Annex 2. Abemaciclib toxicity: An overview
Introduction
Abemaciclib is an orally administered, selective CDK-4 and -6 inhibitor (CDK4/6i) that is structurally distinct from other CDK-4 and -6 inhibitors
Among the three approved CDK4/6i abemaciclib has the highest activity against CDK4 and CDK6 (half maximal inhibitory concentration (IC50) of 2 nmol/L and 10 nmol/L, respectively). Unlike palbociclib and ribociclib, abemaciclib is 14 times more specific for CDK4 than it is for CDK6 which may explain a lower proportion of neutropenia in comparison with the former ones. Additionally, abemaciclib has shown activity against CDK7 (300nmon/L) and CDK9 (57 nmol/L) which are transcriptional cyclin-dependent kinases. It has been proposed that its activity against CDK9 could partially explain the increased gastrointestinal toxicity showed by abemaciclib in comparison with palbociclib and ribociclib.
The recommended dose of abemaciclib is 150 mg twice daily when used in combination with endocrine therapy (FDA and EMA approval) and 200mg twice daily in monotherapy (only FDA approval). If dose reductions are needed, the consecutive reduced doses are the following: 150mg b.i.d (if the starting dose has been 200mg), 100mg b.i.d and 50mg b.i.d.
Adverse events of abemaciclib: incidence and management
Diarrhea
Low grade diarrhea is the most common adverse event (AE) of abemaciclib. Diarrhea appears early after treatment initiation and tends to improve along time and with dose reduction. In MONARCH 2 and MONARCH 3 studies diarrhea caused treatment discontinuation in 2.3%–2.9% of patients. The incidence and severity of diarrhea, together with the distribution of its worst grade in patients experiencing this AE is indicated in the table below (Table 1):
Table 1: Incidence of diarrhea in MONARCH trials
|
Diarrhea N (%) |
MONARCH 1 N= 132 Abemaciclib |
MONARCH 2 N=441 Abemaciclib + fulvestrant |
MONARCH 3 N=325 Abemaciclib +NSAI |
|---|---|---|---|
|
Any Grade |
119 (90.2) | 381 (86.4) | 269 (82.3) |
| G3 | 26 (19.7) | 59 (13.4) | 31 (9.5) |
| Worst grade of diarrhea G3 per patient (only patient with diarrhea) | |||
|---|---|---|---|
| 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) |
In a pooled analysis of the three MONARCH trials, the median time to onset of diarrhea was between day 6 and 8 after treatment initiation. 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 duration of diarrhea was 9 to 12 days (Grade 2) and 6 to 8 days (Grade 3) across studies.
The incidence of diarrhea appears to be lower in the most recent next –MONARCH trial. In this study, 234 patients were randomized to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H plus prophylactic loperamide (Arm C) and the proportion of all grades and G3 diarrhea were: arm A: 53.8%, G3: 1.3%; arm B: 67.1%, G3: 3.8%; and arm C: 62.3%, G3: 7.8%.
Management recommendations for diarrhea are clearly stated in the abemaciclib summary of product characteristics (SmPC) and shown in Table 2. Of note, treatment with antidiarrheal agents, such as loperamide, should be started at the first sign of loose stools. In the MONARCH 2 and 3 trials, antidiarrheal medication, most commonly loperamide, was taken by 69%–76% of patients.
Table 2: Management recommendations for abemaciclib-induced diarrhea
| Toxicity (N CTCAE) | Management recommendation |
|---|---|
| Grade 1 | No dose adjustment required. |
| Grade 2 |
If toxicity does not resolve within 24 hours to Grade 1 or less,
suspend dose until resolution. Dose reduction is not required. Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures, suspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose. |
| Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures | Suspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose. |
| Grade 3 or 4 or requires hospitalization |
Hematologic toxicity
Before treatment initiation, absolute neutrophil counts (ANC) ≥1500/mm3, platelets ≥100,000/mm3, and hemoglobin ≥8 g/dL are recommended.
