Background: Approximately 30% of NSCLC tumors harbor KRAS mutations, for which there is no specific treatment. Abemaciclib is a potent and selective inhibitor of CDK4 & 6 approved for treatment of HR+, HER2- advanced breast cancer. In a Phase 1 study, abemaciclib showed greater clinical activity in patients with advanced NSCLC with KRAS mutant tumors versus KRAS wild type tumors. This study compared abemaciclib with erlotinib, both with best supportive care, in previously treated patients with advanced NSCLC and KRAS mutations. Methods: This was a global, Phase 3, comparator-controlled, multicenter, open-label trial for patients with confirmed stage IV NSCLC, detectable KRAS mutations in codons 12 or 13, with progressive disease after platinum-based chemotherapy and 1 additional line of therapy, measurable disease by RECIST v1.1, ECOG performance status 0-1, and adequate organ function. Patients were randomized 3:2 to receive either abemaciclib 200 mg PO Q12H or erlotinib 150 mg PO Q24H until disease progression or unacceptable toxicity. Primary objective was overall survival (OS). Secondary objectives included progression-free survival (PFS), objective response rate (ORR, complete response + partial response), and safety and tolerability. Results: A total of 453 patients were randomized, 270 to abemaciclib and 183 to erlotinib. Median OS was 7.4 months with abemaciclib and 7.8 months with erlotinib (HR [95% CI]: 0.97 [0.77, 1.22]; stratified log-rank, p = 0.77). Median PFS was 3.6 months with abemaciclib and 1.9 months with erlotinib (HR [95% CI]: 0.58 [0.47, 0.72]; stratified log-rank, p < 0.001). The ORR was 8.9% (95% CI: 5.5, 12.3%) with abemaciclib and 2.7% (0.4, 5.1%) with erlotinib (p = 0.01). The disease control rate was 54.4% (95% CI: 48.5, 60.4%) with abemaciclib and 31.7% (25.0, 38.4%) with erlotinib. There were no new safety signals with abemaciclib in this study. Conclusions: In previously treated patients with stage IV NSCLC harboring KRAS mutations, abemaciclib did not improve OS but demonstrated improvement in PFS and ORR compared with erlotinib. Further molecular subgroup analysis based on abemaciclib’s mechanism of action is underway. Clinical trial information: NCT02152631