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Alimta

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Alimta

CLINICAL PHARMACOLOGY

Mechanism of Action

ALIMTA, pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folatedependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Pharmacodynamics

Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.

Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure, or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Time to ANC nadir with pemetrexed systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg•hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.

Pharmacokinetics

Absorption

The pharmacokinetics of ALIMTA 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) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.

Distribution

Pemetrexed has a steady-state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.

Metabolism and Excretion

Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The clearance decreases, and exposure (AUC) increases, as renal function decreases. 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).

The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies.

In vitro studies indicate that pemetrexed is a substrate of OAT3 (organic anion transporter 3), a transporter that may play a role in active secretion of pemetrexed.

Effect of Age, Gender or Race

No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years.

The pharmacokinetics of pemetrexed were not different in male and female patients.

The pharmacokinetics of pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.

Effect of Hepatic Insufficiency

There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Effect of Renal Insufficiency

Pharmacokinetic analyses of pemetrexed included 127 patients with reduced 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 pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/min [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Effect of Third Space Fluid

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is not fully defined. A study of ALIMTA 500 mg/m² was performed in 31 solid tumor patients with stable third space fluid (All but 2 of the 31 patients included in study had mild or moderate amounts of third space fluid). Moderate pleural effusion was defined in the study as less than 1/3 the way up on one side with obscuring of the entire hemidiaphragm. Moderate ascites was defined as that detectable on physical exam. The pemetrexed plasma concentrations in these patients were comparable to those observed in previous clinical trials in patients without third space fluid collections. Thus, drainage of mild or moderate third space fluid collection prior to ALIMTA treatment should be considered, but is probably not necessary. The effect of severe third space fluid on pharmacokinetics is not known.

Effect of Ibuprofen

Ibuprofen doses of 400 mg four times a day reduce pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown [see DRUG INTERACTIONS].

Effect of Aspirin

Aspirin, administered in low to moderate doses (325 mg every 6 hours), does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.

Effect of Cisplatin

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

Effect of Vitamins

Coadministration of oral folic acid or intramuscular vitamin B12 does not affect the pharmacokinetics of pemetrexed.

Drugs Metabolized by Cytochrome P450 Enzymes

Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Clinical Studies

Non-Small Cell Lung Cancer (NSCLC) – Combination with Cisplatin

A multi-center, randomized, open-label study in 1725 chemonaive patients with Stage IIIb/IV NSCLC was conducted to compare the overall survival following treatment with ALIMTA in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² with cisplatin administered intravenously at a dose of 75 mg/m² after ALIMTA administration, on Day 1 of each 21-day 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 after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone [see DOSAGE AND ADMINISTRATION].

Patient demographics of the intent to treat (ITT) population are shown in Table 10. The demographics and disease characteristics were well balanced.

Table 10: First-Line Therapy: Summary of Patient Characteristics in Study of NSCLC

Patient characteristic ALIMTA plus Cisplatin (AC)
(N=862)
Gemcitabine plus Cisplatin (GC)
(N=863)
Age (yrs)
  Median (range) 61.1 (28.8-83.2) 61.0 (26.4-79.4)
Gender
  Male/Female 70.2%/29.8% 70.1%/29.9%
Origin
  Caucasian 669 (77.6%) 680 (78.8%)
  Hispanic 27 (3.1%) 23 (2.7%)
  Asian 146 (16.9%) 141 (16.3%)
  African descent 18 (2.1%) 18 (2.1%)
Stage at Entry
  IIIb/IV 23.8%/76.2% 24.3%/75.7%
Histology
  Nonsquamous NSCLCa 618 (71.7%) 634 (73.5%)
  Adenocarcinoma 436 (50.6%) 411 (47.6%)
  Large cell 76 (8.8%) 77 (8.9%)
  Otherb 106 (12.3%) 146 (16.9%)
  Squamous 244 (28.3%) 229 (26.5%)
ECOG PSc,d
  0/1 35.4%/64.6% 35.6%/64.3%
Smoking Historye
  Ever/never smoker 83.1%/16.9% 83.9%/16.1%
aIncludes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
bThe subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.
cEastern Cooperative Oncology Group Performance Status.
dECOG PS was not reported for all randomized patients. Percentages are representative of N=861 for the ALIMTA plus cisplatin arm, and N=861 for the gemcitabine plus cisplatin arm.
eSmoking history was collected for 88% of randomized patients (N=757 for the ALIMTA plus cisplatin arm and N=759 for the gemcitabine plus cisplatin arm).

