National Stroke Foundation

Alimta (pemetrexed for injection)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved September 2008

Specific Treatments:

non-small cell lung cancer

General Information

Alimta (pemetrexed for injection) is a folate analog metabolic inhibitor.

Alimta is specifically indicated for the following:

Non-Squamous Non-Small Cell Lung Cancer (NSCLC):

• in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations.

• in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, nonsquamous, non-small cell lung cancer (NSCLC).

• as a single agent for the maintenance treatment of patients with locally advanced or metastatic, nonsquamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

• as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

Alimta is supplied as an injection for intravenous administration. The recommended dose of Alimta is as follows:

 • When administered with pembrolizumab and platinum chemotherapy for the initial treatment of metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45mL/min or greater the recommended dose of Alimta is 500mg/m2 as an intravenous infusion over 10 minutes administered after pembrolizumab and prior to carboplatin or cisplatin on Day 1 of each 21-day cycle for 4 cycles. Following completion of platinum-based therapy, treatment with Alimta with or without pembrolizumab is administered until disease progression or unacceptable toxicity. Please refer to the full prescribing information for pembrolizumab and for carboplatin or cisplatin.

• The recommended dose of Alimta when administered with cisplatin for initial treatment of locally advanced or metastatic non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500mg/m2 as an intravenous infusion over 10 minutes administered prior to cisplatin on Day 1 of each 21-day cycle for up to six cycles in the absence of disease progression or unacceptable toxicity.

• The recommended dose of Alimta for maintenance treatment of non-squamous NSCLC in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45mL/min or greateris 500 mg/m2 as an intravenous infusion over 10minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy. 

• The recommended dose of Alimta for treatment of recurrent non-squamous NSCLC inpatients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45mL/min or greater is 500 mg/m2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Clinical Results

FDA Approval

The FDA approval of Alimta for the treatment of non-small cell lung cancer was based on the following data:

Initial Treatment in combination with pembrolizumab and platinum chemotherapy, for patients with metastatic non-squamous NSCLC, with no EGFR or ALK genomic tumor aberrations

The efficacy of Alimta in combination with pembrolizumab and platinum chemotherapy was investigated in KEYNOTE-189, a randomized, double-blind, phase III study in patients (n=616) with metastatic non-squamous NSCLC who received no prior treatment for metastatic disease. The patients were randomized, 2:1, to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab (test arm) or placebo (control arm). Patients were stratified based on PD-L1 tumor proportion score (<1 percent or ≥ 1 percent), among other factors. After a median follow-up of 10.5 months, median OS was not reached in the test arm, versus 11.3 months in the control arm. Compared with patients in the control arm, those in the test arm were 51 percent less likely to die, and those in the high PD-L1 score group were 58 percent less likely to die. Median PFS was 8.8 months for the pembrolizumab arm, versus 4.9 months for the control arm.

Initial Treatment in combination with cisplatin for patients with locally advanced or metastatic, non-squamous NSCLC

Study JMDB was 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 Alimta 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. Alimta was administered intravenously over 10 minutes at a dose of 500mg/m2 on Day 1 of each 21-day cycle. Cisplatin was administered intravenously at a dose of 75mg/m2 approximately 30 minutes after Alimta administration on Day 1 of each cycle, gemcitabine was administered at a dose of 1250mg/m2 on Day 1 and Day 8, and cisplatin was administered intravenously at a dose of 75mg/m2 approximately 30minutes 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, vitaminB12, and dexamethasone. The primary efficacy outcome measure was overall survival. The median overall survival was 10.3 months for both arms. 

As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy

Study JMEI was a multi-center, randomized (1:1), open-label study conducted in patients (n=571) with Stage III or IV NSCLC that had recurred or progressed following one prior chemotherapy regimen for advanced disease. Patients were randomized to receive Alimta 500mg/m2 intravenously or docetaxel 75 mg/m2 as a 1-hour intravenous infusion once every 21 days. Patients randomized to Alimta also received folic acid and vitaminB12. The primary endpoint was reached, with data showing that overall survival with Alimta was non-inferior to docetaxel. 

Maintenance Treatment Following First-line Non-ALIMTA Containing Platinum-Based Chemotherapy

The efficacy of Alimta as maintenance therapy following first-line platinum-based chemotherapy was evaluated in Study JMEN, 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 Alimta 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. The major efficacy outcome measures were progression-free survival based on assessment by independent review and overall survival. The median overall survival was 13.4 months in the Alimta arm and 10.6 months in the placebo arm. The median progression free survival was four months for the Alimta arm versus 2.0 months for the placebo arm.

Maintenance Treatment Following First-line ALIMTA Plus Platinum Chemotherapy

The efficacy of Alimta as maintenance therapy following first-line platinum-based chemotherapy was also evaluated in PARAMOUNT, 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 Alimta 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 Alimta 500mg/m2 intravenously every 21 days or placebo until disease progression. Randomization was stratified by response to Alimta 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). The median overall survival was 13.9 months for the Alimta arm versus 11.0 for the placebo arm. The median progression free survival was 4.1 months versus 2.8 months, respectively. 

Side Effects

Adverse effects associated with the use of Alimta when administered as a single agent may include, but are not limited to, the following:

fatigue

nausea

anorexia

Adverse effects associated with the use of Alimta when administered with cisplatin may include, but are not limited to, the following:

vomiting

neutropenia

anemia

stomatitis/pharyngitis

thrombocytopenia

constipation 

Adverse effects associated with the use of Alimta when administered in combination with pembrolizumab and platinum chemotherapy may include, but are not limited to, the following:

fatigue/asthenia

nausea

constipation

diarrhea

decreased appetite

rash

vomiting

cough

dyspnea

pyrexia

Mechanism of Action

Alimta (pemetrexed) is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. Invitro 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. 

Additional Information

For additional information regarding Alimta or non-small cell lung cancer, please visit https://www.alimta.com/