Pemetrexed (Page 3 of 8)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

Non-Squamous NSCLC

First-line Treatment of Metastatic Non-squamous NSCLC with Pembrolizumab and Platinum Chemotherapy

The safety of pemetrexed, in combination with pembrolizumab and investigator’s choice of platinum (either carboplatin or cisplatin), was investigated in Study KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated, metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations. A total of 607 patients received pemetrexed, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed and pembrolizumab (n=405), or placebo, pemetrexed, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed (n=202). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies (14.1)].

The median duration of exposure to pemetrexed was 7.2 months (range: 1 day to 1.7 years). Seventy-two percent of patients received carboplatin. The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 years or older, 59% male, 94% White and 3% Asian, and 18% with history of brain metastases at baseline.

Pemetrexed was discontinued for adverse reactions in 23% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed occurred in 49% of patients in the pemetrexed, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).

Table 2 summarizes the adverse reactions that occurred in ≥20% of patients treated with pemetrexed, pembrolizumab, and platinum.

Table 2: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-189

Pemetrexed

Pembrolizumab

Platinum Chemotherapy

n=405

Placebo

Pemetrexed

Platinum Chemotherapy

n=202

Adverse Reaction

All Gradesa

(%)

Grade 3-4 (%)

All Grades

(%)

Grade 3-4 (%)

Gastrointestinal Disorders

Nausea

56

3.5

52

3.5

Constipation

35

1.0

32

0.5

Diarrhea

31

5

21

3.0

Vomiting

24

3.7

23

3.0

General Disorders and Administration Site Conditions

Fatigueb

56

12

58

6

Pyrexia

20

0.2

15

0

Metabolism and Nutrition Disorders

Decreased appetite

28

1.5

30

0.5

Skin and Subcutaneous Tissue Disorders

Rashc

25

2.0

17

2.5

Respiratory, Thoracic and Mediastinal Disorders

Cough

21

0

28

0

Dyspnea

21

3.7

26

5

a Graded per NCI CTCAE version 4.03.

b Includes asthenia and fatigue.

c Includes genital rash, rash, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and rash pustular.

Table 3 summarizes the laboratory abnormalities that worsened from baseline in at least 20% of patients treated with pemetrexed, pembrolizumab, and platinum.

Table 3: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-189

Pemetrexed

Pembrolizumab

Platinum Chemotherapy

Placebo

Pemetrexed

Platinum Chemotherapy

Laboratory Testa

All Gradesb

%

Grades 3-4

%

All Grades

%

Grades 3-4

%

Chemistry

Hyperglycemia

63

9

60

7

Increased ALT

47

3.8

42

2.6

Increased AST

47

2.8

40

1.0

Hypoalbuminemia

39

2.8

39

1.1

Increased creatinine

37

4.2

25

1.0

Hyponatremia

32

7

23

6

Hypophosphatemia

30

10

28

14

Increased alkaline phosphatase

26

1.8

29

2.1

Hypocalcemia

24

2.8

17

0.5

Hyperkalemia

24

2.8

19

3.1

Hypokalemia

21

5

20

5

Hematology

Anemia

85

17

81

18

Lymphopenia

64

22

64

25

Neutropenia

48

20

41

19

Thrombocytopenia

30

12

29

8

a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Pemetrexed/pembrolizumab/platinum chemotherapy (range: 381 to 401 patients) and placebo/pemetrexed/platinum chemotherapy (range: 184 to 197 patients).

b Graded per NCI CTCAE version 4.03

Initial Treatment in Combination with Cisplatin

The safety of pemetrexed was evaluated in Study JMDB, a randomized (1:1), open-label, multicenter trial conducted in chemotherapy-naive patients with locally advanced or metastatic NSCLC. Patients received either pemetrexed 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1250 mg/m2 intravenously on Days 1 and 8 and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=830). All patients were fully supplemented with folic acid and vitamin B12 .

Study JMDB excluded patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS of 2 or greater), uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26-83 years); 70% of patients were men; 78% were White, 16% were Asian, 2.9% were Hispanic or Latino, 2.1% were Black or African American, and <1% were other ethnicities; 36% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed.

Table 4 provides the frequency and severity of adverse reactions that occurred in ≥5% of 839 patients receiving pemetrexed in combination with cisplatin in Study JMDB. Study JMDB was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in Table 4.