Neutropenia is less common with abemaciclib than with palbociclib and ribociclib. Nevertheless, it constitutes the most common G3/4 AE. In a combined analysis of MONARCH 2 and 3 trials grade ≥ 3 neutropenia occurred in 25.4% of abemaciclib-treated patients. The median time to onset of grade 3/4 neutropenia was 29-36.5 days and resolved at a median of 11-15 days. Neutropenia was managed with dose omissions (16.8%) and/or dose reductions (11.2%). Infection temporally related to grade ≥ 3 neutropenia ranged from 1.5% to 4.0% in both trials. Febrile neutropenia was rare (0.7%). The use of GCSF, which was allowed according to ASCO guidelines, was low (MONARCH 2 :7.0%, MONARCH 3:4.6%).
Incidence of other hematological grade ≥ 3 toxicities was < 10% in both trials: leukopenia (9%), anemia (7%), thrombocytopenia and lymphopenia (3% each).
The recommended management of hematologic toxicity according to SmPC is summarized in table 3.
Table 3: Management recommendations for abemaciclib-induced neutropenia
| Toxicity (NCI-CTCAE) | Management recommendation |
|---|---|
| Grade 1 or 2 | Suspend dose until toxicity resolves to Grade 2 or less. Dose reductions are not required. |
| Grade 3 recurrent or Grade 4 | Suspend dose until toxicity resolves to Grade 2 or less. Resume at next lower dose. |
| Patient requires administration of blood cell growth factors |
Suspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth factors was administered and until the toxicity resolves to Grade 2 or less.
Resume at next lower dose unless the dose was already reduced for the toxicity that led to the use of the growth factor. |
NCI Common Terminology Criteria for Adverse Events (CTCAE)
ANC (absolute neutrophil counts): Grade 1: ANC < LLN - 1500/mm3;
Grade 2: ANC 1000 - < 1500/mm3;
Grade 3: ANC 500 - < 1000/mm3; Grade 4: ANC < 500/mm3
LLN = lower limit of normal
Increases of aminotransferases
Rises in the level of aminotransferases have been observed during abemaciclib treatment. Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the abemaciclib and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were seen in the abemaciclib and placebo arms respectively, in MONARCH 2.
According to SmPC, ALT and AST should be monitored prior to the start of abemaciclib therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated. The recommended management for aminotransferases toxicity is shown in Table 4.
No dose adjustments are necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) pre-existing hepatic impairment. In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosing frequency to once daily is recommended.
Table 4. Management recommendations for increased aminotransferases
| Toxicity (NCI-CTCAE) | Management recommendation |
|---|---|
|
Grade 1 (>ULN-3.0 x ULN) Grade 2 (>3.0-5.0 x ULN) |
No dose adjustment required. |
| Persistent or Recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN) | Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose. |
| Elevation in AST and/or ALT >3 x ULN WITH total bilirubin >2 x ULN, in the absence of cholestasis | Discontinue abemaciclib. |
| Grade 4 (>20.0 x ULN) | Discontinue abemaciclib. |
Elevation in serum creatinine levels
Similarly to other drugs (e.g trimethoprim, cimetidine) abemaciclib has shown to cause elevation in serum creatinine levels without impairment of glomerular function (all grades = 98.5%; grade 3 = 0.8%). This rise is consequence of the inhibition of renal tubular transporters and it is not accompanied by changes in other renal markers, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration based on cystatin C. The levels of serum creatinine typically remain elevated during abemaciclib therapy and return to basal values upon abemaciclib discontinuation. In case of suspected renal injury in a patient on abemaciclib treatment, alternative measurements of renal function (mentioned above) must be used to evaluate renal impairment and to guide abemaciclib dose adjustment (management recommendations for abemaciclib-related AEs other than hematology toxicity, diarrhea and Interstitial Lung Disease/Pneumonitis, table 7).