Patients received a median of 5 cycles of treatment in both study arms. Patients treated with ALIMTA plus cisplatin received a relative dose intensity of 94.8% of the protocol-specified ALIMTA dose intensity and 95.0% of the protocol-specified cisplatin dose intensity. Patients treated with gemcitabine plus cisplatin received a relative dose intensity of 85.8% of the protocol-specified gemcitabine dose intensity and 93.5% of the protocol-specified cisplatin dose intensity.

The primary endpoint in this study was overall survival. The median survival time was 10.3 months in the ALIMTA plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94.

Table 11: First-Line Therapy: Efficacy in NSCLC – ITT Population

  ALIMTA plus Cisplatin
(N=862)
Gemcitabine plus Cisplatin
(N=863)
Median overall survival (95% CI) 10.3 mos
(9.8-11.2)
10.3 mos
(9.6-10.9)
  Adjusted hazard ratio (HR)a,b (95% CI) 0.94
(0.84-1.05)
Median progression-free survival (95% CI) 4.8 mos
(4.6-5.3)
5.1 mos
(4.6-5.5)
  Adjusted 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)
aAdjusted for gender, stage, basis of diagnosis, and performance status.
bA HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm.

Figure 1: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC – ITT Population.

Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin - Illustration

A pre-specified analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 12. This difference in treatment effect for ALIMTA based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the single-agent, second-line study and the maintenance study [see Clinical Studies].

Table 12: First-Line Therapy: Overall Survival in NSCLC Histologic Subgroups

Histology Subgroup Median Overall Survival in Months (95% CI) Unadjusted Hazard Ratio (HR)a,b (95% CI) Adjusted Hazard Ratio (HR)a,b,c (95% CI)
ALIMTA plus Cisplatin Gemcitabine plus Cisplatin
Nonsquamous NSCLCd (N=1252) 11.0 (10.1-12.5) N=618 10.1 (9.3-10.9) N=634 0.84 (0.74-0.96) 0.84 (0.74-0.96)
Adenocarcinoma (N=847) 12.6 (10.7-13.6) N=436 10.9 (10.2-11.9) N=411 0.84 (0.71-0.98) 0.84
(0.71-0.99)
Large Cell (N=153) 10.4 (8.6-14.1) N=76 6.7 (5.5-9.0) N=77 0.68 (0.48-0.97) 0.67 (0.48-0.96)
Othere (N=252) 8.6 (6.8-10.2) N=106 9.2 (8.1-10.6) N=146 1.12 (0.84-1.49) 1.08 (0.81-1.45)
Squamous Cell (N=473) 9.4 (8.4-10.2) N=244 10.8 (9.5-12.1) N=229 1.22 (0.99-1.50) 1.23 (1.00-1.51)
aA HR that is less than 1.0 indicates that survival is better in the AC arm than in the GC arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the GC arm than in the AC arm.
bUnadjusted for multiple comparisons.
cHRs adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
dIncludes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
eThe subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

Figure 2: Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC – Nonsquamous NSCLC and Squamous Cell NSCLC.

Kaplan-Meier Curves for Overall Survival ALIMTA plus Cisplatin (AC) versus Gemcitabine plus Cisplatin (GC) in NSCLC - Illustration

Non-Small Cell Lung Cancer – Maintenance

ALIMTA Maintenance Following Non-ALIMTA Containing Platinum-Based, Induction Therapy

A multi-center, randomized, double-blind, placebo-controlled study was conducted in 663 patients with Stage IIIb/IV NSCLC who did not progress after four cycles of platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive ALIMTA or placebo immediately following platinum-based chemotherapy. Of the randomized patients, 47.2% versus 52.7% achieved a complete or partial response to induction therapy and 51.9% versus 47.3% had stable disease after induction therapy in the ALIMTA and placebo arms, respectively. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² on Day 1 of each 21-day cycle, until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see DOSAGE AND ADMINISTRATION].

