Pemetrexed (Page 3 of 9)

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.

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.

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% 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 JMCH^a

Adverse Reactionb	Pemetrexed /cisplatin (N=168)		Cisplatin (N=163)
	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

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 JMCH^a

Grade 3-4 Adverse Reactions	Fully Supplemented Patients N=168(%)	Never Supplemented Patients N=32(%)
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.

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%