Abstract 5157
Background
Abemaciclib is a CDK4 & 6 inhibitor dosed continuously with demonstrated efficacy and an acceptable safety profile in pts with HR+, HER2-negative advanced breast cancer as monotherapy (MONARCH 1) and in combination with endocrine therapy; with fulvestrant (MONARCH 2) or with non-steroidal aromatase inhibitors (MONARCH 3). The most frequent adverse event (AE) is low-grade diarrhea; neutropenia is the most frequent grade 3/4 AE. We describe the timing and management of common AEs in the MONARCH trials.
Methods
Enrollment criteria, study designs and key eligibility criteria of MONARCH 1, 2 and 3 have been reported (Dickler et al. 2017; Sledge et al. 2017; Goetz et al. 2017). Pts were advised to initiate antidiarrheal therapy at first sign of diarrhea and notify the investigator, drink fluids. If not improved within 24 hours to < grade 1, treatment was suspended until diarrhea resolved. Dose reductions required for grade ≥3 or persistent grade 2 diarrhea. For grade 3 neutropenia, abemaciclib was held until < grade 2. The dose was reduced for recurrent grade 3 or grade 4 neutropenia.
Results
Across MONARCH, the median time to onset of diarrhea was between day 6-8. First dose reductions for diarrhea occurred at a median of 28-41 days. Dose holds for diarrhea were brief, constituting 1.7-3.8% off total treatment time. The median time to onset of grade 3/4 neutropenia was 29-36.5 days, and resolved at a median of 11-15 days. AEs were managed by dose adjustments and/or supportive medication (Table).Table: 339P
| Summary of Dose Adjustments in Pts Experiencing Diarrhea or Neutropenia | |||
|---|---|---|---|
| Characteristics | MONARCH 1 Abemaciclib | MONARCH 2 Abemaciclib + F | MONARCH 3 Abemaciclib + NSAI |
| N = 132 | N = 441 | N = 327 | |
| Diarrhea (any grade), n(%) | 119 (90.2) | 381 (86.4) | 269 (82.3) |
| Grade 3 | 26 (19.7) | 59 (13.4) | 31 (9.5) |
| Incidences per patient, n (%) | |||
| 1 | 60 (50.4) | 185 (48.6) | 124 (46.1) |
| 2 | 29 (24.4) | 90 (23.6) | 52 (19.3) |
| ≥3 | 30 (25.2) | 106 (27.8) | 93 (34.6) |
| Outcome, number (%) of events | 263 | 995 | 802 |
| Not recovered/resolved | 15 (5.7) | 106 (10.7) | 70 (8.7) |
| Treatment change, n (%) | 119 | 381 | 269 |
| Dose reduction of study drug | 27 (22.7) | 83 (21.8) | 45 (16.7) |
| Dose omission | 32 (24.2) | 83 (21.8) | 51 (19.0) |
| Treatment discontinuation | 1 (0.8) | 13 (3.4) | 6 (2.2) |
| Antidiarrheal medication, n (%) | 80 (60.6) | 333 (75.5) | 226 (69.1) |
| Neutropenia (any grade), N (%) | 49 (37.1) | 203 (46.0) | 143 (43.7) |
| Grade ¾ | 32 (24.2) | 117 (26.5) | 78 (23.9) |
| Treatment change, n (%) | |||
| Dose reduction of study drug | 14 (10.6) | 44 (10.0) | 42 (12.8) |
| Dose omission | 21 (15.9) | 72 (16.3) | 57 (17.4) |
| Treatment discontinuation | 0 | 7 (1.6) | 9 (2.8) |
Conclusions
The dose adjustment strategy used in the MONARCH studies was effective at managing AEs by dose adjustment and/or supportive medication. Understanding the safety profile of abemaciclib can inform AE management and can extend time on treatment.
Clinical trial identification
NCT02102490 (MONARCH 1), NCT02107703 (MONARCH 2), NCT02246621 (MONARCH 3).
Legal entity responsible for the study
Eli Lilly and Company.
Funding
Eli Lilly and Company.
Editorial Acknowledgement
Disclosure
H.S. Rugo: Grants/research support: GSK, Genentech/Roche, Novartis, Pfizer, Merck, Eisai, Plexxikon, Macrogenics, Lilly, OBI (all funding to UC Regents only). V. André, S. Barriga, T. Forrester: Employee and stakeholder: Eli Lilly and Company. M.P. Goetz: Consultant: Eli Lilly and Company, bioTheranostics, Novartis, Genomic Health, Eisai, Biovica, and Sermonix; Grant/Research support from Eli Lilly and Pfizer. All other authors have declared no conflicts of interest.