Pemetrexed Dailymed

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Myelosuppression [see Warnings and Precautions (5.1)]
• Renal failure [see Warnings and Precautions (5.2)]
• Bullous and exfoliative skin toxicity [see Warning and Precautions (5.3)]
• Interstitial pneumonitis [see Warnings and Precautions (5.4)]
• Radiation recall [see Warnings and Precautions (5.5)]

• The most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent are fatigue, nausea, and anorexia. (6.1)
• The most common adverse reactions (incidence ≥20%) of pemetrexed when administered with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. (6.1)
• 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. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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

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.
	Pemetrexed Pembrolizumab Platinum Chemotherapy n=405		Placebo Pemetrexed Platinum Chemotherapy n=202
Adverse Reaction	All Grades a (%)	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

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

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.
	Pemetrexed Pembrolizumab Platinum Chemotherapy		Placebo Pemetrexed Platinum Chemotherapy
Laboratory Test a	All Grades b %	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

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 uled 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

a NCI CTCAE version 2.0.
Adverse Reaction a	Pemetrexed/Cisplatin (N=839)		Gemcitabine/Cisplatin (N=830)
	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

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 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 438 patients in Study JMEN. Median age was 61 years (range 26-83 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

a NCI CTCAE version 3.0.
Adverse Reaction a	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

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

a NCI CTCAE version 3.0.
Adverse Reaction a	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

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 uled in the Table 7 below.

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

a NCI CTCAE version 2.0.
Adverse Reaction a	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

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 90-100. 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 uled in the table below.

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

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.
Adverse Reaction b	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

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

a NCI CTCAE version 2.0.
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

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%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pemetrexed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis

14.1 Non-Squamous NSCLC

Initial Treatment in Combination with Pembrolizumab and Platinum

The efficacy of pemetrexed in combination with pembrolizumab and platinum chemotherapy was investigated in Study KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in patients with metastatic non-squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. 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. Randomization was stratified by smoking status (never versus former/current), choice of platinum (cisplatin versus carboplatin), and tumor PD-L1 status (TPS <1% [negative] versus TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:

• Pemetrexed 500 mg/m², pembrolizumab 200 mg, and investigator's choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by pemetrexed 500 mg/m² and pembrolizumab 200 mg intravenously every 3 weeks. Pemetrexed was administered after pembrolizumab and prior to platinum chemotherapy on Day 1.
• Placebo, pemetrexed 500 mg/m², and investigator's choice of cisplatin 75 mg/m² or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m² intravenously every 3 weeks.

Treatment with pemetrexed continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients randomized to placebo, pemetrexed, and platinum chemotherapy were offered pembrolizumab as a single agent at the time of disease progression.

Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

A total of 616 patients were randomized: 410 patients to the pemetrexed, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, pemetrexed, and platinum chemotherapy arm. The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1%. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo, pemetrexed, and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to pemetrexed in combination with pembrolizumab and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy (see Table 10 and Figure 1).

Table 10: Efficacy Results of KEYNOTE-189

a Based on the stratified Cox proportional hazard model.
b Based on stratified log-rank test.
c Response: Best objective response as confirmed complete response or partial response.
d Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status.
NR = not reached
Endpoint	Pemetrexed Pembrolizumab Platinum Chemotherapy n=410	Placebo Pemetrexed Platinum Chemotherapy n=206
OS
Number (%) of patients with event	127 (31%)	108 (52%)
Median in months (95% CI)	NR(NR, NR)	11.3(8.7, 15.1)
Hazard ratioa (95% CI)	0.49 (0.38, 0.64)
p-valueb	<0.0001
PFS
Number of patients with event (%)	245 (60%)	166 (81%)
Median in months (95% CI)	8.8 (7.6, 9.2)	4.9 (4.7, 5.5)
Hazard ratioa (95% CI)	0.52 (0.43, 0.64)
p-valueb	<0.0001
ORR
Overall response ratec (95% CI)	48% (43, 53)	19% (14, 25)
Complete response	0.5%	0.5%
Partial response	47%	18%
p-valued	<0.0001
Duration of Response
Median in months (range)	11.2 (1.1+, 18.0+)	7.8 (2.1+, 16.4+)

At the protocol specified final OS analysis, the median in the pemetrexed in combination with pembrolizumab and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).


