Coverage Policy Manual
Policy #: 2017020
Category: Pharmacy
Initiated: June 2017
Last Review: June 2018
  Pemetrexed (Alimta)

Description:
Pemetrexed is a novel multi-targeted antifolate that inhibits > or = 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.
 
In August 2004, pemetrexed was FDA-approved as single agent therapy in patients with locally advanced or metastatic NSCLC following prior chemotherapy. In September 2008, pemetrexed was FDA-approved in combination with cisplatin for first-line therapy in patients with locally advanced or metastatic non-squamous NSCLC. In July 2009, pemetrexed received FDA approval for the maintenance treatment of advanced or metastatic nonsquamous NSCLC after first-line treatment with platinum-based chemotherapy. Pemetrexed is the first agent to receive FDA approval for the maintenance treatment of advanced or metastatic NSCLC (US FDA, 2004, 2008, 2009).

Policy/
Coverage:
Effective June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria  
Pemetrexed meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
    1. Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
        • In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, NSCLC.
        • In combination with carboplatin and pembrolizumab for the initial treatment of patients with metastatic, non-squamous NSCLC.  
        • As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after 4 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.  
2.  Mesothelioma
        • In combination with cisplatin, for the initial treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.  
3.  NCCN 2A and 2b recommendations in accordance with Coverage Policy #2000030
Dosing
 
    • The recommended dose, administered as a single agent or with cisplatin or with carboplatin and pembrolizumab is   500 mg/m2 IV over 10 mins on Day 1 of each 21-day cycle.
    • Initiate folic acid 400 mcg – 1000 mcg orally, once daily, beginning 7 days prior to the first dose of pemetrexed and continue until 21 days after the last dose of pemetrexed.
    • Administer vitamin B12, 1 mg IM, 1 wk prior to the last dose of pemetrexed and every 3 cycles.
    • Administer dexamethasone 4 mg orally, twice daily the day before, the date of, and the day after pemetrexed administration.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
The use of Pemetrexed for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of Pemetrexed for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to June 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
  
Pemetrexed meets primary coverage criteria for the following indications:
 
NSCLC: Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer in combination with cisplatin or carboplatin
    1. Nonsquamous Non-Small Cell Lung Cancer when one of the following applies:
        1. As adjuvant therapy (NCCN 2A) in combination with cisplatin  OR in combination with cisplatin or carboplatin with radiation , OR
        2. As chemoradiotherapy in combination with cisplatin or carboplatin (NCCN 2A)  as definitive treatment  or  for locoregional recurrence, OR  
        3. In combination with cisplatin or carboplatin with or without bevacizumab as: (NCCN, FDA label) first line therapy for unresectable, recurrent or metastatic disease OR  
        4. as second line therapy after targeted treatment
    2. As maintenance therapy after: \
        1. Response or stable disease to at least 4 cycles of platinum-based first-line therapy. (NCCN FDA label) OR
        2. As a single agent after prior chemotherapy, if not already received
 
Mesothelioma:
    • In combination with cisplatin (FDA label) as first line treatment of unresectable or metastatic disease,  OR
    • As a single agent, (NCCN 2A), OR
    • In combination with cisplatin or carboplatin with or without bevacizumab, OR
    • As a single agent or in combination with cisplatin or carboplatin as post-operative treatment for individuals not treated with induction chemotherapy. (NCCN 2A) OR
    • As single agent (NCCN 2A) as second line therapy for unresectable disease             
 
 
 
Urothelial carcinoma,
    • Recurrent or metastatic, when used, as a single agent for progressive disease (NCCN 2A)
 
Cervical carcinoma,
    • Recurrent or metastatic when used as single agent as a second line treatment (NCCN 2B)
 
Epithelial ovarian cancer,
    • As single agent therapy for persistent or recurrent disease (NCCN 2A)
 
Thymic carcinoma or thymoma,
    • As single agent therapy for recurrent or progressive disease (NCCN 2A)
 
 
 
Dosing: Adult
 
Note: Start vitamin supplements 1 week before initial pemetrexed dose: Folic acid 400 to 1000 mcg daily orally (begin 7 days prior to treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) and vitamin B12 1000 mcg IM 7 days prior to treatment initiation and then every 3 cycles. Give dexamethasone 4 mg orally twice daily for 3 days, beginning the day before treatment to minimize cutaneous reactions. New treatment cycles should not begin unless ANC ≥1500/mm3, platelets ≥100,000/mm3, and CrCl ≥45 mL/minute.
 
Malignant pleural mesothelioma: IV: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin) or (off-label) in combination with carboplatin (Castagneto 2008; Ceresoli 2006) or (off-label) as single-agent therapy (Taylor 2008)
 
Non-small cell lung cancer, nonsquamous: IV:
Initial treatment: 500 mg/m2 on day 1 of each 21-day cycle (in combination with cisplatin)
Maintenance or second-line treatment: 500 mg/m2 on day 1 of each 21-day cycle (as a single-agent)
 
Bladder cancer, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity (Sweeney 2006)
 
Cervical cancer, persistent or recurrent (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity occurs (Lorusso 2010) or 900 mg/m2 on day 1 of each 21-day cycle (Miller 2008)
 
Ovarian cancer, platinum-resistant (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle (Vergote 2009)
 
Thymic malignancies, metastatic (off-label use): IV: 500 mg/m2 on day 1 of each 21-day cycle for 6 cycles or until disease progression
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary
Coverage Criteria
 
The use of Pemetrexed for the treatment of any other indications or any other circumstances than those outlined above does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of Pemetrexed for the treatment of any other indications or any other circumstances than those outlined above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
Pemetrexed was approved in 2004 as a single agent for second line treatment of patients with advanced NSCLC (all histologic subtypes) after Hanna et al (2004) conducted a large randomized phase III trial of pemetrexed vs. docetaxel.  In this trial 571 patients were randomly assigned to receive either pemetrexed 500 mg/sq meter intravenously with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/ sq meter intravenously with dexamethasone every 21 days. The primary end point was overall survival. Overall response rates were 9.1% and 8.8% for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia , febrile neutropenia, neutropenia with infections, hospitalizations for neutropenic fever, hospitalizations due to other drug related adverse events, use of granulocyte colony-stimulating factor support,  and all grade alopecia compared with patients receiving pemetrexed. The study concluded that treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.
 