No dose adjustments of abemaciclib are necessary in patients with mild or moderate renal impairment. There are no data regarding abemaciclib therapy in patients with severe renal impairment, end stage renal disease, or in patients on dialysis. Abemaciclib should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.
Venous Thromboembolism (VTE)
VTEs are a known AE of special interest (AESI) for abemaciclib. Any-grade VTEs, including deep vein thrombosis or pulmonary embolism, occurred in a statistically significant higher proportion of abemaciclib-treated patients in MONARCH 2 and 3 trials (4.8% and 6.1%, respectively) in comparison with the placebo arm. VTEs were most commonly managed with low-molecular-weight heparin, and anticoagulant treatment continued for the duration of the study. VTEs rarely resulted in abemaciclib dose reduction or discontinuation (≤1%). The vast majority of patients (≥95%) who experienced VTEs had pre-existing risk factors for VTE.
Interstitial lung disease/pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis
can occur in patients treated with abemaciclib, similarly to other CDK4/6 inhibitors
and it is considered an AESI. Across clinical trials (MONARCH 1, MONARCH 2, MONARCH 3),
3.3% of abemaciclib-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4,
and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis, some of them with resulting
in death, have also been observed in the post-authorization setting. Symptoms suggesting ILD
may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and should
be monitored during abemaciclib treatment. Other causes for such symptoms as infectious, neoplastic, etc. should be excluded.
In MONARCH 2 and MONARCH 3 patients experiencing ILD/pneumonitis were managed at physician discretion.
Treatment included steroids (2 of 9 patients in MONARCH 2 and 4 of 17 in MONARCH 3) and/or antibiotics
(6 of 9 patients in MONARCH 2 and 7 of 17 in MONARCH 3). Dose reductions (0.0% in MONARCH 2 and 0.6% in MONARCH 3)
and/or discontinuation (0.4% in MONARCH 2 and 1.2% in MONARCH 3) were infrequent. Abemaciclib dose adjustments for
ILD/pneumonitis are summarized in table below (Table 5)
Table 5. Management recommendations for ILD/pneumonitis
| Toxicity (NCI-CTCAE) | Management recommendation |
|---|---|
| Grade 1 or 2 | No dose adjustment required |
| Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures to baseline or Grade 1 within 7 days | Suspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose. |
| Grade 3 or 4 | Discontinue abemaciclib |
Other AE
Other AE and G≥3 AE reported in phase 3 trials of abemaciclib in combination with endocrine therapy are presented in Table 6. Only AE with an incidence ≥ 10% are included. For more comprehensive information about other AE, see references 2 and 3..Management recommendation for abemaciclib–related toxicity with the exception of neutropenia, diarrhea and ILD/pneumonitis are described in table 7.
Table 6. Adverse reaction reported in phase 3 studies of abemaciclib in combination with endocrine therapy (N=768). Only AEs with a reported incidence ≥ 10% are shown.
| Toxicity (NCI-CTCAE) |
All grades (%) |
Grade 3 (%) |
Grade 4 (%) |
|---|---|---|---|
| Infections | 43.6 | 5.2 | 1.0 |
| Nausea | 43.5 | 2.1 | 0 |
| Fatigue | 40.5 | 2.3 | 0 |
| Vomiting | 27.7 | 1.2 | 0 |
| Decreased appetite | 26.4 | 1.3 | 0 |
| Alopecia | 20.7 | 0 | 0 |
| Dysgeusia | 14.3 | 0 | 0 |
| Pruritus | 13.5 | 0 | 0 |
| Dizzines | 12.9 | 0.5 | 0 |
| Rash | 12.9 | 1.0 | 0 |
| Pyrexia | 10.7 | 0.1 | 0 |
Table 7. Management recommendation for abemaciclib–related toxicity with the exception of neutropenia, diarrhea and ILD/pneumonitis
| Toxicity (NCI-CTCAE) | Management recommendation |
|---|---|
| Grade 1 or 2 | No dose adjustment required. |
| Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures to baseline or Grade 1 within 7 days | Suspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose. |
| Grade 3 or 4 |
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