The study was designed to demonstrate superior progression-free survival and overall survival of ALIMTA over placebo. Progression-free survival (PFS) was assessed by independent review. Patient characteristics of the intent to treat (ITT) population are shown in Table 13. The demographics and baseline disease characteristics were well balanced between study arms.

Table 13: Maintenance Therapy Following Platinum-Based Induction Therapy: Summary of Patient Characteristics in Study of NSCLC

Patient characteristic ALIMTA
(N=441)
Placebo
(N=222)
Age (yrs)
  Median (range) 60.6 (25.6-82.6) 60.4 (35.4-78.5)
Gender
  Male/Female 73.0%/27.0% 72.5%/27.5%
Ethnic Origin
  Caucasian 279 (63.3%) 149 (67.1%)
  East Asian 104 (23.6%) 50 (22.5%)
  Other 58 (13.2%) 23 (10.4%)
Stage at Entrya
  IIIb/IV 18.0%/82.0% 21.2%/78.8%
Histology (%)
  Nonsquamous NSCLCb 325 (73.7%) 156 (70.3%)
     Adenocarcinoma 222 (50.3%) 106 (47.7%)
     Large cell 10 (2.3%) 10 (4.5%)
     Otherc 93 (21.1%) 40 (18.0%)
  Squamous 116 (26.3%) 66 (29.7%)
ECOG PSd
  0/1 40.1%/59.9% 38.3%/61.7%
Smoking Historye
  Ever/never smoker 74.1%/25.9% 71.5%/28.5%
Time from start of induction therapy to study randomization (months)
  Median (range) 3.25 (1.6-4.8) 3.29 (2.7-5.1)
aStage at Entry was not reported for all randomized patients. Percentages are representative of N=440 for the ALIMTA arm and N=222 for the placebo arm.
bIncludes patients with adenocarcinoma, large cell, and other histologic diagnoses.
cThe subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
dEastern Cooperative Oncology Group Performance Status (ECOG PS) was not reported for all randomized patients. Percentages are representative of N=439 for the ALIMTA arm, and N=222 for the placebo arm.
eSmoking history was not reported for all randomized patients. Percentages are representative of N=437 for the ALIMTA arm and N=221 for the placebo arm.

Patients received a median of 5 cycles of ALIMTA and 3.5 cycles of placebo. Patients randomized to ALIMTA received a relative dose intensity of 95.7%. A total of 213 patients (48.3%) completed ≥ 6 cycles and a total of 98 patients (22.6%) completed ≥ 10 cycles of treatment with ALIMTA.

In the overall study population, ALIMTA was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months, HR=0.79 (95% CI: 0.65-0.95), p-value=0.012) and PFS (median 4.0 months versus 2.0 months, HR=0.60 (95% CI: 0.49-0.73), p-value < 0.00001). A difference in treatment outcomes was observed according to histologic classification. For the population of patients with nonsquamous NSCLC, ALIMTA was superior to placebo for OS (median 15.5 months versus 10.3 months, HR=0.70 (95% CI: 0.56-0.88)) and PFS (median 4.4 months versus 1.8 months, HR=0.47 (95% CI: 0.37-0.60)). For the population of patients with squamous NSCLC, ALIMTA did not improve OS compared to placebo (median 9.9 months versus 10.8 months, HR=1.07 (95% CI: 0.77-1.50)) or PFS (median 2.4 months versus 2.5 months, HR=1.03 (95% CI: 0.71-1.49)). This difference in treatment effect for ALIMTA based on histology demonstrating lack of benefit in squamous cell histology was also observed in the first-line and second-line studies. [see Clinical Studies]

Efficacy results for the overall patient population are presented in Table 14 and Figure 3, and efficacy results by pre-specified histologic subgroups are presented in Table 15 and Figure 4, below.

Table 14: Maintenance Therapy Following Platinum-Based Induction Therapy: Efficacy of ALIMTA versus Placebo in NSCLC – ITT Population

Efficacy Parametera,b ALIMTA
(N=441)
Placebo
(N=222)
Median overall survivalc (95% CI) 13.4 mos (11.9-15.9) 10.6 mos (8.7-12.0)
  Hazard ratio (HR)c (95% CI) 0.79 (0.65-0.95)
  p-value p=0.012
Median progression-free survival (95% CI) 4.0 mos (3.1-4.4) 2.0 mos (1.5-2.8)
  Hazard ratio (HR)c (95% CI) 0.60 (0.49-0.73)
  p-value p<0.00001
aPFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy.
bValues for PFS given based on independent review (ALIMTA N=387, Placebo N=194).
cUnadjusted hazard ratios are provided. A HR < 1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm.