Figure 1: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189*

* Based on the protocol-specified final OS analysis

Initial Treatment in Combination with Cisplatin

The efficacy of pemetrexed was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS 0 versus 1), gender, disease stage, basis for pathological diagnosis (histopathological/cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m² on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m² approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m² on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m² approximately 30 minutes after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B₁₂, and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival.

A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes.

Efficacy results in Study JMDB are presented in Table 11 and Figure 2.

Table 11: Efficacy Results in Study JMDB

a Unadjusted for multiple comparisons.
b Adjusted for gender, stage, basis of diagnosis, and performance status.
Efficacy Parameter	Pemetrexed plus Cisplatin (N=862)	Gemcitabine plus Cisplatin (N=863)
Overall Survival
Median (months) (95% CI)	10.3(9.8-11.2)	10.3(9.6-10.9)
Hazard ratio (HR)a,b (95% CI)	0.94(0.84-1.05)
Progression-Free Survival
Median (months) (95% CI)	4.8(4.6-5.3)	5.1(4.6-5.5)
Hazard ratio (HR)a,b (95% CI)	1.04(0.94-1.15)
Overall Response Rate (95% CI)	27.1%(24.2-30.1)	24.7%(21.8-27.6)

Figure 2: Kaplan-Meier Curves for Overall Survival in Study JMDB

In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 12 and Figures 3 and 4 . This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI.

Table 12: Overall Survival in NSCLC Histologic Subgroups in Study JMDB

a Unadjusted for multiple comparisons.
b Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
Histologic Subgroups	Pemetrexed plus Cisplatin (N=862)	Gemcitabine plus Cisplatin (N=863)
Non-squamous NSCLC (N=1252)
Median (months) (95% CI)	11.0(10.1-12.5)	10.1(9.3-10.9)
HRa,b (95% CI)	0.84(0.74-0.96)
Adenocarcinoma (N=847)
Median (months) (95% CI)	12.6(10.7-13.6)	10.9(10.2-11.9)
HRa,b (95% CI)	0.84(0.71-0.99)
Large Cell (N=153)
Median (months) (95% CI)	10.4(8.6-14.1)	6.7(5.5-9.0)
HRa,b (95% CI)	0.67(0.48-0.96)
Non-squamous, not otherwise specified (N=252)
Median (months) (95% CI)	8.6(6.8-10.2)	9.2(8.1-10.6)
HRa,b (95% CI)	1.08(0.81-1.45)
Squamous Cell (N=473)
Median (months) (95% CI)	9.4(8.4-10.2)	10.8(9.5-12.1)
HRa,b (95% CI)	1.23(1.00-1.51)

Figure 3: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMDB
Figure 4: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMDB

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

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN (NCT00102804), a multicenter, randomized (2:1), double-blind, placebo-controlled study conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients were randomized to receive pemetrexed 500 mg/m² intravenously every 21 days or placebo until disease progression or intolerable toxicity. Patients in both study arms received folic acid, vitamin B₁₂, and dexamethasone [see Dosage and Administration (2.4)]. Randomization was carried out using a minimization approach [Pocock and Simon (1975)] using the following factors: gender, ECOG PS (0 versus 1), response to prior chemotherapy (complete or partial response versus stable disease), history of brain metastases (yes versus no), non-platinum component of induction therapy (docetaxel versus gemcitabine versus paclitaxel), and disease stage (IIIb versus IV). The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival; both were measured from the date of randomization in Study JMEN.