Scagliotti et al (2008) published the results of a multi-center, randomized, open-label phase III study comparing the efficacy of cisplatin plus gemcitabine with cisplatin plus pemetrexed in patient with NSCLC. This trial randomized 1725 chemotherapy naive patients with Stage IIIb/IV NSCLC to compare the overall survival following treatment with pemetrexed in combination with cisplatin (AC) versus gemcitabine in combination with cisplatin (GC). Treatment was administered up to a total of 6 cycles, and patients in both treatment arms received folic acid, vitamin B12, and dexamethasone.  The primary endpoint in this study was overall survival. Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine.  The median survival time was 10.3 months in the pemetrexed plus cisplatin treatment arm and 10.3 months in the gemcitabine plus cisplatin arm, with an adjusted hazard ratio of 0.94. Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (12.6 vs 10.9 months, respectively) and large-cell carcinoma histology (10.4 vs 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (10.8 vs 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia; febrile neutropenia; and alopecia were significantly lower, whereas grade 3 or 4 nausea was more common. The authors concluded that in advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This was the first prospective phase III study in NSCLC to show survival differences based on histologic type.
 
Ciuleanu et al (2009) conducted a multi-center, randomized, double-blind, placebo-controlled study on 663 patients with Stage IIIb/IV NSCLC who did not progress after treatment with platinum-based chemotherapy. Patients who did not progress were randomized 2:1 to receive pemetrexed 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 pemetrexed and placebo arms, respectively. Pemetrexed was administered intravenously at a dose of 500 mg/m2 in 21-day cycles, until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone. In the overall study population, pemetrexed was statistically superior to placebo in terms of overall survival (OS) (median 13.4 months versus 10.6 months), and PFS (median 4.0 months versus 2.0 months). A difference in treatment outcomes was observed according to histologic classification. For the population of patients with nonsquamous NSCLC, pemetrexed was superior to placebo for OS (median 15.5 months versus 10.3 months) and PFS (median 4.4 months versus 1.8 months). For the population of patients with squamous NSCLC, pemetrexed did not improve OS compared to placebo (median 9.9 months versus 10.8 months) or PFS (median 2.4 months versus 2.5 months). This difference in treatment effect for pemetrexed based on histology demonstrating lack of benefit in squamous cell histology was also observed in the first-line and second-line studies. The authors concluded that maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer.
 
Paz-Ares et al (2013) conducted a multi-center, randomized, double-blind, placebo-controlled study to evaluate continuation of pemetrexed in patients with Stage IIIb/IV nonsquamous NSCLC. 539 patients completing induction treatment of four cycles of pemetrexed plus cisplatin with stable disease were randomized (2:1) to maintenance treatment with pemetrexed 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). Pemetrexed was administered intravenously at a dose of 500 mg/m2 in 21-day cycles and continued until disease progression. Patients in both study arms received folic acid, vitamin B12, and dexamethasone.  The main efficacy outcome was investigator-assessed progression-free survival. 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 pemetrexed or the placebo arms respectively. The study concluded that pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo.  Pemetrexed an efficacious maintenance treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.
 
Vogelzang et al (2003) conducted a multi-center, randomized, single-blind study in 448 chemotherapy naive patients with malignant pleural mesothelioma (MPM) compared survival in patients treated with pemetrexed in combination with cisplatin to survival in patients receiving cisplatin alone. Pemetrexed was administered intravenously at a dose of 500 mg/m2 and cisplatin was administered intravenously at a dose of 75 mg/m2 after the end of administration of pemetrexed. Both regimens were given intravenously every 21 days. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm. The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months. Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm. After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. The authors concluded that treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

CPT/HCPCS:
J9305Injection, pemetrexed, 10 mg

References: Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, et al.(2009) Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009 Oct 24;374(9699):1432-40.

Elsevier.(2018) Pemetrexed [Internet] c2018- [cited 2018 June 28]. Available from: http://www.clinicalpharmacology.com

Hanna N, Shepherd FA, Fossella FV, Pereira JR et al.(2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004 May 1;22(9):1589-97. PMID:15117980

Lilly USA, LLC(2015) Alimta (pemetrexed) injection package insert. Indianapolis, IN: Lilly USA, LLC; 2015 Feb.

Lily USA, LLC(2018) Alimta (pemtrexed) injection package insert Indianapolis, IN: Lily USA, LLC; June 4,2018

NCCN(2018) NCCN Compendia. https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=5. Accessed June 20, 2018.

Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, et al.(2013) PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non–Small-Cell Lung Cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. PMID: 23835707.

Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, et al.(2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. PMID:18506025

U.S. Food & Drug Administration.(2015) Pemetrexed approval https://www.fda.gov/search. Accessed June 21, 2017.

Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P.(2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. PMID: 12860938.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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