Taofeek K Owonikoko1, Huifeng Niu2, Kristiaan Nackaerts3, Tibor Csoszi4, Gyula Ostoros5, Zsuzsanna Mark6, Christina Baik7, Anil Abraham Joy8, Christos Chouaid9, Jesus Corral Jaime10, Vitezslav Kolek11, Margarita Majem12, Jaromir Roubec13, Edgardo S Santos14, Anne C Chiang15, Giovanna Speranza16, Chandra P Belani17, Alberto Chiappori18, Manish R Patel19, Krisztina Czebe20, Lauren Byers20, Brittany Bahamon2, Cong Li2, Emily Sheldon-Waniga2, Eric F Kong21, Miguel Williams2, Sunita Badola2, Hyunjin Shin2, Lisa Bedford2, Jeffrey A Ecsedy2, Matthew Bryant21, Sian Jones21, John Simmons21, E Jane Leonard2, Claudio Dansky Ullmann2, David R Spigel22. 1. Winship Cancer Institute of Emory University, Atlanta, Georgia. Electronic address: towonik@emory.edu. 2. Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts. 3. KU Leuven, Universitaire Ziekenhuizen, Leuven, Belgium. 4. Hetenyi G Korhaz, Szolnok, Hungary. 5. Orszagos Koranyi TBC es Pulmonologiai Intezet, Budapest, Hungary. 6. Tudogyogyintezet Torokbalint, Torokbalint, Hungary. 7. University of Washington Seattle Cancer Care Alliance, Seattle, Washington. 8. University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada. 9. CHI de Créteil, Créteil, France. 10. Hospital Universitario Virgen del Rocio, Seville, Spain. 11. Fakultni Nemocnice Olomouc, Olomouc, Czech Republic. 12. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 13. Fakultni Nemocnice Ostrava, Ostrava Poruba, Czech Republic. 14. Lynn Cancer Institute/Boca Raton Regional Hospital, Boca Raton, Florida. 15. Yale University School of Medicine, New Haven, Connecticut. 16. Université de Sherbrooke, Centre intégré de cancérologie de la Montéregie, Hôpital Charles Le Moyne, Greenfield Park, Quebec City, Canada. 17. Penn State Cancer Institute, Hershey, Pennsylvania. 18. H. Lee Moffitt Cancer Center, Tampa, Florida. 19. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida. 20. Tudogyogyintezet Torokbalint, Törökbálint, Hungary. 21. University of Texas M. D. Anderson Cancer Center, Houston, Texas. 22. Personal Genome Diagnostics, Baltimore, Maryland.
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.
RCT Entities:
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.
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