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Summarized Data of the Safety Populations of MONARCH-1, MONARCH-2, and MONARCH-3 by Age

900 patients received abemaciclib in the clinical trials MONARCH-1, MONARCH-2, and MONARCH-3. Of those

  • 38% were ≥65 years of age, and 
  • 10% were ≥75 years of age.1 

We observed no overall differences in the safety of abemaciclib between these patients and patients who were <65 years of age.1-3

Please find a summary of the treatment-emergent adverse events (TEAEs) by age group in MONARCH-1, MONARCH-2, and MONARCH-3 in Summary of TEAEs by Age Group for the MONARCH-1 Safety Population, Summary of TEAEs by Age Group for the MONARCH-2 Safety Population, and Summary of TEAEs by Age Group for the MONARCH-3 Safety Population.1

Summary of TEAEsa by Age Group for the MONARCH-1 Safety Population1

TEAE - All Grade, %

Abemaciclib 200 mg

Age <65
(n=90)

Age ≥65
(n=42)

Age 65-74
(n=32)

Age 75-84
(n=9)

Age ≥85
(n=1)

Nausea

63.3

66.7

59.4

88.9

100.0

Fatigue

64.4

66.7

65.6

77.8

0

Decreased appetite

38.9

59.5

56.3

66.7

100.0

Abdominal pain

38.9

38.1

34.4

55.6

0

Constipation

15.6

21.4

15.6

44.4

0

Vomiting

34.4

35.7

34.4

44.4

0

Weight decreased

12.2

16.7

12.5

33.3

0

Anemia

23.3

28.6

28.1

22.2

100.0

Dry mouth

13.3

14.3

12.5

22.2

0

Neutropenia

36.7

38.1

40.6

22.2

100.0

Abbreviation: TEAE = treatment-emergent adverse event(s).

aEvents where the incidence in the groups age 65-74 or 75-84 of the abemaciclib arm is ≥10% and where incidence in the groups age 65-74 or 75-84 of the abemaciclib arm is higher relative to the age <65 group.

