Background: Abemaciclib is a CDK4 & 6 inhibitor dosed on a continuous schedule and has demonstrated efficacy with an acceptable safety profile in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer as monotherapy and in combination with endocrine therapy in the MONARCH 1, 2, and 3 trials. Early onset, low grade diarrhea was the most common toxicity and was typically manageable and reversible with antidiarrheal medication and/or dose reduction. Neutropenia was the most frequent grade 3/4 toxicity in the abemaciclib arms, typically occurring in the first 2 cycles. Here we provide an assessment of the association between these early toxicities, dose adjustment, and progression-free survival (PFS). Methods: Enrollment criteria, study designs, and endpoints were previously reported (Dickler et al. 2017; Sledge et al. 2017; Goetz et al. 2017). To examine the impact of dose reductions on efficacy, a time-dependent covariate analysis of dose level versus PFS was performed. A landmark analysis was performed for pts with/without toxicity occurring early in treatment (diarrhea: 7 days; neutropenia: 56 days) by comparing PFS for each of these arms to the placebo arm using a Cox model. Results: Discontinuation of abemaciclib due to diarrhea or neutropenia were each < 3% in the abemaciclib arms. Management of toxicity included dose adjustment as necessary. An exploratory time-dependent covariate analysis showed no difference in PFS for pts who dose-reduced compared to those who did not. Compared to placebo, pts in the abemaciclib arms received benefit whether or not diarrhea or neutropenia was observed early in treatment. Conclusions: The dose adjustment strategy used in the MONARCH trials appeared to be an effective way to manage toxicity without compromising efficacy. Clinical trial information: NCT02102490, NCT02107703, NCT02246621

*HR is compared to placebo arm