Limitations of Use: Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer [see Clinical Studies (14.1)].

Non-Squamous NSCLC

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

The safety of pemetrexed for injection, 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 for injection, pembrolizumab, and platinum every 3 weeks for 4 cycles followed by pemetrexed for injection and pembrolizumab (n=405), or placebo, pemetrexed for injection, and platinum every 3 weeks for 4 cycles followed by placebo and pemetrexed for injection (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 for injection 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 for Injection was discontinued for adverse reactions in 23% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions resulting in discontinuation of pemetrexed for injection in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to interruption of pemetrexed for injection occurred in 49% of patients in the pemetrexed for injection, pembrolizumab, and platinum arm. The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed for injection 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 for injection, pembrolizumab, and platinum.

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

Initial Treatment in Combination with Cisplatin

The safety of pemetrexed for injection 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 for injection 500 mg/m2 intravenously and cisplatin 75 mg/m2 intravenously on Day 1 of each 21-day cycle (n=839) or gemcitabine 1,250 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 for injection plus cisplatin in 839 patients in Study JMDB. Median age was 61 years (range 26 to 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 for injection.

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

The following additional adverse reactions of pemetrexed for injection 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 for Injection Containing Platinum-Based Chemotherapy

In Study JMEN, the safety of pemetrexed for injection 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 for injection 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 for injection 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 for injection and a relative dose intensity of pemetrexed for injection 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 for injection.

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

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 for injection arm compared to the placebo arm.

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

 

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 for Injection Plus Platinum Chemotherapy

The safety of pemetrexed for injection 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 for injection in combination with cisplatin as first-line therapy for NSCLC. Patients were randomized to receive pemetrexed for injection 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 for injection 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 for injection and placebo arms. Dose reductions for adverse reactions occurred in 3.3% of patients in the pemetrexed for injection arm and 0.6% in the placebo arm. Dose delays for adverse reactions occurred in 22% of patients in the pemetrexed for injection arm and 16% in the placebo arm.

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

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 for injection arm compared to the placebo arm.

The following additional Grade 3 or 4 adverse reactions were observed more frequently in the pemetrexed for injection 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 for injection 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 for injection 500 mg/m2 intravenously or docetaxel 75 mg/m2 intravenously on Day 1 of each 21-day cycle. All patients on the pemetrexed for injection 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 for injection 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 for injection-treated patients in Study JMEI. Study JMEI is not designed to demonstrate a statistically significant reduction in adverse reaction rates for pemetrexed for injection, as compared to the control arm, for any specified adverse reaction listed in the Table 7 below.

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

 

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 for injection 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 for injection 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 for injection in combination with cisplatin and 222 patients who received at least one dose of cisplatin alone. Among 226 patients who received pemetrexed for injection 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 for injection 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 for injection/cisplatin fully supplemented group and 2 in the pemetrexed for injection/cisplatin never supplemented group. Patients receiving pemetrexed for injection in the fully supplemented group had a relative dose intensity of 93% of the protocol-specified pemetrexed for injection 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 for injection-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 for injection, as compared to the control arm, for any specified adverse reaction listed in the table below.

The following additional adverse reactions were observed in patients receiving pemetrexed for injection 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 for injection-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).

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%

Risk Summary

Based on findings from animal studies and its mechanism of action, pemetrexed for injection can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on pemetrexed for injection use in pregnant women. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and malformations at doses lower than the recommended human dose of 500 mg/m2 [see Data]. Advise pregnant women of the potential risk to a fetus [see Use in Special Populations (8.3)].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Pemetrexed was teratogenic in mice. Daily dosing of pemetrexed by intravenous injection to pregnant mice during the period of organogenesis increased the incidence of fetal malformations (cleft palate; protruding tongue; enlarged or misshaped kidney; and fused lumbar vertebra) at doses (based on BSA) 0.03 times the human dose of 500 mg/m2. At doses, based on BSA, greater than or equal to 0.0012 times the 500 mg/m2 human dose, pemetrexed administration resulted in dose-dependent increases in developmental delays (incomplete ossification of talus and skull bone; and decreased fetal weight).

Risk Summary

There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from pemetrexed for injection, advise women not to breastfeed during treatment with pemetrexed for injection and for one week after the last dose.

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating Pemetrexed for Injection [see Use in Specific Populations (8.1)].

Contraception

Females

Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 6 months after the last dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with pemetrexed for injection and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

Pemetrexed for Injection may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Absorption

The pharmacokinetics of pemetrexed when pemetrexed for injection was administered as a single agent in doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (Cmax) increased proportionally with increase of dose. The pharmacokinetics of pemetrexed did not change over multiple treatment cycles.