Table 15: Maintenance Therapy Following Platinum-Based Induction Therapy: Efficacy in NSCLC by Histologic Subgroupsa

  Overall Survival Progression-Free Survivalb
ALIMTA Placebo ALIMTA Placebo
Median (months) Median (months) Median (months) Median (months)
HRc (95% CI) HRc (95% CI)
Nonsquamous NSCLCd 15.5 10.3 4.4 1.8
  N=481 0.70 (0.56-0.88) 0.47 (0.37-0.60)
  Adenocarcinoma 16.8 11.5 4.6 2.7
  N=328 0.73 (0.56-0.96) 0.51 (0.38-0.68)
  Large cell carcinoma 8.4 7.9 4.5 1.5
  N=20 0.98 (0.36-2.65) 0.40 (0.12-1.29)
  Othere 11.3 7.7 4.1 1.6
  N=133 0.61 (0.40-0.94) 0.44 (0.28-0.68)
Squamous cell 9.9 10.8 2.4 2.5
N=182 1.07 (0.77-1.50) 1.03 (0.71-1.49)
a PFS and OS were calculated from time of randomization, after completion of 4 cycles of induction platinum-based chemotherapy. All results unadjusted for multiple comparisons.
b Values for PFS are given based on independent review (ALIMTA N=387, Placebo N=194).
cUnadjusted hazard ratios are provided. A HR < 1.0 indicates that the result is better in the ALIMTA arm than in the placebo arm. A HR > 1.0 indicates that the result is better in the placebo arm than in the ALIMTA arm.
dIncludes patients with adenocarcinoma, large cell carcinoma, and other histology.
eThe subgroup of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.

Figure 3: Kaplan-Meier Curve for Overall Survival ALIMTA (A) versus Placebo (P) in NSCLC – ITT Population.

Kaplan-Meier Curve for Overall Survival ALIMTA (A) versus Placebo (P) in NSCLC - Illustration

Figure 4: Kaplan-Meier Curves for Overall Survival ALIMTA versus Placebo in NSCLC – Nonsquamous NSCLC and Squamous Cell NSCLC.

Kaplan-Meier Curves for Overall Survival ALIMTA versus Placebo in NSCLC - Illustration

Continuation of ALIMTA as Maintenance Following ALIMTA Plus Platinum Induction Therapy

A multi-center, randomized, double-blind, placebo-controlled study was conducted to evaluate continuation of ALIMTA in patients with Stage IIIb/IV nonsquamous NSCLC. Patients completing induction treatment of four cycles of ALIMTA plus cisplatin with stable disease or better and PS 0/1 were randomized (2:1) to maintenance treatment with ALIMTA or placebo. Randomization was stratified by response to induction (complete response (CR)/partial response (PR) versus stable disease (SD)), disease stage (IIIb versus IV), and ECOG performance status (0 versus 1). ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² on Day 1 of each 21-day cycle and continued until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone [see DOSAGE AND ADMINISTRATION]. The main efficacy outcome was investigator-assessed progression-free survival.

A total of 539 patients were randomized; all completed four cycles of ALIMTA and cisplatin induction prior to randomization. Of the randomized patients, 44% versus 42% achieved a complete or partial response to induction therapy and 53% versus 53% had stable disease after induction treatment in the ALIMTA or the placebo arms respectively.

Patient demographics of the intent to treat (ITT) population are shown in Table 16.

Table 16: ALIMTA as Maintenance Therapy Following ALIMTA Plus Cisplatin Induction Therapy: Summary of Patient Characteristics in Study of Nonsquamous NSCLC