Summary of TEAEsa by Age Group for the MONARCH-2 Safety Population1

TEAE - All Grade; ≥ Grade 3, %

Age <65

Age ≥65

Age 65-74 

Age 75-84

Age ≥85

ABE+
FULV
n=287

PBO+
FULV
n=133

ABE+
FULV
n=154

PBO+
FULV
n=90

ABE+
FULV
n=113

PBO+
FULV
n=60

ABE+
FULV
n=38

PBO+
FULV
n=28

ABE+
FULV
n=3

PBO+
FULV
n=2

Diarrhoea

86.8; 11.5

20.3; 0

85.7; 16.9

31.1; 1.1

84.1; 15.9

31.7; 0

89.5; 18.4

25.0; 3.6

100.0; 33.3

100.0; 0

Fatigue

34.1; 2.4

25.6; 0

50.6; 3.2

28.9; 1.1

51.3; 4.4

30.0; 1.7

50.0; 0

28.6; 0

33.3; 0

0; 0

Nausea

40.8; 2.4

21.8; 0.8

53.2; 3.2

24.4; 1.1

55.8; 2.7

21.7; 1.7

44.7; 5.3

25.0; 0

66.7; 0

100.0; 0

Decreased appetite

20.6; 1.4

11.3; 0.8

37.7; 0.6

13.3; 1.1

38.9; 0.9

11.7; 0

34.2; 0

17.9; 3.6

33.3; 0

0; 0

Dyspnea

7.7; 1.0

10.5; 0.8

16.9; 5.8

12.2; 2.2

14.2; 5.3

11.7; 0

21.1; 5.3

10.7; 7.1

66.7; 33.3

50.0; 0

Constipation

12.9; 0.7

12.8; 0

14.9; 0.6

14.4; 1.1

15.9; 0.9

16.7; 1.7

13.2; 0

10.7; 0

0; 0

0; 0

Dysgeusia

13.9; 0

2.3; 0

25.3; 0

3.3; 0

26.5; 0

5.0; 0

21.1; 0

0; 0

33.3; 0

0; 0

Anemia

29.3; 7.7

3.0; 0.8

28.6; 6.5

4.4; 1.1

31.9; 7.1

6.7; 1.7

18.4; 5.3

0; 0

33.3; 0

0; 0

Muscular weakness

9.4; 0.7

5.3; 0

13; 1.3

6.7; 0

12.4; 0.9

6.7; 0

13.2; 2.6

7.1; 0

33.3; 0

0; 0

Neuropathy

7.3; 0

9.8; .8

7.1; 0

10; 0

5.3; 0

10.0; 0

10.5; 0

10.7; 0

33.3; 0

0; 0

Pyrexia

11.8; 0.7

9.0; 0.8

9.1; 0.6

1.1; 0

6.2; 0

1.7; 0

18.4; 2.6

0; 0

0; 0

0; 0

Weight decreased

8.4; 0

1.5; 0.8

14.3; 0.6

3.3; 0

13.3; 0

5.0; 0

18.4; 2.6

0; 0

0; 0

0; 0

Dehydration

1.4; 0.3

0.8; 0.8

9.7; 1.9

3.3; 1.1

8.8; 1.8

3.3; 1.7

13.2; 2.6

3.6; 0

0; 0

0; 0

Dizziness

9.4; 0.7

6.0; 0

18.2; 0.6

5.6; 0

19.5; 0.9

5.0; 0

10.5; 0

7.1; 0

66.7; 0

0; 0

Thrombocytopenia

15.0; 3.8

2.3; 0.8

16.9; 2.6

3.3; 0

16.8; 1.8

5.0; 0

15.8; 5.3

0; 0

33.3; 0

0; 0

Cough

11.1; 0

12.0; 0

17.5; 0

10; 0

19.5; 0

13.3; 0

10.5; 0

3.6; 0

33.3; 0

0; 0

Embolism

4.5; 2.4

0; 0

5.2; 1.9

2.2; 1.1

2.7; 1.8

1.7; 1.7

10.5; 0

3.6; 0

33.3; 33.3

0; 0

Edema peripheral

10.5; 0

4.5; 0

13.6; 0

10; 0

16.8; 0

8.3; 0

5.3; 0

10.7; 0

0; 0

50.0; 0

Blood creatinine increased

7.3; 0.3

0; 0

20.1; 1.9

1.1; 0

23.9; 2.7

1.7; 0

10.5; 0

0; 0

0; 0

0; 0

Conjunctivitis

3.8; 0

0.8; 0

3.2; 0

0; 0

0.9; 0

0; 0

10.5; 0

0; 0

0; 0

0; 0

Dry mouth

5.9; 0

6.8; 0

8.4; 0

5.6; 0

8.0; 0

8.3; 0

10.5; 0

0; 0

0; 0

0; 0

Skin infection

3.1; 0.3

3.0; 0.8

5.2; 1.3

2.2; 1.1

3.5; 1.8

1.7; 1.7

10.5; 0

0; 0

0; 0

50.0; 0

Hypokalemia

5.2; 3.1

2.3; 0

9.7; 3.9

2.2; 1.1

10.6; 5.3

3.3; 1.7

5.3; 0

0; 0

33.3; 0

0; 0

Urinary tract infection

8.4; 0.7

3.8; 0

9.7; 0.6

1.1; 0

11.5; 0.9

1.7; 0

5.3; 0

0; 0

0; 0

0; 0

Lymphopenia

6.6; 3.1

0; 0

8.4; 3.2

1.1; 0

10.6; 4.4

1.7; 0

2.6; 0

0; 0

0; 0

0; 0

Dry skin

8.7; 0

0.8; 0

8.4; 0

2.2; 0

11.5; 0

3.3; 0

0; 0

0; 0

0; 0

0; 0

Abbreviations: ABE = abemaciclib; FULV = fulvestrant; PBO = placebo; TEAE = treatment-emergent adverse event(s).

aEvents where the incidence in the groups age 65-74 or 75-84 of the abemaciclib arm is ≥10% and where incidence in the groups age 65-74 or 75-84 of the abemaciclib arm is higher relative to the age <65 group.

