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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. Niu, Huifeng Nackaerts, Kristiaan Csoszi, Tibor Ostoros, Gyula Mark, Zsuzsanna Baik, Christina Joy, Anil Abraham Chouaid, Christos Jaime, Jesus Corral Kolek, Vitezslav Majem, Margarita Roubec, Jaromir Santos, Edgardo S. Chiang, Anne C. Speranza, Giovanna Belani, Chandra P. Chiappori, Alberto Patel, Manish R. Czebe, Krisztina Byers, Lauren Bahamon, Brittany Li, Cong Sheldon-Waniga, Emily Kong, Eric F. Williams, Miguel Badola, Sunita Shin, Hyunjin Bedford, Lisa Ecsedy, Jeffrey A. Bryant, Matthew Jones, Sian Simmons, John Leonard, E. Jane Ullmann, Claudio Dansky Spigel, David R. Universitat Autònoma de Barcelona Alisertib Aurora A kinase Paclitaxel Phase II SCLC 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. 2020 Article Journal of thoracic oncology ; Vol. 15 Núm. 2 (february 2020), p. 274-287 open access 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. https://creativecommons.org/licenses/by-nc-nd/4.0/