Pemetrexed (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, 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.

12.2 Pharmacodynamics

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin.

Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12 . There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

12.3 Pharmacokinetics

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.

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 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).

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 for Injection Pembrolizumab Platinum Chemotherapy n=410 Placebo Pemetrexed for Injection Platinum Chemotherapy n=206
OS
Number (%) of patients with event127 (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 response0.5%0.5%
Partial response47%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 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).

Figure 1
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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 1725 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 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 for injection 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 for Injection 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
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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.

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

Figure 4
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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 26-83 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 for Injection Placebo
Overall survival N=441N=222
Median (months) (95% CI)13.4(11.9-15.9)10.6(8.7-12.0)
Hazard ratioa (95% CI)0.79(0.65-0.95)
p-valuep=0.012
Progression-free survival per independent review N=387N=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-valuep<0.00001
Figure 5
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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.

Efficacy Parameter Overall Survival Progression-Free Survival Per Independent Review
Pemetrexed for Injection (N=441) Placebo (N=222) Pemetrexed for Injection (N=387) Placebo (N=194)
Non-squamous NSCLC (n=481)
Median (months)15.510.34.41.8
HRa 0.700.47
(95% CI)(0.56-0.88)(0.37-0.60)
Adenocarcinoma (n=328)
Median (months)16.811.54.62.7
HRa 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
HRa 0.980.40
(95% CI)(0.36-2.65)(0.12-1.29)
Otherb (n=133)
Median (months)11.37.74.11.6
HRa 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
HRa 1.071.03
(95% CI)(0.77-1.50)(0.71-1.49)
Figure 6
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Figure 6: Kaplan-Meier Curves for Overall Survival in Non-squamous NSCLC in Study JMEN

Figure 7
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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.

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 for Injection (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-valuep=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-valuep<0.0001
Figure 8
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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)].

Table 16: Efficacy Results in Study JMEI

a Hazard ratios are not adjusted for multiplicity or for stratification variables.

Efficacy Parameter Pemetrexed for Injection (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 for Injection (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)

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