A total of 663 patients were enrolled with 441 patients randomized to pemetrexed and 222 patients randomized to placebo. The median age was 61 years (range 26-83 years); 73% were male; 65% were White, 32% were Asian, 2.9% were Hispanic or Latino, and <2% were other ethnicities; 60% had an ECOG PS of 1; and 73% were current or former smokers. Median time from initiation of platinum-based chemotherapy to randomization was 3.3 months (range 1.6 to 5.1 months) and 49% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 81% had Stage IV disease, 73% had non-squamous NSCLC and 27% had squamous NSCLC. Among the 481 patients with non-squamous NSCLC, 68% had adenocarcinoma, 4% had large cell, and 28% had other histologies.

Efficacy results are presented in Table 13 and Figure 5.

Table 13: Efficacy Results in Study JMEN

a Hazard ratios are adjusted for multiplicity but not for stratification variables.
Efficacy Parameter	Pemetrexed	Placebo
Overall survival	N=441	N=222
Median (months)	13.4	10.6
(95% CI)	(11.9-15.9)	(8.7-12.0)
Hazard ratioa (95% CI)	0.79(0.65-0.95)
p-value	p=0.012
Progression-free survival per independent review	N=387	N=194
Median (months) (95% CI)	4.0(3.1-4.4)	2.0(1.5-2.8)
Hazard ratioa (95% CI)	0.60(0.49-0.73)
p-value	p<0.00001

Figure 5: Kaplan-Meier Curves for Overall Survival in Study JMEN

The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 14 and Figures 6 and 7 .

Table 14: Efficacy Results in Study JMEN by Histologic Subgroup

a Hazard ratios are not adjusted for multiplicity
b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
	Overall Survival		Progression-Free Survival Per Independent Review
Efficacy Parameter	Pemetrexed (N=441)	Placebo (N=222)	Pemetrexed (N=387)	Placebo (N=194)
Non-squamous NSCLC (n=481)
Median (months)	15.5	10.3	4.4	1.8
HRa (95% CI)	0.70(0.56-0.88)		0.47(0.37-0.60)
Adenocarcinoma (n=328)
Median (months)	16.8	11.5	4.6	2.7
HRa (95% CI)	0.73(0.56-0.96)		0.51(0.38-0.68)
Large cell carcinoma (n=20)
Median (months)	8.4	7.9	4.5	1.5
HRa (95% CI)	0.98(0.36-2.65)		0.40(0.12-1.29)
Otherb (n=133)
Median (months)	11.3	7.7	4.1	1.6
HRa (95% CI)	0.61(0.40-0.94)		0.44(0.28-0.68)
Squamous cell NSCLC (n=182)
Median (months)	9.9	10.8	2.4	2.5
HRa (95% CI)	1.07(0.77-1.50)		1.03(0.71-1.49)

Figure 6: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN
Figure 7: Kaplan-Meier Curves for Overall Survival in Squamous NSCLC in Study JMEN

Maintenance Treatment Following First-line Pemetrexed Plus Platinum Chemotherapy

The efficacy of pemetrexed as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT (NCT00789373), a multi-center, randomized (2:1), double-blind, placebo-controlled study conducted in patients with Stage IIIb/IV non-squamous NSCLC who had completed four cycles of pemetrexed in combination with cisplatin and achieved a complete response (CR) or partial response (PR) or stable disease (SD). Patients were required to have an ECOG PS of 0 or 1. Patients were randomized to receive pemetrexed 500 mg/m² intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed in combination with cisplatin induction therapy (CR or PR versus SD), disease stage (IIIb versus IV), and ECOG PS (0 versus 1). Patients in both arms received folic acid, vitamin B₁₂, and dexamethasone. The main efficacy outcome measure was investigator-assessed progression-free survival (PFS) and an additional efficacy outcome measure was overall survival (OS); PFS and OS were measured from the time of randomization.