Patient characteristic ALIMTA
(N=359)
Placebo
(N=180)
Age (yrs)
  Median 61 62.4
  Range 31.9-78.7 34.9-83.3
Gender (%)
  Male 201 (56%) 112 (62%)
  Female 158 (44%) 68 (38%)
Ethnic Origin (%)
  Caucasian 339 (94%) 171 (95%)
  Asian 16 (4.5%) 8 (4.4%)
  African 4 (1.1%) 1 (0.6%)
Stage at Entry
  IIIb 31 (9%) 18 (10%)
  IV 328 (91%) 162 (90%)
Histology (%)
  Nonsquamous NSCLCa
    Adenocarcinoma 310 (86%) 161 (89%)
    Large cell 24 (7%) 12 (7%)
    Otherb 25 (7%) 7 (3.9%)
ECOG PS (%)
  0 113 (32%) 60 (33%)
  1 245 (68%) 118 (66%)
Smoking Historyc
  Ever 274 (76%) 144 (80%)
  Never smoker 83 (23%) 34 (19%)
aHistological or cytological diagnosis of NSCLC defined as other than predominantly squamous cell histology (squamous cell and/or mixed small cell, non-small cell histology were not permitted on this study).
bThe subcategory of “Other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma or large-cell carcinoma.
cSmoking history was not reported for all randomized patients.

Patients received a median of four cycles of ALIMTA maintenance or placebo. The percentages of patients that received post-study treatment were similar (64% in the ALIMTA arm and 72% in the placebo arm).

The trial showed a statistically significant improvement in progression-free survival and in overall survival for patients randomized to ALIMTA maintenance. Efficacy results are presented in Table 17 and Figure 5.

Table 17: ALIMTA Maintenance Therapy Following ALIMTA Plus Cisplatin Induction Therapy: Efficacy of ALIMTA versus Placebo in Nonsquamous NSCLC

Efficacy Parametera,b ALIMTA
(N=359)
Placebo
(N=180)
Median overall survivalc (95% CI) 13.9 mos (12.8-16.0) 11.0 mos (10.0-12.5)
  Hazard ratio (HR)c (95% CI) 0.78 (0.64-0.96)
  p-value p=0.02
Median progression-free survival (95% CI) 4.1 mos (3.2-4.6) 2.8 mos (2.6-3.1)
  Hazard ratio (HR)c (95% CI) 0.62 (0.49-0.79)
  p-value p < 0.0001
aPFS and OS were calculated from time of randomization, after completion of 4 cycles of ALIMTA plus cisplatin induction therapy.
bValues for PFS given based on investigator assessment.
cA hazard ratio of less than 1 indicates that the maintenance treatment with pemetrexed is associated with lower risk of progression or death compared to treatment with placebo.

Figure 5: Kaplan-Meier Curves for Overall Survival ALIMTA versus Placebo in Nonsquamous NSCLC Following ALIMTA Plus Cisplatin Induction Therapy.

Kaplan-Meier Curves for Overall Survival ALIMTA versus Placebo in Nonsquamous NSCLC - Illustration

Non-Small Cell Lung Cancer –After Prior Chemotherapy

A multi-center, randomized, open label study was conducted in patients with Stage III or IV NSCLC after prior chemotherapy to compare the overall survival following treatment with ALIMTA versus docetaxel. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² and docetaxel was administered at 75 mg/m² as a 1hour intravenous infusion. Both drugs were given on Day 1 of each 21-day cycle. All patients treated with ALIMTA received vitamin supplementation with folic acid and vitamin B12. The study was intended to show either an overall survival superiority or non-inferiority of ALIMTA to docetaxel. Patient demographics of the intent to treat (ITT) population are shown in Table 18.

Table 18: Second-Line Therapy: Summary of Patient Characteristics in NSCLC Study

Patient characteristic ALIMTA
(N=283)
Docetaxel
(N=288)
Age (yrs)
  Median (range) 59 (22-81) 57 (28-87)
Gender (%)
  Male/Female 68.6/31.4 75.3/24.7
Stage at Entry (%)
  III/IV 25.1/74.9 25.3/74.7
Diagnosis/Histology (%)
  Adenocarcinoma   154 (54.4) 142 (49.3)
  Squamous 78 (27.6) 94 (32.6)
  Bronchoalveolar 4 (1.4) 1 (0.3)
  Other 47 (16.6) 51 (17.7)
Performance Status (%)a
  0-1 234 (88.6) 240 (87.6)
  2 30 (11.4) 34 (12.4)
aPerformance status was not reported for all randomized patients. Percentages are representative of N=264 for the ALIMTA arm and N=274 for the docetaxel arm.