Table 4: Adverse Reactions Occurring in ≥5% of Fully Vitamin-Supplemented Patients Receiving Pemetrexed in Combination with Cisplatin Chemotherapy in Study JMDB

Pemetrexed/Cisplatin

Gemcitabine/Cisplatin

(N=839)

(N=830)

Adverse Reactiona

All Grades

Grade 3-4

All Grades

Grade 3-4

(%)

(%)

(%)

(%)

All adverse reactions

90

37

91

53

Laboratory

Hematologic

Anemia

33

6

46

10

Neutropenia

29

15

38

27

Thrombocytopenia

10

4

27

13

Renal

Elevated creatinine

10

1

7

1

Clinical

Constitutional symptoms

Fatigue

43

7

45

5

Gastrointestinal

Nausea

56

7

53

4

Vomiting

40

6

36

6

Anorexia

27

2

24

1

Constipation

21

1

20

0

Stomatitis/pharyngitis

14

1

12

0

Diarrhea

12

1

13

2

Dyspepsia/heartburn

5

0

6

0

Neurology

Sensory neuropathy

9

0

12

1

Taste disturbance

8

0

9

0

Dermatology/Skin

Alopecia

12

0

21

1

Rash/Desquamation

7

0

8

1

a NCI CTCAE version 2.0.

The following additional adverse reactions of pemetrexed were observed.

Incidence 1% to <5%

Body as a Whole — febrile neutropenia, infection, pyrexia

General Disorders — dehydration

Metabolism and Nutrition — increased AST, increased ALT

Renal —renal failure

Eye Disorder — conjunctivitis

Incidence <1%

Cardiovascular — arrhythmia

General Disorders — chest pain

Metabolism and Nutrition — increased GGT

Neurology — motor neuropathy

Maintenance Treatment Following First-line Non- Pemetrexed Containing Platinum-Based Chemotherapy

In Study JMEN, the safety of pemetrexed was evaluated in a randomized (2:1), placebo-controlled, multicenter trial conducted in patients with non-progressive locally advanced or metastatic NSCLC following four cycles of a first-line, platinum-based chemotherapy regimen. Patients received either pemetrexed 500 mg/m2 or matching placebo intravenously every 21 days until disease progression or unacceptable toxicity. Patients in both study arms were fully supplemented with folic acid and vitamin B12 .

Study JMEN excluded patients with an ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance (CLcr) < 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS) or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed in 438 patients in Study JMEN. Median age was 61 years (range 26 to 83 years), 73% of patients were men; 65% were White, 31% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 39% had an ECOG PS 0. Patients received a median of 5 cycles of pemetrexed and a relative dose intensity of pemetrexed of 96%. Approximately half the patients (48%) completed at least six, 21-day cycles and 23% completed ten or more 21-day cycles of pemetrexed.

Table 5 provides the frequency and severity of adverse reactions reported in ≥5% of the 438 pemetrexed-treated patients in Study JMEN.

Table 5: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in Study JMEN

Adverse Reactiona

Pemetrexed

(N=438)

Placebo

(N=218)

All Grades

(%)

Grade 3-4

(%)

All Grades

(%)

Grade 3-4

(%)

All adverse reactions

66

16

37

4

Laboratory

Hematologic

Anemia

15

3

6

1

Neutropenia

6

3

0

0

Hepatic

Increased ALT

10

0

4

0

Increased AST

8

0

4

0

Clinical

Constitutional symptoms

Fatigue

25

5

11

1

Gastrointestinal

Nausea

19

1

6

1

Anorexia

19

2

5

0

Vomiting

9

0

1

0

Mucositis/stomatitis

7

1

2

0

Diarrhea

5

1

3

0

Infection

5

2

2

0

Neurology

Sensory neuropathy

9

1

4

0

Dermatology/Skin

Rash/desquamation

10

0

3

0

a NCI CTCAE version 3.0.

The requirement for transfusions (9.5% versus 3.2%), primarily red blood cell transfusions, and for erythropoiesis stimulating agents (5.9% versus 1.8%) were higher in the pemetrexed arm compared to the placebo arm.

The following additional adverse reactions were observed in patients who received pemetrexed.

Incidence 1% to<5%

Dermatology/Skin — alopecia, pruritus/itching

Gastrointestinal — constipation

General Disorders — edema, fever

Hematologic — thrombocytopenia

Eye Disorder — ocular surface disease (including conjunctivitis), increased lacrimation

Incidence <1%

Cardiovascular — supraventricular arrhythmia

Dermatology/Skin — erythema multiforme

General Disorders — febrile neutropenia, allergic reaction/hypersensitivity

Neurology — motor neuropathy

Renal — renal failure

Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The safety of pemetrexed was evaluated in PARAMOUNT, a randomized (2:1), placebo-controlled study conducted in patients with non-squamous NSCLC with non-progressive (stable or responding disease) locally advanced or metastatic NSCLC following four cycles of pemetrexed in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed 500 mg/m2 or matching placebo intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients in both study arms received folic acid and vitamin B12 supplementation.