A total of 539 patients were enrolled with 359 patients randomized to pemetrexed and 180 patients randomized to placebo. The median age was 61 years (range 32 to 83 years); 58% were male; 95% were White, 4.5% were Asian, and <1% were Black or African American; 67% had an ECOG PS of 1; 78% were current or former smokers; and 43% of the population achieved a partial or complete response to first-line, platinum-based chemotherapy. With regard to tumor characteristics, 91% had Stage IV disease, 87% had adenocarcinoma, 7% had large cell, and 6% had other histologies.

Efficacy results for PARAMOUNT are presented in Table 15 and Figure 8.

Table 15: Efficacy Results in PARAMOUNT

a Hazard ratios are adjusted for multiplicity but not for stratification variables.
b Based on investigator's assessment.
Efficacy Parameter	Pemetrexed (N=359)	Placebo (N=180)
Overall survival
Median (months) (95% CI)	13.9(12.8-16.0)	11.0(10.0-12.5)
Hazard ratio (HR)a (95% CI)	0.78(0.64-0.96)
p-value	p=0.02
Progression-free survival b
Median (months) (95% CI)	4.1(3.2-4.6)	2.8(2.6-3.1)
Hazard ratio (HR)a (95% CI)	0.62(0.49-0.79)
p-value	p<0.0001

Figure 8: Kaplan-Meier Curves for Overall Survival in PARAMOUNT

Treatment of Recurrent Disease After Prior Chemotherapy

The efficacy of pemetrexed was evaluated in Study JMEI (NCT00004881), a multicenter, randomized (1:1), open-label study conducted in patients with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive pemetrexed 500 mg/m² intravenously or docetaxel 75 mg/m² as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed also received folic acid and vitamin B₁₂. The study was designed to show that overall survival with pemetrexed was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed compared to docetaxel, as a secondary outcome measure.

A total of 571 patients were enrolled with 283 patients randomized to pemetrexed and 288 patients randomized to docetaxel. The median age was 58 years (range 22 to 87 years); 72% were male; 71% were White, 24% were Asian, 2.8% were Black or African American, 1.8% were Hispanic or Latino, and <2% were other ethnicities; 88% had an ECOG PS of 0 or 1. With regard to tumor characteristics, 75% had Stage IV disease; 53% had adenocarcinoma, 30% had squamous histology; 8% large cell; and 9% had other histologic subtypes of NSCLC.

The efficacy results in the overall population and in subgroup analyses based on histologic subtype are provided in Tables 16 and 17, respectively. Study JMEI did not show an improvement in overall survival in the intent-to-treat population. In subgroup analyses, there was no evidence of a treatment effect on survival in patients with squamous NSCLC; the absence of a treatment effect in patients with NSCLC of squamous histology was also observed Studies JMDB and JMEN [see Clinical Studies (14.1)].

Table 16: Efficacy Results in Study JMEI

a Hazard ratios are not adjusted for multiplicity or for stratification variables.
Efficacy Parameter	Pemetrexed (N=283)	Docetaxel (N=288)
Overall survival
Median (months) (95% CI)	8.3(7.0-9.4)	7.9(6.3-9.2)
Hazard ratioa (95% CI)	0.99(0.82-1.20)
Progression-free survival
Median (months) (95% CI)	2.9(2.4-3.1)	2.9(2.7-3.4)
Hazard ratioa (95% CI)	0.97(0.82-1.16)
Overall response rate (95% CI)	8.5%(5.2-11.7)	8.3%(5.1-11.5)

Table 17: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI

a Hazard ratio unadjusted for multiple comparisons.
b Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
Histologic Subgroups	Pemetrexed (N=283)	Docetaxel (N=288)
Non-squamous NSCLC (N=399)
Median (months) (95% CI)	9.3(7.8-9.7)	8.0(6.3-9.3)
HRa (95% CI)	0.89(0.71-1.13)
Adenocarcinoma (N=301)
Median (months) (95% CI)	9.0(7.6-9.6)	9.2(7.5-11.3)
HRa (95% CI)	1.09(0.83-1.44)
Large Cell (N=47)
Median (months) (95% CI)	12.8(5.8-14.0)	4.5(2.3-9.1)
HRa (95% CI)	0.38(0.18-0.78)
Otherb (N=51)
Median (months) (95% CI)	9.4(6.0-10.1)	7.9(4.0-8.9)
HRa (95% CI)	0.62(0.32-1.23)
Squamous NSCLC (N=172)
Median (months) (95% CI)	6.2(4.9-8.0)	7.4(5.6-9.5)
HRa (95% CI)	1.32(0.93-1.86)