Summary of TEAEsa by Age Group for the MONARCH-3 Safety Population1

TEAE - All Grade; ≥ Grade 3, %

Age <65

Age ≥65

Age 65-74

Age 75-84

Age ≥85

ABE+
NSAI
n=179

PBO+
NSAI
n=89

ABE+
NSAI
n=148

PBO+
NSAI
n=72

ABE+
NSAI
n=106

PBO+
NSAI
n=52

ABE+
NSAI
n=37

PBO+
NSAI
n=18

ABE+
NSAI
n=5

PBO+
NSAI
n=2

Diarrhoea

82.1; 7.3

33.7; 1.1

81.1; 12.2

26.4; 1.4

83.0; 9.4

26.9; 0

83.8; 18.9

44.4; 5.6

60.0; 20.0

0; 0

Fatigue

35.8; 1.7

36.0; 0

45.9; 2.0

27.8; 0

45.3; 2.8

30.8; 0

56.8; 0

27.8; 0

40.0; 0

50.0; 0

Nausea

35.8; 0.6

23.6; 1.1

45.3; 2.0

16.7; 1.4

48.1; 1.9

21.2; 1.9

45.9; 2.7

5.6; 0

60.0; 0

0; 0

Vomiting

25.7; 0

13.5; 1.1

33.8; 2.7

11.1; 2.8

33.0; 1.9

15.4; 3.8

45.9; 8.1

5.6; 5.6

20.0; 0

0; 0

Anemia

24.0; 3.9

4.5; 1.1

35.8; 8.1

6.9; 1.4

40.6; 13.2

9.6; 1.9

35.1; 2.7

16.7; 0

80.0; 20.0

50.0; 0

Decreased appetite

20.1; 0.6

12.4; 1.1

30.4; 2.0

6.9; 0

29.2; 1.9

11.5; 0

43.2; 5.4

0; 0

60.0; 0

0; 0

Blood creatinine increased

11.7; 2.8

2.2; 0

28.4; 1.4

5.6; 0

30.2; 0.9

5.8; 0

32.4; 2.7

11.1; 0

40.0; 0

0; 0

Neutropenia

42.5; 21.8

1.1; 1.1

41.9; 23.6

2.8; 1.4

50.9; 28.3

3.8; 1.9

32.4; 21.6

0; 0

20.0; 20.0

0; 0

Constipation

12.3; 0

13.5; 0

20.9; 1.4

13.9; 0

25.5; 1.9

13.5; 0

18.9; 0

22.2; 0

20.0; 0

0; 0

Urinary tract infection

5.6; 1.1

6.7; 0

14.2; 0

13.9; 1.4

17.9; 2.8

11.5; 1.9

16.2; 2.7

27.8; 0

20.0; 0

0; 0

Arthralgia

13.4; 0

22.5; 0

16.2; 0

13.9; 0

23.6; 0

19.2; 0

13.5; 0

16.7; 0

60.0; 0

0; 0

Cough

9.5; 0

13.5; 0

18.2; 0

6.9; 0

23.6; 0

11.5; 0

16.2; 0

11.1; 0

0; 0

0; 0

Dizziness

12.8; 0

14.6; 0

12.2; 0.7

6.9; 0

13.2; 0

5.8; 0

16.2; 2.7

11.1; 0

20.0; 0

0; 0

Leukopenia

20.7; 7.3

4.5; 1.1

22.3; 9.5

0; 0

24.5; 10.4

0; 0

21.6; 8.1

0; 0

20.0; 20.0

0; 0

Pruritus

14.0; 0

9.0; 0

12.8; 0

9.7; 0

15.1; 0

9.6; 0

16.2; 0

11.1; 0

0; 0

0; 0

Dyspnea

7.8; 0.6

6.7; 1.1

16.9; 1.4

4.2; 0

17.9; 1.9

7.7; 0

16.2; 0

5.6; 0

20.0; 0

0; 0

Pain in extremity

8.9; 0.6

10.1; 0

10.1; 0.7

12.5; 0

12.3; 0.9

15.4; 0

13.5; 0

11.1; 0

20.0; 0

0; 0

Rash

15.1; 0.6

6.7; 0

14.2; 1.4

2.8; 0

16.0; 0.9

1.9; 0

16.2; 2.7

5.6; 0

0; 0

0; 0

Weight decreased

7.8; 0

2.2; 0

12.8; 1.4

4.2; 1.4

15.1; 0.9

3.8; 1.9

16.2; 5.4

0; 0

0; 0

50.0; 0

Acute kidney injury

0; 0

0; 0

4.7; 2.0

1.4; 1.4

4.7; 0.9

0; 0

10.8; 8.1

5.6; 5.6

0; 0

0; 0

AST increased

16.2; 2.8

9.0; 1.1

14.9; 4.1

5.6; 1.4

20.8; 5.7

3.8; 0

8.1; 2.7

11.1; 5.6

20.0; 0

0; 0

Hot flush

10.1; 0

21.3; 0

9.5; 0

12.5; 0

11.3; 0

11.5; 0

5.4; 0

16.7; 0

20.0; 0

0; 0

Lymphopenia

5.0; 1.7

3.4; 0

9.5; 4.1

2.8; 0

10.4; 4.7

3.8; 0

10.8; 5.4

5.6; 0

0; 0

0; 0

Myalgia

8.4; 0

