Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for Small-Cell Lung Cancer: Primary and Correlative Biomarker Analyses

Abstract Introduction We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel as second-line treatment for small-cell lung cancer (SCLC). Methods In this double-blind study, patients with relapsed/refractory SCLC were stratified by relapse type (sensitive versus resistant/refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo/paclitaxel (28-day cycles). Primary endpoint 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 178 patients were enrolled (89 in each arm). Median PFS with alisertib/paclitaxel versus placebo/paclitaxel was 3.32 versus 2.17 months (hazard ratio [HR]: 0.77; 95% CI: 0.557–1.067; p = 0.113 in intent-to-treat population, and HR: 0.71; 95% CI: 0.509–0.985; p = 0.038 applying corrected analysis). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (CDK6/RBL1/ RBL2/RB1) had significantly improved PFS (3.68 versus 1.80 months, HR: 0.395; 95% CI: 0.239–0.654; p = 0.0003) and overall survival (7.20 versus 4.47 months, HR: 0.427; 95% CI: 0.259–0.704; p = 0.00085) with alisertib/paclitaxel versus placebo/paclitaxel. A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. Incidence of grade ≥3 drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve (14%) versus 11 (12%) patients died on-study, including 4 versus 0 treatment-related deaths. Conclusions Efficacy signals were seen with alisertib/paclitaxel in relapsed/refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.