The primary endpoint in this study was overall survival. The median survival time was 8.3 months in the ALIMTA treatment arm and 7.9 months in the docetaxel arm, with a hazard ratio of 0.99 (see Table 19). The study did not show an overall survival superiority of ALIMTA.

Table 19: Efficacy of ALIMTA versus Docetaxel in Non-Small Cell Lung Cancer – ITT Population

  ALIMTA
(N=283)
Docetaxel
(N=288)
Median overall survival (95% CI) 8.3 mos (7.0-9.4) 7.9 mos (6.3-9.2)
  Hazard ratio (HR) (95% CI) 0.99 (0.82-1.20)
Median progression-free survival (95% CI) 2.9 mos (2.4-3.1) 2.9 mos (2.7-3.4)
  Hazard ratio (HR) (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)

A retrospective analysis of the impact of NSCLC histology on overall survival was examined. Clinically relevant differences in survival according to histology were observed and are shown in Table 20. This difference in treatment effect for ALIMTA based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in the first-line combination study and in the maintenance study [see Clinical Studies].

Table 20: Second-Line Therapy: Overall Survival of ALIMTA versus Docetaxel in NSCLC by Histologic Subgroups

Histology Subgroup Median Overall Survival in Months (95% CI) Unadjusted Hazard Ratio (HR)a,b (95% CI) Adjusted Hazard Ratio (HR)a,b,c (95% CI)
ALIMTA Docetaxel
Nonsquamous NSCLCd (N=399) 9.3 (7.8-9.7) N=205 8.0 (6.3-9.3) N=194 0.89 (0.71-1.13) 0.78 (0.61-1.00)
  Adenocarcinoma (N=301) 9.0 (7.6-9.6) N=158 9.2 (7.5-11.3) N=143 1.09 (0.83-1.44) 0.92 (0.69-1.22)
  Large Cell (N=47) 12.8 (5.8-14.0) N=18 4.5 (2.3-9.1) N=29 0.38 (0.18-0.78) 0.27 (0.11-0.63)
  Othere (N=51) 9.4(6.0-10.1) N=29 7.9 (4.0-8.9) N=22 0.62 (0.32-1.23) 0.57(0.27-1.20)
Squamous Cell (N=172) 6.2 (4.9-8.0) N=78 7.4 (5.6-9.5) N=94 1.32 (0.93-1.86) 1.56 (1.08-2.26)
aA HR that is less than 1.0 indicates that survival is better in the ALIMTA arm than in the docetaxel arm. Alternatively, a HR that is greater than 1.0 indicates survival is better in the docetaxel arm than in the ALIMTA arm.
bUnadjusted for multiple comparisons.
cHRs adjusted for ECOG PS, time since prior chemotherapy, disease stage, and gender.
dIncludes adenocarcinoma, large cell, and other histologies except those with squamous cell type.
eThe subgroup of “other” represents patients with a primary diagnosis of NSCLC whose disease did not clearly qualify as adenocarcinoma, squamous cell carcinoma, or large cell carcinoma.

Malignant Pleural Mesothelioma

A multi-center, randomized, single-blind study in 448 chemonaive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with ALIMTA in combination with cisplatin to survival in patients receiving cisplatin alone. ALIMTA was administered intravenously over 10 minutes at a dose of 500 mg/m² and cisplatin was administered intravenously over 2 hours at a dose of 75 mg/m² beginning approximately 30 minutes after the end of administration of ALIMTA. Both drugs were given on Day 1 of each 21-day cycle. After 117 patients were treated, white cell and GI toxicity led to a change in protocol whereby all patients were given folic acid and vitamin B12 supplementation.

The primary analysis of this study was performed on the population of all patients randomly assigned to treatment who received study drug (randomized and treated). An analysis was also performed on patients who received folic acid and vitamin B12 supplementation during the entire course of study therapy (fully supplemented), as supplementation is recommended [see DOSAGE AND ADMINISTRATION]. Results in all patients and those fully supplemented were similar. Patient demographics are shown in Table 21.