PARAMOUNT excluded patients with an ECOG PS of 2 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed in 333 patients in PARAMOUNT. Median age was 61 years (range 32 to 83 years); 58% of patients were men; 94% were White, 4.8% were Asian, and <1% were Black or African American; 36% had an ECOG PS 0. The median number of maintenance cycles was 4 for pemetrexed and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed arm and 16% in the placebo arm.

Table 6 provides the frequency and severity of adverse reactions reported in ≥5% of the 333 pemetrexed-treated patients in PARAMOUNT.

Table 6: Adverse Reactions Occurring in ≥5% of Patients Receiving Pemetrexed in PARAMOUNT

Adverse Reactiona

Pemetrexed

(N=333)

Placebo

(N=167)

All Grades

(%)

Grade 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

All adverse reactions

53

17

34

4.8

Laboratory

Hematologic

Anemia

15

4.8

4.8

0.6

Neutropenia

9

3.9

0.6

0

Clinical

Constitutional symptoms

Fatigue

18

4.5

11

0.6

Gastrointestinal

Nausea

12

0.3

2.4

0

Vomiting

6

0

1.8

0

Mucositis/stomatitis

5

0.3

2.4

0

General disorders

Edema

5

0

3.6

0

a NCI CTCAE version 3.0.

The requirement for red blood cell (13% versus 4.8%) and platelet (1.5% versus 0.6%) transfusions, erythropoiesis stimulating agents (12% versus 7%), and granulocyte colony stimulating factors (6% versus 0%) were higher in the pemetrexed arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed arm.

Incidence 1% to <5%

Blood/Bone Marrow — thrombocytopenia

General Disorders — febrile neutropenia

Incidence <1%

Cardiovascular — ventricular tachycardia, syncope

General Disorders — pain

Gastrointestinal — gastrointestinal obstruction

Neurologic — depression

Renal — renal failure

Vascular — pulmonary embolism

Treatment of Recurrent Disease After Prior Chemotherapy

The safety of pemetrexed was evaluated in Study JMEI, a randomized (1:1), open-label, active-controlled trial conducted in patients who had progressed following platinum-based chemotherapy. Patients received pemetrexed 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed arm received folic acid and vitamin B12 supplementation.

Study JMEI excluded patients with an ECOG PS of 3 or greater, uncontrolled third-space fluid retention, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to discontinue aspirin or other non-steroidal anti-inflammatory drugs or unable to take folic acid, vitamin B12 or corticosteroids were also excluded from the study.

The data described below reflect exposure to pemetrexed in 265 patients in Study JMEI. Median age was 58 years (range 22 to 87 years); 73% of patients were men; 70% were White, 24% were Asian, 2.6% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 19% had an ECOG PS 0.

Table 7 provides the frequency and severity of adverse reactions reported in ≥5% of the 265 pemetrexed-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the Table 7 below.

Table 7: Adverse Reactions Occurring in ≥5% of Fully Supplemented Patients Receiving Pemetrexed in Study JMEI

Adverse Reactiona

Pemetrexed

(N=265)

Docetaxel

(N=276)

All Grades

(%)

Grades 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

Laboratory

Hematologic

Anemia

19

4

22

4

Neutropenia

11

5

45

40

Thrombocytopenia

8

2

1

0

Hepatic

Increased ALT

8

2

1

0

Increased AST

7

1

1

0

Clinical

Gastrointestinal

Nausea

31

3

17

2

Anorexia

22

2

24

3

Vomiting

16

2

12

1

Stomatitis/pharyngitis

15

1

17

1

Diarrhea

13

0

24

3

Constipation

6

0

4

0

Constitutional symptoms

Fatigue

34

5

36

5

Fever

8

0

8

0

Dermatology/Skin

Rash/desquamation

14

0

6

0

Pruritus

7

0

2

0

Alopecia

6

1

38

2

a NCI CTCAE version 2.0.

The following additional adverse reactions were observed in patients assigned to receive pemetrexed.

Incidence 1% to <5%

Body as a Whole — abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection

Dermatology/Skin — erythema multiforme

Neurology — motor neuropathy, sensory neuropathy

Incidence <1%

Cardiovascular — supraventricular arrhythmias

Renal — renal failure

Mesothelioma

The safety of pemetrexed was evaluated in Study JMCH, a randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy for MPM. Patients received pemetrexed 500 mg/m2 intravenously in combination with cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle or cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle administered until disease progression or unacceptable toxicity. Safety was assessed in 226 patients who received at least one dose of pemetrexed in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed in combination with cisplatin, 74% (n=168) received full supplementation with folic acid and vitamin B12 during study therapy, 14% (n=32) were never supplemented, and 12% (n=26) were partially supplemented.

