Longer follow-up solidifies adjuvant abemaciclib plus endocrine therapy as standard of care for patients with high-risk HR+/HER2- early breast cancer

January 2023 Cancer trials Tom Feys

Previously, the phase III MonarchE trial showed that adding abemaciclib to adjuvant ET significantly improves the invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients with high-risk, HR+/HER2-, node positive early breast cancer. During the 2022 annual SABCS meeting updated results of this trial were presented. At 4 years, the absolute reduction in the recurrence risk obtained from adding abemaciclib to ET was almost 7%, with a relative risk reduction of about 35% compared to ET alone. Overall survival data are still immature at this point, but fewer deaths were observed with abemaciclib + ET than with ET alone. Given the higher incidence of metastatic disease in the control arm, this difference in OS will likely increase in the years to come.

Introduction

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer remains to be the most common breast cancer subtype accounting for about 70% of all early breast cancer (EBC) cases.1,2 Over the last decades, adjuvant endocrine therapy (ET) has become a fundamental pillar of the treatment for patients with HR+/HER2- EBC, significantly decreasing their risk of recurrence and death.3,4 However, despite adjuvant ET, still about 20% of patients will suffer a recurrence with or without distant metastases in the first 10 years following surgery.5 This recurrence risk is even more pronounced in patients with high-risk clinicopathologic features. For example, real-world data show that this recurrence risk mounts to 50% among HR+/HER2- EBC patients with 4 positive axillary nodes, or with 3 positive axillary nodes and either a grade 3 tumor, or a tumor of ≥5cm. Of note, this patient profile is not rare and actually makes up 9% of all breast cancer diagnoses in Belgium, corresponding to about 1,000 patients per year.1,2 Strikingly, 30% of the relapses that occur in these patients during the first 5 years prove to be metastatic, increasing to 50% within the first 9 years, condemning these patients to a palliative treatment.6 As such, these findings clearly underscore the need for more effective adjuvant strategies in this setting.

MonarchE: convincing evidence for a benefit of adjuvant abemaciclib in high-risk HR+/HER2- EBC

MonarchE recruited a total of 5,637 patients with high-risk node positive HR+/HER2- EBC. The intention-to-treat (ITT) population consisted of two cohorts. Cohort 1 (91% of the patients) included patients with high risk based on clinical pathological features (≥4 nodes or 1-3 nodes with grade 3 disease or a tumor size ≥5 cm). A second, smaller exploratory cohort (9% of the patients) was later added and enrolled patients with intermediate risk factors (e.g., 1-3 positive nodes, grade 1-2 disease, T1-T2 tumors), but a high cell proliferation (Ki-67 ≥20%). Following standard of care treatment in the EBC setting, patients in the trial were randomized (1:1) to receive adjuvant ET with or without abemaciclib (150 mg twice daily) for two years. During the follow-up period (3-8 years), adjuvant ET was administered as clinically indicated. The primary endpoint of the study consisted of IDFS, with DRFS and OS as key secondary study objectives.

Previously, results from this pivotal study showed that the addition of abemaciclib to ET resulted in a significant improvement in invasive disease-free (IDFS) and distant relapse-free survival (DRFS).7 In a follow-up analysis of this trial it was subsequently shown that the treatment benefit obtained with adjuvant abemaciclib persisted beyond the 2-year treatment period.8 During the 2022 annual SABCS meeting, results were presented of a pre-planned OS interim analysis that was performed two years following the primary outcomes analysis. At that time, all patients were off abemaciclib.9,10