Distribution

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicated that pemetrexed is 81% bound to plasma proteins.

Elimination

The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half-life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). As renal function decreases, the clearance of pemetrexed decreases and exposure (AUC) of pemetrexed increases.

Metabolism

Pemetrexed is not metabolized to an appreciable extent.

Excretion

Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. In vitro studies indicated that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that is involved in the active secretion of pemetrexed.

Specific Populations

Age (26 to 80 years) and sex had no clinically meaningful effect on the systemic exposure of pemetrexed based on population pharmacokinetic analyses.

Racial Groups

The pharmacokinetics of pemetrexed were similar in Whites and Blacks or African Americans. Insufficient data are available for other ethnic groups.

Patients with Hepatic Impairment

Pemetrexed has not been formally studied in patients with hepatic impairment. No effect of elevated AST, ALT, or total bilirubin on the PK of pemetrexed was observed in clinical studies.

Patients with Renal Impairment

Pharmacokinetic analyses of pemetrexed included 127 patients with impaired renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

Third-Space Fluid

The pemetrexed plasma concentrations in patients with various solid tumors with stable, mild to moderate third-space fluid were comparable to those observed in patients without third space fluid collections. The effect of severe third space fluid on pharmacokinetics is not known.

Drug Interaction Studies

Drugs Inhibiting OAT3 Transporter

Ibuprofen, an OAT3 inhibitor, administered at 400 mg four times a day decreased the clearance of pemetrexed and increased its exposure (AUC) by approximately 20% in patients with normal renal function (creatinine clearance >80 mL/min).

In Vitro Studies

Pemetrexed is a substrate for OAT3. Ibuprofen, an OAT3 inhibitor inhibited the uptake of pemetrexed in OAT3-expressing cell cultures with an average [Iu]/IC50 ratio of 0.38. In vitro data predict that at clinically relevant concentrations, other NSAIDs (naproxen, diclofenac, celecoxib) would not inhibit the uptake of pemetrexed by OAT3 and would not increase the AUC of pemetrexed to a clinically significant extent. [see Drug Interactions (7)].

Pemetrexed is a substrate for OAT4. In vitro, ibuprofen and other NSAIDs (naproxen, diclofenac, celecoxib) are not inhibitors of OAT4 at clinically relevant concentrations.

Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed.

Cisplatin

Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.

Vitamins

Neither folic acid nor vitamin B12 affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

In vitro studies suggest that pemetrexed does not inhibit the clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Initial Treatment in Combination with Pembrolizumab and Platinum

The efficacy of pemetrexed for injection 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 for Injection 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 for injection 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. Pemetrexed for Injection was administered after pembrolizumab and prior to platinum chemotherapy on Day 1.
• Placebo, pemetrexed for injection 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 for injection 500 mg/m2 intravenously every 3 weeks.

Treatment with pemetrexed for injection 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 for injection, 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 for injection, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, pemetrexed for injection, 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 for injection, 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 for injection in combination with pembrolizumab and platinum chemotherapy compared with placebo, pemetrexed for injection, and platinum chemotherapy (see Table 10 and Figure 1).

At the protocol specified final OS analysis, the median in the pemetrexed for injection 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 for injection and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).

P+P+C = Pemetrexed for Injection + pembrolizumab + platinum chemotherapy.

P+C = Pemetrexed for Injection + platinum chemotherapy + placebo.

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 for injection was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1,725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed for injection 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 for Injection 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 for injection administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1,250 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 1,725 patients were enrolled with 862 patients randomized to pemetrexed for injection in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26 to 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=1,722) and smoking history (n=1,516) 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 1,252 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.

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 for injection based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI.

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 for Injection Containing Platinum-Based Chemotherapy

The efficacy of pemetrexed for injection 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 for injection 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 for injection and 222 patients randomized to placebo. The median age was 61 years (range 26 to 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.

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.

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 for Injection Plus Platinum Chemotherapy

The efficacy of pemetrexed for injection 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 for injection 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 for injection 500 mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to pemetrexed for injection 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 for injection 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.

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

Treatment of Recurrent Disease After Prior Chemotherapy

The efficacy of pemetrexed for injection 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 for injection 500 mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to pemetrexed for injection also received folic acid and vitamin B12. The study was designed to show that overall survival with pemetrexed for injection was non-inferior to docetaxel, as the major efficacy outcome measure, and that overall survival was superior for patients randomized to pemetrexed for injection compared to docetaxel, as a secondary outcome measure.

A total of 571 patients were enrolled with 283 patients randomized to pemetrexed for injection 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)].