University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
Hope S. Rugo , George W. Sledge Jr., Stephen R. D. Johnston , Matthew P. Goetz , Miguel Martin , Masakazu Toi , Tammy D Forrester , Martin Frenzel , Joanne Cox , Susana Barriga , Sara M. Tolaney
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
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