Deepened clinical benefit for adjuvant abemaciclib with longer follow-up

The presented analysis was performed after a median follow-up of 42 months at which time all patients were off abemaciclib. Interestingly, the IDFS benefit obtained with abemaciclib persisted beyond completion of the treatment, underscoring a carry-over effect. In cohort 1, the updated results revealed a 34.6% reduction in the risk of developing an IDFS event when abemaciclib was added to ET (HR[95%CI]: 0.653[0.567-0.753]). At the four-year landmark, this translates into an absolute IDFS benefit of 6.9% in favour of abemaciclib. Also the DRFS benefit of abemaciclib persisted beyond treatment completion with a significant 35% reduction in the risk of developing a DRFS event with abemaciclib + ET arm vs. ET alone (HR[95%CI]: 0.659[0.567-0.767]). At four years, the absolute DRFS benefit between both arms was 6.1% in favour of abemaciclib. Interestingly, an exploratory analysis in which HRs for IDFS and DRFS were estimated within each year demonstrates that the magnitude of the benefit obtained with abemaciclib increased year after year, beyond the completion of the study treatment period.9,10 At the time of this analysis data on OS remained immature. However, a numerical benefit in OS events was observed with abemaciclib + ET compared to ET alone, with 147 and 168 deaths, respectively ([HR[95%CI]: 0.890 [0.714-1.111]). The 5-year data of this trial are expected next year and based on the significant difference in the number of patients with metastatic disease between both arms (125 with abemaciclib + ET vs. 249 with ET alone), the benefit in OS will likely further increase in favour of abemaciclib.9,10

In this updated analysis, safety data were consistent with previous analyses, without any new safety signals. The most common adverse events with the abemaciclib + ET combination were diarrhea (84% vs. 9%), neutropenia (46% vs. 6%) and fatigue (41% vs. 18%). Adverse events were mostly low-grade and the overall safety profile of abemaciclib was considered manageable and acceptable in this high-risk setting. The incidence of venous thromboembolism was reported at 2.5% in the abemaciclib arm as compared to 0.7% in the control arm. Corresponding rates of interstitial lung disease were 3.3% and 1.3%, respectively. Abemaciclib dose reductions were deemed necessary in 43.6% of patients, with treatment discontinuation in 18.5%.9,10

Conclusions

The benefit of adjuvant abemaciclib in this curative treatment setting deepened in magnitude with longer follow-up, with an increased absolute IDFS and DRFS benefit at 4 years compared to the rates reported after 2, or 3 years. At 4 years, the absolute reduction in the recurrence risk obtained from adding abemaciclib to ET was almost 7%, with a relative risk reduction of about 35% compared to ET alone.9,10 To put this in historical perspective, the relative reduction in the recurrence risk obtained with anastrozole vs. tamoxifen in HR+ EBC was only 25% at 5 years, with an absolute reduction in the 5-year recurrence rate of 2.8%.11 OS data are still immature,  but fewer deaths were observed with abemaciclib + ET than with ET alone. Given the higher incidence of metastatic disease in the control arm, this difference will likely increase in the years to come. As such, these data further support the addition of adjuvant abemaciclib to ET for patients with HR+/HER2-, node-positive, high-risk EBC. In line with this, abemaciclib was scored with an ‘A’ on the ESMO magnitude of clinical benefit score for curative therapies.12

References

  1. http://kankerregister.org/media/docs/CancerFactSheets/2020/Cancer_Fact_Sheet_FemaleBreastCancer_2020.pdf
  2. Van Walle L, et al. BJMO 2020;14(6):263-73.
  3. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
  4. Cardoso F, et al. Ann Oncol 2019;30(8):1194-1220.
  5. EBCTG. Lancet 2015;386(10001):1341-52.
  6. Sheffield KM et al. Future Oncol (2022)18(21),2667-2682
  7. Johnston S, et al. J Clin Oncol. 2020;38(34):3987-3998.
  8. Harbeck N, et al. Ann Oncol. 2021;32(12):1571-1581.
  9. Johnston S, et al. Presented at SABCS 2022; Abstract GS1-09.
  10. Johnston S, et al. Lancet Oncol 2022; Online ahead of print.
  11. ATAC. Lancet Oncol 2008;9(1):45-53.
  12. https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-307-1

Early Breast Cancer: Verzenios▼ in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative, node‑positive early breast cancer at high risk of recurrence (defined by clinical and pathological features: either ≥ 4 pALN (positive axillary lymph nodes), or 1-3 pALN and at least one of the following criteria: tumor size ≥ 5 cm or histological grade 3). In pre‑ or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

Advanced or Metastatic Breast Cancer: Verzenios is indicated for the treatment of women with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

This material is meant only for individuals allowed by law to prescribe or deliver.