14.2 Mesothelioma

The efficacy of pemetrexed was evaluated in Study JMCH (NCT00005636), a multicenter, randomized (1:1), single-blind study conducted in patients with MPM who had received no prior chemotherapy. Patients were randomized (n=456) to receive pemetrexed 500 mg/m² intravenously over 10 minutes followed 30 minutes later by cisplatin 75 mg/m² intravenously over two hours on Day 1 of each 21-day cycle or to receive cisplatin 75 mg/m² intravenously over 2 hours on Day 1 of each 21-day cycle; treatment continued until disease progression or intolerable toxicity. The study was modified after randomization and treatment of 117 patients to require that all patients receive folic acid 350 mcg to 1,000 mcg daily beginning 1 to 3 weeks prior to the first dose of pemetrexed and continuing until 1 to 3 weeks after the last dose, vitamin B₁₂ 1,000 mcg intramuscularly 1 to 3 weeks prior to first dose of pemetrexed and every 9 weeks thereafter, and dexamethasone 4 mg orally, twice daily, for 3 days starting the day prior to each pemetrexed dose. Randomization was stratified by multiple baseline variables including KPS, histologic subtype (epithelial, mixed, sarcomatoid, other), and gender. The major efficacy outcome measure was overall survival and additional efficacy outcome measures were time to disease progression, overall response rate, and response duration.

A total of 448 patients received at least one dose of protocol-specified therapy; 226 patients were randomized to and received at least one dose of pemetrexed plus cisplatin, and 222 patients were randomized to and received cisplatin. Among the 226 patients who received cisplatin with pemetrexed, 74% received full supplementation with folic acid and vitamin B₁₂ during study therapy, 14% were never supplemented, and 12% were partially supplemented. Across the study population, the median age was 61 years (range: 20 to 86 years); 81% were male; 92% were White, 5% were Hispanic or Latino, 3.1% were Asian, and <1% were other ethnicities; and 54% had a baseline KPS score of 90-100% and 46% had a KPS score of 70-80%. With regard to tumor characteristics, 46% had Stage IV disease, 31% Stage III, 15% Stage II, and 7% Stage I disease at baseline; the histologic subtype of mesothelioma was epithelial in 68% of patients, mixed in 16%, sarcomatoid in 10% and other histologic subtypes in 6%. The baseline demographics and tumor characteristics of the subgroup of fully supplemented patients was similar to the overall study population.

The efficacy results from Study JMCH are summarized in Table 18 and Figure 9.

Table 18: Efficacy Results in Study JMCH

a Hazard ratios are not adjusted for stratification variables.
b Not a pre-specified analysis.
Efficacy Parameter	All Randomized and Treated Patients (N=448)		Fully Supplemented Patients (N=331)
	Pemetrexed/Cisplatin (N=226)	Cisplatin (N=222)	Pemetrexed/Cisplatin (N=168)	Cisplatin (N=163)
Median overall survival (months)	12.1	9.3	13.3	10.0
(95% CI)	(10.0-14.4)	(7.8-10.7)	(11.4-14.9)	(8.4-11.9)
Hazard ratioa	0.77		0.75
Log rank p-value	0.020		NAb

Figure 9: Kaplan-Meier Curves for Overall Survival in Study JMCH

Based upon prospectively defined criteria (modified Southwest Oncology Group methodology) the objective tumor response rate for pemetrexed plus cisplatin was greater than the objective tumor response rate for cisplatin alone. There was also improvement in lung function (forced vital capacity) in the pemetrexed plus cisplatin arm compared to the control arm.