Table 21: Summary of Patient Characteristics in MPM Study

Patient characteristic Randomized and Treated Patients Fully Supplemented Patients
ALIMTA/cis
(N=226)
Cisplatin
(N=222)
ALIMTA/cis
(N=168)
Cisplatin
(N=163)
Age (yrs)
  Median (range) 61 (29-85) 60 (19-84) 60 (29-85) 60 (19-82)
Gender (%)
  Male 184 (81.4) 181 (81.5) 136 (81.0) 134 (82.2)
  Female 42 (18.6) 41 (18.5) 32 (19.0) 29 (17.8)
Origin (%)
  Caucasian 204 (90.3) 206 (92.8) 150 (89.3) 153 (93.9)
  Hispanic 11 (4.9) 12 (5.4) 10 (6.0) 7 (4.3)
  Asian 10 (4.4) 4 (1.9) 7 (4.2) 3 (1.8)
  African descent 1 (0.4) 0 1 (0.6) 0
Stage at Entry (%)
  I 16 (7.1) 14 (6.3) 15 (8.9) 12 (7.4)
  II 35 (15.6) 33 (15.0) 27 (16.2) 27 (16.8)
  III 73 (32.4) 68 (30.6) 51 (30.5) 49 (30.4)
  IV 101 (44.9) 105 (47.2) 74 (44.3) 73 (45.3)
  Unspecified 1 (0.4) 2 (0.9) 1 (0.6) 2 (1.2)
Diagnosis/Histologya (%)
  Epithelial 154 (68.1) 152 (68.5) 117 (69.6) 113 (69.3)
  Mixed 37 (16.4) 36 (16.2) 25 (14.9) 25 (15.3)
  Sarcomatoid 18 (8.0) 25 (11.3) 14 (8.3) 17 (10.4)
  Other 17 (7.5) 9 (4.1) 12 (7.1) 8 (4.9)
Baseline KPSb (%)
  70-80 109 (48.2) 97 (43.7) 83 (49.4) 69 (42.3)
  90-100 117 (51.8) 125 (56.3) 85 (50.6) 94 (57.7)
aOnly 67% of the patients had the histologic diagnosis of malignant mesothelioma confirmed by independent review.
bKarnofsky Performance Scale.

Table 22 and Figure 6 summarize the survival results for all randomized and treated patients regardless of vitamin supplementation status and those patients receiving vitamin supplementation from the time of enrollment in the trial.

Table 22: Efficacy of ALIMTA plus Cisplatin versus Cisplatin in Malignant Pleural Mesothelioma

Efficacy Parameter Randomized and Treated Patients Fully Supplemented Patients
ALIMTA/cis
(N=226)
Cisplatin
(N=222)
ALIMTA/cis
(N=168)
Cisplatin
(N=163)
Median overall survival 12.1 mos 9.3 mos 13.3 mos 10.0 mos
(95% CI) (10.0-14.4) (7.8-10.7) (11.4-14.9) (8.4-11.9)
Hazard ratio 0.77 0.75
Log rank p-valuea 0.02 0.051
ap-value refers to comparison between arms.

Similar results were seen in the analysis of patients (N=303) with confirmed histologic diagnosis of malignant pleural mesothelioma. There were too few non-white patients to assess possible ethnic differences. The effect in women (median survival 15.7 months with the combination versus 7.5 months on cisplatin alone), however, was larger than the effect in males (median survival 11 versus 9.4 respectively). As with any exploratory analysis, it is not clear whether this difference is real or is a chance finding.

Figure 6: Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone in all Randomized and Treated Patients.

Kaplan-Meier Estimates of Survival Time for ALIMTA plus Cisplatin and Cisplatin Alone - Illustration

Objective tumor response for malignant pleural mesothelioma is difficult to measure and response criteria are not universally agreed upon. However, based upon prospectively defined criteria, the objective tumor response rate for ALIMTA 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 ALIMTA plus cisplatin arm compared to the control arm.

Patients who received full supplementation with folic acid and vitamin B12 during study therapy received a median of 6 and 4 cycles in the ALIMTA/cisplatin (N=168) and cisplatin (N=163) arms, respectively. Patients who never received folic acid and vitamin B12 during study therapy received a median of 2 cycles in both treatment arms (N=32 and N=38 for the ALIMTA/cisplatin and cisplatin arm, respectively). Patients receiving ALIMTA in the fully supplemented group received a relative dose intensity of 93% of the protocol specified ALIMTA dose intensity; patients treated with cisplatin in the same group received 94% of the projected dose intensity. Patients treated with cisplatin alone had a dose intensity of 96%.

Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.

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