; Lynn Cancer Institute/Boca Raton Regional Hospital, Boca Raton, Florida., Chiang AC; Yale University School of Medicine, New Haven, Connecticut., Speranza G; Université de Sherbrooke, Centre intégré de cancérologie de la Montéregie, Hôpital Charles Le Moyne, Greenfield Park, Quebec City, Canada., Belani CP; Penn State Cancer Institute, Hershey, Pennsylvania., Chiappori A; H. Lee Moffitt Cancer Center, Tampa, Florida., Patel MR; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida., Czebe K; Tudogyogyintezet Torokbalint, Törökbálint, Hungary., Byers L; Tudogyogyintezet Torokbalint, Törökbálint, Hungary., Bahamon B; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Li C; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Sheldon-Waniga E; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Kong EF; University of Texas M. D. Anderson Cancer Center, Houston, Texas., Williams M; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Badola S; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Shin H; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Bedford L; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Ecsedy JA; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Bryant M; University of Texas M. D. Anderson Cancer Center, Houston, Texas., Jones S; University of Texas M. D. Anderson Cancer Center, Houston, Texas., Simmons J; University of Texas M. D. Anderson Cancer Center, Houston, Texas., Leonard EJ; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Ullmann CD; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts., Spigel DR; Personal Genome Diagnostics, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2020 Feb; Vol. 15 (2), pp. 274-287. Date of Electronic Publication: 2019 Oct 23.
DOI:	10.1016/j.jtho.2019.10.013
Abstrakt:	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. (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu