Prescription Drug Information: PEMETREXED (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay).

Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

14 CLINICAL STUDIES

14.1 Non-Squamous NSCLC

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 8 and Figure 1.

Table 8: Efficacy Results in Study JMDB
Efficacy ParameterPemetrexed plus Cisplatin (N=862)Gemcitabine plus Cisplatin (N=863)
*
Unadjusted for multiple comparisons.
Adjusted for gender, stage, basis of diagnosis, and performance status.
Overall Survival
Median (months)10.310.3
(95% CI)(9.8–11.2)(9.6–10.9)
Hazard ratio (HR)*, 0.94
(95% CI)(0.84–1.05)
Progression-Free Survival
Median (months)4.85.1
(95% CI)(4.6–5.3)(4.6–5.5)
Hazard ratio (HR)*, 1.04
(95% CI)(0.94–1.15)
Overall Response Rate 27.1%24.7%
(95% CI)(24.2–30.1)(21.8–27.6)
Figure 1
(click image for full-size original)

Figure 1: 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 9 and Figures 2 and 3. 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 9: Overall Survival in NSCLC Histologic Subgroups in Study JMDB
Histologic SubgroupsPemetrexed plus Cisplatin(N=862)Gemcitabine plus Cisplatin(N=863)
*
Unadjusted for multiple comparisons.
Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
Non-squamous NSCLC (N=1252)
Median (months)11.010.1
(95% CI)(10.1–12.5)(9.3–10.9)
HR *, 0.84
(95% CI)(0.74–0.96)
Adenocarcinoma (N=847)
Median (months)12.610.9
(95% CI)(10.7–13.6)(10.2–11.9)
HR *, 0.84
(95% CI)(0.71–0.99)
Large Cell (N=153)
Median (months)10.46.7
(95% CI)(8.6–14.1)(5.5–9.0)
HR *, 0.67
(95% CI)(0.48–0.96)
Non-squamous, not otherwise specified (N=252)
Median (months)8.69.2
(95% CI)(6.8–10.2)(8.1–10.6)
HR *, 1.08
(95% CI)(0.81–1.45)
Squamous Cell (N=473)
Median (months)9.410.8
(95% CI)(8.4–10.2)(9.5–12.1)
HR *, 1.23
(95% CI)(1.00–1.51)
Figure 2
(click image for full-size original)

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

Figure 3
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Figure 3: 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 10 and Figure 4.

Table 10: Efficacy Results in Study JMEN
Efficacy ParameterPemetrexedPlacebo
*
Hazard ratios are adjusted for multiplicity but not for stratification variables.
Overall survival N=441 N=222
Median (months)13.410.6
(95% CI)(11.9–15.9)(8.7–12.0)
Hazard ratio *0.79
(95% CI)(0.65–0.95)
p-valuep=0.012
Progression-free survival per independent review N=387N=194
Median (months)4.02.0
(95% CI)(3.1–4.4)(1.5–2.8)
Hazard ratio *0.60
(95% CI)(0.49–0.73)
p-valuep<0.00001
Figure 4
(click image for full-size original)

Figure 4: Kaplan-Meier Curves for Overall Survival in Study JMEN

The results of pre-specified subgroup analyses by NSCLC histology are presented in Table 11 and Figures 5 and 6.

Table 11: Efficacy Results in Study JMEN by Histologic Subgroup
Efficacy ParameterOverall SurvivalProgression-Free Survival Per Independent Review
Pemetrexed (N=441)Placebo (N=222)Pemetrexed (N=387)Placebo (N=194)
*
Hazard ratios are not adjusted for multiplicity
Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
Non-squamous NSCLC (n=481)
Median (months)15.510.34.41.8
HR *0.700.47
(95% CI)(0.56–0.88)(0.37–0.60)
Adenocarcinoma (n=328)
Median (months)16.811.54.62.7
HR *0.730.51
(95% CI)(0.56–0.96)(0.38–0.68)
Large cell carcinoma (n=20)
Median (months)8.47.94.51.5
HR *0.980.40
(95% CI)(0.36–2.65)(0.12–1.29)
Other (n=133)
Median (months)11.37.74.11.6
HR *0.610.44
(95% CI)(0.40–0.94)(0.28–0.68)
Squamous cell NSCLC (n=182)
Median (months)9.910.82.42.5
HR *1.071.03
(95% CI)(0.77–1.50)(0.71–1.49)
Figure 5
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Figure 5: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN

Figure 6
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Figure 6: 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 12 and Figure 7.

Table 12: Efficacy Results in PARAMOUNT
Efficacy ParameterPemetrexed (N=359)Placebo (N=180)
*
Hazard ratios are adjusted for multiplicity but not for stratification variables.
Based on investigator’s assessment.
Overall survival
Median (months)13.911.0
(95% CI)(12.8–16.0)(10.0–12.5)
Hazard ratio (HR)*0.78
(95% CI)(0.64–0.96)
p-valuep=0.02
Progression-free survival
Median (months)4.12.8
(95% CI)(3.2–4.6)(2.6–3.1)
Hazard ratio (HR)*0.62
(95% CI)(0.49–0.79)
p-valuep<0.0001
Figure 7
(click image for full-size original)

Figure 7: 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 13 and 14, 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 in Studies JMDB and JMEN [see Clinical Studies (14.1)].

Table 13: Efficacy Results in Study JMEI
Efficacy Parameter Pemetrexed (N=283) Docetaxel (N=288)
*
Hazard ratios are not adjusted for multiplicity or for stratification variables.
Overall survival
Median (months) 8.3 7.9
(95% CI) (7.0–9.4) (6.3–9.2)
Hazard ratio * 0.99
(95% CI) (0.82–1.20)
Progression-free survival
Median (months) 2.9 2.9
(95% CI) (2.4–3.1) (2.7–3.4)
Hazard ratio * 0.97
(95% CI) (0.82–1.16)
Overall response rate 8.5% 8.3%
(95% CI) (5.2–11.7) (5.1–11.5)
Table 14: Exploratory Efficacy Analyses by Histologic Subgroup in Study JMEI
Histologic Subgroups Pemetrexed (N=283) Docetaxel (N=288)
*
Hazard ratio unadjusted for multiple comparisons.
Primary diagnosis of NSCLC not specified as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma.
Non-squamous NSCLC (N=399)
Median (months) 9.3 8.0
(95% CI) (7.8–9.7) (6.3–9.3)
HR * 0.89
(95% CI) (0.71–1.13)
Adenocarcinoma (N=301)
Median (months) 9.0 9.2
(95% CI) (7.6–9.6) (7.5–11.3)
HR * 1.09
(95% CI) (0.83–1.44)
Large Cell (N=47)
Median (months) 12.8 4.5
(95% CI) (5.8–14.0) (2.3–9.1)
HR * 0.38
(95% CI) (0.18–0.78)
Other (N=51)
Median (months) 9.4 7.9
(95% CI) (6.0–10.1) (4.0–8.9)
HR * 0.62
(95% CI) (0.32–1.23)
Squamous NSCLC (N=172)
Median (months) 6.2 7.4
(95% CI) (4.9–8.0) (5.6–9.5)
HR * 1.32
(95% CI) (0.93–1.86)

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