Responsible publisher: ELB-Markiesstraat 1/4B Rue du Marquis – 1000 Brussels

PP-AL-BE-0291 JANUARY 2023


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Verzenios® 150 mg€ 3.820,11€ 0
Verzenios® 100 mg€ 3.820,11€ 0
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MINIMAL INFORMATIONS OF THE SPC ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.   1. NAME OF THE MEDICINAL PRODUCT  Verzenios 50 mg film-coated tablets Verzenios 100 mg film-coated tablets Verzenios 150 mg film-coated tablets   2. QUALITATIVE AND QUANTITATIVE COMPOSITION  Verzenios 50 mg film-coated tablets  Each film-coated tablet contains 50 mg abemaciclib.  Excipients with known effect Each film-coated tablet contains 14 mg of lactose monohydrate.  Verzenios 100 mg film-coated tablets  Each film-coated tablet contains 100 mg abemaciclib.  Excipients with known effect Each film-coated tablet contains 28 mg of lactose monohydrate.  Verzenios 150 mg film-coated tablets  Each film-coated tablet contains 150 mg abemaciclib.  Excipients with known effect Each film-coated tablet contains 42 mg of lactose monohydrate.  For the full list of excipients, see section 6.1.   3. PHARMACEUTICAL FORM  Film-coated tablet (tablet).  Verzenios 50 mg film-coated tablets  Beige, oval tablet of 5.2 x 9.5 mm, debossed with “Lilly” on one side and “50” on the other.  Verzenios 100 mg film-coated tablets  White, oval tablet of 6.6 x 12.0 mm, debossed with “Lilly” on one side and “100” on the other.  Verzenios 150 mg film-coated tablets  Yellow, oval tablet of 7.5 x 13.7 mm, debossed with “Lilly” on one side and “150” on the other.   4. CLINICAL PARTICULARS  4.1 Therapeutic indications  Early Breast Cancer  Verzenios in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative, node‑positive early breast cancer at high risk of recurrence (see section 5.1).  In pre‑ or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.  Advanced or Metastatic Breast Cancer  Verzenios is indicated for the treatment of women with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy.  In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.  4.2 Posology and method of administration  Verzenios therapy should be initiated and supervised by physicians experienced in the use of anti‑cancer therapies.  Posology  Verzenios in combination with endocrine therapy The recommended dose of abemaciclib is 150 mg twice daily when used in combination with endocrine therapy. Please refer to the Summary of Product Characteristics of the endocrine therapy combination partner for the recommended posology.   Duration of treatment  Early Breast Cancer Verzenios should be taken continuously for two years, or until disease recurrence or unacceptable toxicity occurs.  Advanced or Metastatic Breast Cancer Verzenios should be taken continuously as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.  If a patient vomits or misses a dose of Verzenios, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.  Dose adjustments  Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Tables 1-7.   Table 1. Dose adjustment recommendations for adverse reactions

 Verzenios dose combination therapy
Recommended dose150 mg twice daily
First dose adjustment100 mg twice daily
Second dose adjustment50 mg twice daily

 Table 2. Management recommendations for haematologic toxicities  Complete blood counts should be monitored prior to the start of Verzenios therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated. Before treatment initiation, absolute neutrophil counts (ANC) ≥ 1 500 / mm3, platelets ≥ 1 00 000 / mm3, and haemoglobin ≥ 8 g/dL are recommended.   

Toxicitya, bManagement recommendations
Grade 1 or 2No dose adjustment required.
Grade 3Suspend dose until toxicity resolves to Grade 2 or less.  Dose reduction is not required.
Grade 3, recurrent; or Grade 4Suspend dose until toxicity resolves to Grade 2 or less.  Resume at next lower dose.
Patient requires administration of blood cell growth factorsSuspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth factors was administered and until 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.

a NCI Common Terminology Criteria for Adverse Events (CTCAE) b ANC: Grade 1: ANC < LLN – 1 500 / mm3; Grade 2: ANC 1 000 – < 1 500 / mm3;
 Grade 3: ANC 500 – < 1 000 / mm3; Grade 4: ANC < 500 / mm3  LLN = lower limit of normal  Table 3. Management recommendations for diarrhoea  Treatment with antidiarrhoeal agents, such as loperamide, should be started at the first sign of loose stools.

Toxicity aManagement recommendations
Grade 1No dose adjustment required.
Grade 2If 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 measuresSuspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose.
Grade 3 or 4 or requires hospitalisation

a NCI CTCAE Table 4. Management recommendations for increased aminotransferases  Alanine aminotransferase (ALT) and aspartate aminostransferase (AST) should be monitored prior to the start of Verzenios therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated.

ToxicityaManagement recommendations
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 cholestasisDiscontinue abemaciclib.
Grade 4 (> 20.0 x ULN)Discontinue abemaciclib.

a NCI CTCAEULN = upper limit of normal Table 5. Management recommendations for interstitial lung disease (ILD)/pneumonitis

ToxicityaManagement recommendations
Grade 1 or 2No dose adjustment required.
Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
Grade 3 or 4Discontinue abemaciclib.

a NCI CTCAE  Table 6. Management recommendations for venous thromboembolic events (VTEs)

ToxicityaManagement recommendations
Early Breast Cancer 
All Grades (1, 2, 3, or 4)Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.
Advanced or metastatic breast cancer 
Grade 1 or 2No dose modification is required.
Grade 3 or 4Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.

a NCI CTCAE  Table 7. Management recommendations for non-haematologic toxicities (excluding diarrhoea, increased aminotransferases, and ILD/pneumonitis and VTEs)

Toxicity aManagement recommendations
Grade 1 or 2No dose adjustment required.
Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures to baseline or Grade 1 within 7 daysSuspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose.
Grade 3 or 4

a NCI CTCAE  CYP3A4 inhibitors Concomitant use of strong CYP3A4 inhibitors should be avoided. If strong CYP3A4 inhibitors cannot be avoided, the abemaciclib dose should be reduced to 100 mg twice daily.  In patients who have had their dose reduced to 100 mg abemaciclib twice daily and in whom co‑administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose should be further reduced to 50 mg twice daily.  In patients who have had their dose reduced to 50 mg abemaciclib twice daily and in whom co‑administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose may be continued with close monitoring of signs of toxicity. Alternatively, the abemaciclib dose may be reduced to 50 mg once daily or discontinued.  If the CYP3A4 inhibitor is discontinued, the abemaciclib dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 3 to 5 half-lives of the CYP3A4 inhibitor).  Special populations  Elderly No dose adjustment is required based on age (see section 5.2).  Renal impairment No dose adjustments are necessary in patients with mild or moderate renal impairment. There are no data regarding abemaciclib administration in patients with severe renal impairment, end stage renal disease, or in patients on dialysis (see section 5.2). Abemaciclib should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.  Hepatic impairment No dose adjustments are necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosing frequency to once daily is recommended (see section 5.2).  Paediatric population The safety and efficacy of abemaciclib in children and adolescents aged less than 18 years has not been established.   No data are available.   Method of administration   Verzenios is for oral use.  The dose can be taken with or without food. It should not be taken with grapefruit or grapefruit juice (see section 4.5).  Patients should take the doses at approximately the same times every day.  The tablet should be swallowed whole (patients should not chew, crush, or split tablets before swallowing).  4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  4.8 Undesirable effects  Summary of the safety profile  The most commonly occurring adverse reactions are diarrhoea, infections, neutropenia, leukopenia, anaemia, fatigue, nausea, vomiting, alopecia and decreased appetite.   Of the most common adverse reactions, Grade ≥ 3 events were less than 5 % with the exception of neutropenia, leukopenia, and diarrhoea.  Tabulated list of adverse reactions  In the following table, adverse reactions are listed in order of MedDRA body system organ class and frequency. Frequency gradings are: very common (³ 1 / 10), common (³ 1 / 100 to < 1 / 10), uncommon (³ 1 / 1 000 to < 1 / 100), rare (³ 1 / 10 000 to < 1 / 1 000), very rare (< 1 / 10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.  Table 8. Adverse reactions reported in the phase 3 studies of abemaciclib in combination with endocrine therapya (N = 3 559)  

System Organ ClassVery CommonCommonUncommon
Infections and infestationsInfections b  
Blood and lymphatic system disorders   Neutropenia Leukopenia Anaemia Thrombocytopenia Lymphopenia h Febrile neutropenia e 
Metabolism and nutrition disordersDecreased appetite  
Nervous system disordersHeadache f Dysgeusia g Dizziness g  
Eye disorders Lacrimation increased 
Vascular disorders Venous thromboembolism c 
Respiratory, thoracic and mediastinal disorders ILD/pneumonitis d 
Gastrointestinal disordersDiarrhoeaVomiting  Nausea Stomatitis fDyspepsia f 
Skin and subcutaneous tissue disordersAlopecia g Pruritus g Rash gNail disorder f   Dry skin e 
Musculoskeletal and connective tissue disorders Muscular weakness e 
General disorders and administration site conditionsPyrexia e Fatigue  
InvestigationsAlanine aminotransferase increased g Aspartate aminotransferase increased g  

a Abemaciclib in combination with anastrozole, letrozole, exemestane, tamoxifen, or fulvestrant. b Infections include all reported Preferred Terms that are part of the System Organ Class Infections and Infestations.  c Venous thromboembolic events include deep vein thrombosis (DVT), pulmonary embolism, cerebral venous sinus thrombosis, subclavian, axillary vein thrombosis, DVT inferior vena cava and pelvic venous thrombosis. d Interstitial lung disease (ILD)/pneumonitis for early breast cancer (EBC) include all reported Preferred Terms that are part of the MedDRA SMQ interstitial lung disease. For metastatic breast cancer (mBC) Preferred Terms include interstitial lung disease, pneumonitis, organising pneumonia, pulmonary fibrosis and bronchiolitis obliterans.  e Considered ADRs in the mBC setting only (MONARCH 2 and MONARCH 3).  f  Considered ADRs in the EBC setting only (monarchE). g Common frequency in the EBC setting (monarchE), very common in the mBC setting (MONARCH 2 and MONARCH 3). h Common frequency in mBC setting (MONARCH 2 and MONARCH 3), very common in the EBC setting (monarchE).  Description of selected adverse reactions  Neutropenia Neutropenia was reported frequently across studies. In the monarchE study, neutropenia was reported in 45.8 % of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 19.1 % of patients receiving abemaciclib in combination with endocrine therapy with a median time to onset of 30 days, and median time to resolution of 16 days. Febrile neutropenia was reported in 0.3 % patients. In MONARCH 2 and MONARCH 3 studies, neutropenia was reported in 45.1 % of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 28.2 % of patients receiving abemaciclib in combination with aromatase inhibitors or fulvestrant. The median time to onset of Grade 3 or 4 neutropenia was 29 to 33 days, and median time to resolution was 11 to 15 days. Febrile neutropenia was reported in 0.9 % patients. Dose modification is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2).   Diarrhoea Diarrhoea was the most commonly reported adverse reaction (see Table 8). Incidence was greatest during the first month of abemaciclib treatment and was lower subsequently. In the monarchE study, the median time to onset of the first diarrhoea event of any grade was 8 days. The median duration of diarrhoea was 7 days for Grade 2 and 5 days for Grade 3. In MONARCH 2 and MONARCH 3 studies, the median time to onset of the first diarrhoea event of any grade was approximately 6 to 8 days. The median duration of diarrhoea was 9 to 12 days for Grade 2 and 6 to 8 days for Grade 3. Diarrhoea returned to baseline or lesser grade with supportive treatment such as loperamide and/or dose adjustment (see section 4.2).  Increased aminotransferases In the monarchE study, ALT and AST elevations were reported frequently (12.3 % and 11.8 %, respectively) in patients receiving abemaciclib in combination with endocrine therapy. Grade 3 or 4 ALT or AST elevations (based on laboratory findings) were reported in 2.6 % and 1.6 % patients. The median time to onset of Grade 3 or 4 ALT elevation was 118 days, and median time to resolution was 14.5 days. The median time to onset of Grade 3 or 4 AST elevation was 90.5 days, and median time to resolution was 11 days. In MONARCH 2 and MONARCH 3 studies, ALT and AST elevations were reported frequently (15.1 % and 14.2 %, respectively) in patients receiving abemaciclib in combination with aromatase inhibitors or fulvestrant. Grade 3 or 4 ALT or AST elevations (based on laboratory findings) were reported in 6.1 % and 4.2 % patients. The median time to onset of Grade 3 or 4 ALT elevation was 57 to 61 days, and median time to resolution was 14 days. The median time to onset of Grade 3 or 4 AST elevation was 71 to 185 days, and median time to resolution was 13 to 15 days. Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see section 4.2).  Creatinine Although not an adverse reaction, abemaciclib has been shown to increase serum creatinine. In the monarchE study, 99.3 % of patients had serum creatinine elevations (based on laboratory findings), and of these, 0.5 % of patients had Grade 3 or 4 elevations. In patients receiving endocrine therapy alone, 91.0 % reported an increase in serum creatinine (all laboratory grades). In MONARCH 2 and MONARCH 3 studies, 98.3 % of patients had serum creatinine elevations (based on laboratory findings), and of these, 1.9 % of patients had Grade 3 or 4 elevations. In patients receiving an aromatase inhibitor or fulvestrant alone, 78.4 % reported an increase in serum creatinine (all laboratory grades). Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters without affecting glomerular function (as measured by iohexol clearance) (see section 4.5). In clinical studies, increases in serum creatinine occurred within the first month of abemaciclib dosing, remained elevated but stable through the treatment period, were reversible upon treatment discontinuation, and were not accompanied by changes in markers of renal function, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate based on cystatin C.  Reporting of suspected adverse reactions  Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Belgium : Agence fédérale des médicaments et des produits de santé, Division Vigilance, Boîte Postale 97, B- 1000 Bruxelles Madou, Site internet: www.notifieruneffetindesirable.be, e-mail: adr@afmps.be. Luxembourg :Centre Régional de Pharmacovigilance de Nancy, Bâtiment de Biologie Moléculaire et de Biopathologie (BBB), CHRU de Nancy – Hôpitaux de Brabois, Rue du Morvan, 54 511 VANDOEUVRE LES NANCY CEDEX, Tél : (+33) 3 83 65 60 85 / 87, E-mail : crpv@chru-nancy.fr ou Direction de la Santé, Division de la Pharmacie et des Médicaments, 20, rue de Bitbourg, L-1273 Luxembourg-Hamm, Tél. : (+352) 2478 5592, E-mail : pharmacovigilance@ms.etat.lu. Link pour le formulaire : https://guichet.public.lu/fr/entreprises/sectoriel/sante/medecins/notification-effets-indesirables-medicaments.html.  7. MARKETING AUTHORISATION HOLDER  Eli Lilly Nederland B.V., Papendorpseweg 83, 3528BJ Utrecht, The Netherlands.   8. MARKETING AUTHORISATION NUMBER(S)   EU/1/18/1307/001 EU/1/18/1307/002 EU/1/18/1307/003 EU/1/18/1307/004 EU/1/18/1307/005 EU/1/18/1307/006 EU/1/18/1307/007 EU/1/18/1307/008 EU/1/18/1307/009 EU/1/18/1307/010 EU/1/18/1307/011 EU/1/18/1307/012 EU/1/18/1307/013 EU/1/18/1307/014 EU/1/18/1307/015 EU/1/18/1307/016 EU/1/18/1307/017 EU/1/18/1307/018 EU/1/18/1307/019 EU/1/18/1307/020 EU/1/18/1307/021   9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  Date of first authorisation:  27 September 2018   10. DATE OF REVISION OF THE TEXT 1 April 2022.  Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu  METHOD OF DELIVERY Medicinal product subject to restricted medical prescription.

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