11.2; 0

10.1; 0

1.4; 0

12.3; 0

3.8; 0

13.5; 0

0; 0

20.0; 0

0; 0

Thrombocytopenia

8.9; 1.7

3.4; 1.1

12.8; 4.1

1.4; 0

17.9; 5.7

3.8; 0

13.5; 2.7

0; 0

20.0; 0

0; 0

ALT increased

18.4; 5.0

9.0; 2.2

14.2; 7.4

5.6; 1.4

19.8; 9.4

3.8; 0

5.4; 2.7

11.1; 5.6

20.0; 20.0

0; 0

Embolism

3.9; 1.1

1.1; 1.1

7.4; 4.7

0; 0

6.6; 2.8

0; 0

10.8; 8.1

0; 0

20.0; 20.0

0; 0

Hypocalcemia

2.8; 1.1

2.2; 0

6.1; 1.4

0; 0

4.7; 0.9

3.8; 0

10.8; 2.7

0; 0

0; 0

0; 0

Back pain

16.2; 1.1

16.9; 0

10.8; 0.7

12.5; 1.4

17.9; 0.9

19.2; 1.9

5.4; 0

5.6; 0

40.0; 0

0; 0

Dry skin

6.1; 0

1.1; 0

11.5; 0

4.2; 0

15.1; 0

5.8; 0

8.1; 0

0; 0

20.0; 0

0; 0

Headache

20.7; 1.1

20.2; 0

14.9; 0.7

9.7; 0

22.6; 0.9

13.5; 0

5.4; 0

5.6; 0

40.0; 0

0; 0

Hypertension

3.9; 0.6

5.6; 1.1

6.8; 3.4

6.9; 0

13.2; 8.5

7.7; 0

5.4; 2.7

5.6; 0

20.0; 0

0; 0

Hypokalemia

6.1; 1.7

0; 0

8.8; 4.7

1.4; 0

13.2; 7.5

1.9; 0

5.4; 0

5.6; 0

20.0; 20.0

0; 0

Neuropathy

9.5; 0

9.0; 0

8.8; 0.7

9.7; 0

13.2; 0.9

15.4; 0

8.1; 0

0; 0

20.0; 0

0; 0

Edema peripheral

6.1; 0

6.7; 0

12.2; 0

5.6; 0

17.0; 0

7.7; 0

8.1; 0

0; 0

20.0; 0

0; 0

Pyrexia

10.1; 0.6

16.9; 0

8.1; 0

2.8; 0

12.3; 0

3.8; 0

8.1; 0

0; 0

0; 0

0; 0

Blood alkaline
phosphatase increased

2.8; 0

5.6; 0

6.8; 1.4

1.4; 1.4

11.3; 1.9

0; 0

2.7; 0

5.6; 5.6

20.0; 0

0; 0

Bone pain

11.2; 0

11.2; 0

6.1; 0

5.6; 0

13.2; 0

5.8; 0

0; 0

5.6; 0

0; 0

0; 0

Fall

2.8; 0

2.2; 1.1

6.1; 0.7

1.4; 0

10.4; 0

3.8; 0

2.7; 0

0; 0

20.0; 20.0

0; 0

Lacrimation increased

6.1; 0

1.1; 0

6.8; 0

0; 0

10.4; 0

0; 0

2.7; 0

0; 0

0; 0

0; 0

Abbreviations: ABE = abemaciclib; ALT = alanine aminotransferase; AST = aspartate aminotransferase; NSAI = nonsteroidal aromatase inhibitor; PBO = placebo; TEAE = treatment-emergent adverse event(s).

aEvents where the incidence in the groups age 65-74 or 75-84 of the abemaciclib arm is ≥10% and where incidence in the groups age 65-74 or 75-84 of the abemaciclib arm is higher relative to the age <65 group.

TEAEs of Special Interest Based on the Age-Specific Subgroup Analysis of MONARCH-2 and MONARCH-3 

The most frequent TEAE was any grade diarrhoea. It occurred with similar incidence in abemaciclib-treated patients across age groups (~85%). Clinically relevant diarrhoea (grade 2/3) was higher in the older age groups in the abemaciclib + endocrine therapy (ET) arm. In the placebo + ET arm, grade 2/3 diarrhoea was more common in the ≥75 group compared to the <65 group. Diarrhoea was the most common adverse event leading to study treatment discontinuation in all age groups, which was notably higher in the older subgroups.4

The most common grade ≥3 TEAE was neutropenia.

