Pemetrexed (Page 5 of 9)
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 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 in combination with pembrolizumab and platinum chemotherapy was investigated in Study KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in patients with metastatic non-squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never versus former/current), choice of platinum (cisplatin versus carboplatin), and tumor PD-L1 status (TPS <1% [negative] versus TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:
- Pemetrexed 500 mg/m2 , pembrolizumab 200 mg, and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. Pemetrexed was administered after pembrolizumab and prior to platinum chemotherapy on Day 1.
- Placebo, pemetrexed 500 mg/m2 , and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks.
Treatment with pemetrexed continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator or unacceptable toxicity. Patients randomized to placebo, pemetrexed, and platinum chemotherapy were offered pembrolizumab as a single agent at the time of disease progression.
Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures were ORR and duration of response, as assessed by the BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
A total of 616 patients were randomized: 410 patients to the pemetrexed, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, pemetrexed, and platinum chemotherapy arm. The study population characteristics were: median age of 64 years (range: 34 to 84); 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG performance status of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1%. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo, pemetrexed, and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.
The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to pemetrexed in combination with pembrolizumab and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy (see Table 10 and Figure 1).
Table 10: Efficacy Results of KEYNOTE-189
| Endpoint | Pemetrexed Pembrolizumab Platinum Chemotherapy n=410 | Placebo Pemetrexed Platinum Chemotherapy n=206 |
| OS | ||
| Number (%) of patients with event | 127 (31%) | 108 (52%) |
| Median in months (95% CI) | NR (NR, NR) | 11.3 (8.7, 15.1) |
| Hazard ratioa (95% CI) | 0.49 (0.38, 0.64) | |
| p-valueb | <0.0001 | |
| PFS | ||
| Number of patients with event (%) | 245 (60%) | 166 (81%) |
| Median in months (95% CI) | 8.8 (7.6, 9.2) | 4.9 (4.7, 5.5) |
| Hazard ratioa (95% CI) | 0.52 (0.43, 0.64) | |
| p-valueb | <0.0001 | |
| ORR | ||
| Overall response ratec (95% CI) | 48% (43, 53) | 19% (14, 25) |
| Complete response | 0.5% | 0.5% |
| Partial response | 47% | 18% |
| p-valued | <0.0001 | |
| Duration of Response | ||
| Median in months (range) | 11.2 (1.1+, 18+) | 7.8 (2.1+, 16.4+) |
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
At the protocol specified final OS analysis, the median in the pemetrexed in combination with pembrolizumab and platinum chemotherapy arm was 22 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).
P+P+C = pemetrexed + pembrolizumab + platinum chemotherapy.
P+C = pemetrexed + 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 was evaluated in Study JMDB (NCT00087711), a multi-center, randomized (1:1), open-label study conducted in 1725 chemotherapy-naive patients with Stage IIIb/IV NSCLC. Patients were randomized to receive pemetrexed with cisplatin or gemcitabine with cisplatin. Randomization was stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS 0 versus 1), gender, disease stage, basis for pathological diagnosis (histopathological/cytopathological), history of brain metastases, and investigative center. Pemetrexed was administered intravenously over 10 minutes at a dose of 500 mg/m2 on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after pemetrexed administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250 mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75 mg/m2 approximately 30 minutes after administration of gemcitabine, on Day 1 of each 21-day cycle. Treatment was administered up to a total of 6 cycles; patients in both arms received folic acid, vitamin B12 , and dexamethasone [see Dosage and Administration (2.4)]. The primary efficacy outcome measure was overall survival.
A total of 1725 patients were enrolled with 862 patients randomized to pemetrexed in combination with cisplatin and 863 patients to gemcitabine in combination with cisplatin. The median age was 61 years (range 26-83 years), 70% were male, 78% were White, 17% were Asian, 2.9% were Hispanic or Latino, and 2.1% were Black or African American, and <1% were other ethnicities. Among patients for whom ECOG PS (n=1722) and smoking history (n=1516) were collected, 65% had an ECOG PS of 1, 36% had an ECOG PS of 0, and 84% were smokers. For tumor characteristics, 73% had non-squamous NSCLC and 27% had squamous NSCLC; 76% had Stage IV disease. Among 1252 patients with non-squamous NSCLC histology, 68% had a diagnosis of adenocarcinoma, 12% had large cell histology and 20% had other histologic subtypes.
Efficacy results in Study JMDB are presented in Table 11 and Figure 2.
| Efficacy Parameter | Pemetrexed plus Cisplatin (N=862) | Gemcitabine plus Cisplatin (N=863) |
| Overall Survival | ||
| Median (months) (95% CI) | 10.3 (9.8-11.2) | 10.3 (9.6-10.9) |
| Hazard ratio (HR)a,b (95% CI) | 0.94(0.84-1.05) | |
| Progression-Free Survival | ||
| Median (months) (95% CI) | 4.8 (4.6-5.3) | 5.1(4.6-5.5) |
| Hazard ratio (HR)a,b (95% CI) | 1.04(0.94-1.15) | |
| Overall Response Rate (95% CI) | 27.1%(24.2-30.1) | 24.7%(21.8-27.6) |
a Unadjusted for multiple comparisons.
b Adjusted for gender, stage, basis of diagnosis, and performance status.
Figure 2: Kaplan-Meier Curves for Overall Survival in Study JMDB
In pre-specified analyses assessing the impact of NSCLC histology on overall survival, clinically relevant differences in survival according to histology were observed. These subgroup analyses are shown in Table 12 and Figures 3 and 4. This difference in treatment effect for pemetrexed based on histology demonstrating a lack of efficacy in squamous cell histology was also observed in Studies JMEN and JMEI.
| Histologic Subgroups | Pemetrexed plus Cisplatin (N=862) | Gemcitabine plus Cisplatin (N=863) |
| Non-squamous NSCLC (N=1252) | ||
| Median (months) (95% CI) | 11(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) |
| 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 (1-1.51) | |
a Unadjusted for multiple comparisons.
b Adjusted for ECOG PS, gender, disease stage, and basis for pathological diagnosis (histopathological/cytopathological).
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
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