The association of early toxicity and outcomes for patients treated with abemaciclib.

1053 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 95% CI MONARCH 1 150 vs 200 mg 1.45 .90, 2.33 100 vs 200 mg 1.24 .59, 2.62 MONARCH 2 / 3 100 vs 150 mg 1.03 / .76 (.68, 1.57) / (.47, 1.25) 50 vs 150 mg .92 / .99 (.50, 1.71) / (.51, 1.90) MONARCH 2* / 3* With diarrhea .50 / .49 (.39, .64) / (.35, .67) Without diarrhea .61 / .58 (.48, .77) / (.43, .78) With neutropenia .58 / .54 (.45, .74) / (.39, .75) Without neutropenia .56 / .52 (.43, .73) / (.38, .70) *HR is compared to placebo arm