Treatment-emergent adverse events that were higher in the 2 older subgroups of the abemaciclib + ET arm included

  • gastrointestinal toxicities such as nausea and decreased appetite
  • fatigue, and
  • increased blood creatinine.4

Hepatic events (increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels) had a similar or lower incidence in the older subgroups of the abemaciclib + ET arm compared to the <65 age group.4

The incidence of venous thromboembolic events, including pulmonary embolism or deep vein thrombosis, was more common in patients aged ≥75 compared to the two younger age groups.4

Hematological toxicities including neutropenia, anemia, and leukopenia were higher in the abemaciclib + ET arm compared to the placebo arm, but no differences in the incidence were seen across age groups.4

Description of the Age-Specific Subgroup Analysis of MONARCH-2 and MONARCH-3

The median age of patients was

  • 60 years (range 32-91) in MONARCH-2, and 
  • 63 years (range 32-88) in MONARCH-3.5

We performed an exploratory subgroup analysis of MONARCH-2 and MONARCH-3 with the pooled safety data of 1152 patients.4 The data included

  • 688 (59.7%) patients <65 years
  • 331 (28.7%) patients between 65 and 74 years, and 
  • 133 (11.5%) patients ≥75 years.4

Of those patients, 768 women received abemaciclib plus ET and 384 women received placebo plus ET.4

The age-specific subgroup analyses were based on the pooled safety data and performed for the most common TEAEs associated with either ET or ET plus abemaciclib.4

The baseline disease characteristics were generally balanced among shared characteristics between MONARCH-2 and MONARCH-3, across treatment arms, and between age groups.4

Older patients generally had a higher incidence of comorbidities at baseline related to

  • vascular disorders (mainly hypertension)
  • gastrointestinal disorders (constipation, gastroesophageal reflux disease)
  • cardiac disorders, and
  • metabolism and nutrition disorders (including hypercholesterolemia and hyperglycemia).4

Despite the limited number of patients in the ≥75 group with potentially confounding comorbidities, the safety data suggest that appropriate management of toxicities, including dose adjustments and supportive medication for GI toxicities, could maximize the tolerability of abemaciclib in the elderly.4

Age did not affect the exposure of abemaciclib in a population pharmacokinetic analysis in patients with cancer (135 males and 859 females; age range 24‑91 years).1 A publication by Tate et.al. further supports abemaciclib exposure is not affected by age.6

Food and Drug Administration (FDA) Pooled Analysis of Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor Use in Older Women

The FDA pooled data for older women from 3 randomized controlled studies of different CDK 4/6 inhibitors, including abemaciclib, in combination with an aromatase inhibitor (AI) for the initial treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, metastatic breast cancer. Safety data, were analyzed by age group including

  • ≥70 years,
  • <70 years,
  • ≥75 years, and
  • <75 years.7

The pooled analysis included 1827 patients, of which 1105 received 1 of 3 CDK 4/6 inhibitors along with an AI. In the total population included in this analysis, 456 patients (25%) were age ≥70 years, and 198 (10.8%) were age ≥75 years.7

Incidence of grade 3/4 AEs was 88.8% in patients ≥75 years of age, compared to 73.4% in patients age <75 years.7

Patients ≥75 years experienced higher rates of toxicity, dose modifications, and decreased quality of life scores from baseline.7

References

1Data on file, Eli Lilly and Company and/or one of its subsidiaries.

2Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884. https://doi.org/10.1200/JCO.2017.73.7585

3Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. https://doi.org/10.1200/jco.2017.75.6155

4Goetz MP, Okera M, Wildiers H, et al. Safety and efficacy of abemaciclib plus endocrine therapy in older patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: an age-specific subgroup analysis of MONARCH 2 and 3 trials. Breast Cancer Res Treat. 2021;186(2):417-428. https://doi.org/10.1007/s10549-020-06029-y

5Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

6Tate SC, Sykes AK, Kulanthaivel P, et al. A population pharmacokinetic and pharmacodynamic analysis of abemaciclib in a phase I clinical trial in cancer patients. Clin Pharmacokinet. 2018;57(3):335-344. http://dx.doi.org/10.1007/s40262-017-0559-8

7Howie LJ, Singh H, Bloomquist E, et al. Outcomes of older women with hormone receptor-positive, human epidermal growth factor receptor-negative metastatic breast cancer treated with a CDK4/6 inhibitor and an aromatase inhibitor: an FDA pooled analysis. J Clin Oncol. 2019;37(36):3475-3483. https://doi.org/10.1200/jco.18.02217

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.

Datum fӧr senaste ӧversyn 2021 M03 12


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