Study JMCH excluded patients with Karnofsky Performance Scale (KPS) of less than 70, inadequate bone marrow reserve and organ function, or a calculated creatinine clearance less than 45 mL/min. Patients unable to stop using aspirin or other non-steroidal anti-inflammatory drugs were also excluded from the study.

The data described below reflect exposure to pemetrexed in 168 patients that were fully supplemented with folic acid and vitamin B12 . Median age was 60 years (range 19 to 85 years); 82% were men; 92% were White, 5% were Hispanic or Latino, 3.0% were Asian, and <1% were other ethnicities; 54% had KPS of 90 to 100. The median number of treatment cycles administered was 6 in the pemetrexed/cisplatin fully supplemented group and 2 in the pemetrexed/cisplatin never supplemented group. Patients receiving pemetrexed in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed dose intensity. The most common adverse reaction resulting in dose delay was neutropenia.

Table 8 provides the frequency and severity of adverse reactions ≥5% in the subgroup of pemetrexed-treated patients who were fully vitamin supplemented in Study JMCH. Study JMCH was not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed, as compared to the control arm, for any specified adverse reaction listed in the table below.

Table 8: Adverse Reactions Occurring in ≥5% of Fully Supplemented Subgroup of Patients Receiving Pemetrexed/Cisplatin in Study JMCHa

Pemetrexed/cisplatin

Cisplatin

(N=168)

(N=163)

Adverse Reactionb

All Grades

Grade 3-4

All Grades

Grade 3-4

(%)

(%)

(%)

(%)

Laboratory

Hematologic

Neutropenia

56

23

13

3

Anemia

26

4

10

0

Thrombocytopenia

23

5

9

0

Renal

Elevated creatinine

11

1

10

1

Decreased creatinine clearance

16

1

18

2

Clinical

Eye Disorder

Conjunctivitis

5

0

1

0

Gastrointestinal

Nausea

82

12

77

6

Vomiting

57

11

50

4

Stomatitis/pharyngitis

23

3

6

0

Anorexia

20

1

14

1

Diarrhea

17

4

8

0

Constipation

12

1

7

1

Dyspepsia

5

1

1

0

Constitutional Symptoms

Fatigue

48

10

42

9

Metabolism and Nutrition

Dehydration

7

4

1

1

Neurology

Sensory neuropathy

10

0

10

1

Taste disturbance

8

0

6

0

Dermatology/Skin

Rash

16

1

5

0

Alopecia

11

0

6

0

a In Study JMCH, 226 patients received at least one dose of pemetrexed in combination with cisplatin and 222 patients received at least one dose of cisplatin. Table 8 provides the ADRs for subgroup of patients treated with pemetrexed in combination with cisplatin (168 patients) or cisplatin alone (163 patients) who received full supplementation with folic acid and vitamin B12 during study therapy.

b NCI CTCAE version 2.0.

The following additional adverse reactions were observed in patients receiving pemetrexed plus cisplatin:

Incidence 1% to <5%

Body as a Whole — febrile neutropenia, infection, pyrexia

Dermatology/Skin — urticaria

General Disorders — chest pain

Metabolism and Nutrition — increased AST, increased ALT, increased GGT

Renal — renal failure

Incidence <1%

Cardiovascular — arrhythmia

Neurology — motor neuropathy

Exploratory Subgroup Analyses based on Vitamin Supplementation

Table 9 provides the results of exploratory analyses of the frequency and severity of NCI CTCAE Grade 3 or 4 adverse reactions reported in more pemetrexed-treated patients who did not receive vitamin supplementation (never supplemented) as compared with those who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in Study JMCH (fully-supplemented).

Table 9: Exploratory Subgroup Analysis of Selected Grade 3/4 Adverse Reactions Occurring in Patients Receiving Pemetrexed in Combination with Cisplatin with or without Full Vitamin Supplementation in Study JMCHa

Fully Supplemented

Never Supplemented

Patients

Patients

N=168

N=32

Grade 3-4 Adverse Reactions

(%)

(%)

Neutropenia

23

38

Thrombocytopenia

5

9

Vomiting

11

31

Febrile neutropenia

1

9

Infection with Grade 3/4 neutropenia

0

6

Diarrhea

4

9

a NCI CTCAE version 2.0

The following adverse reactions occurred more frequently in patients who were fully vitamin supplemented than in patients who were never supplemented:

  • hypertension (11% versus 3%),
  • chest pain (8% versus 6%),
  • thrombosis/embolism (6% versus 3%).

Additional Experience Across Clinical Trials

Sepsis, with or without neutropenia, including fatal cases: 1%

Severe esophagitis, resulting in hospitalization: <1%

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