Coverage Policy Manual
Policy #: 2017020
Category: Pharmacy
Initiated: June 2017
Last Review: June 2022
  Pemetrexed (e.g., Alimta)

Description:
Pemetrexed is a novel multi-targeted antifolate that inhibits greater than or equal to  3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.
 
Regulatory Status
 
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).
 
Coding
 
On October 1, 2020, J9304 injection pemetrexed, 10 mg will be effective.

Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective July 13, 2022
 
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:
 
Central Nervous System Cancers - Primary CNS Lymphoma
      • Induction therapy as a single agent (useful in certain circumstances) if patient is unsuitable for or intolerant to high-dose methotrexate (NCCN 2A)
      • Treatment as a single agent for relapsed or refractory disease (NCCN 2A)
          • considered in patients who received prior whole brain radiation therapy.
          • In patients who received a prior high-dose methotrexate-based regimen without prior radiation therapy (rt);
          • In combination with whole brain rt or involved field rt in patients who received a prior high-dose methotrexate-based regimen without prior rt after no response or short response duration (<12 months) to prior regimen.
          • In patients who received prior high-dose chemotherapy with stem cell rescue.
 
Malignant Pleural Mesothelioma - Malignant Pleural Mesothelioma
      • Used in patients not eligible for cisplatin in combination with bevacizumab and carboplatin followed by single-agent maintenance bevacizumab (preferred) as first-line systemic therapy for (NCCN 2A)
          • unresectable clinical stage I-IIIA disease (if induction chemotherapy was not given) and epithelioid histology
          • clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in patients with performance status (PS) 0-2
      • Preferred subsequent systemic therapy if immunotherapy was administered as first-line treatment (NCCN 2A)
          • in combination with cisplatin
          • in combination with cisplatin and bevacizumab
          • in combination with carboplatin in patients not eligible for cisplatin
          • in combination with carboplatin and bevacizumab in patients not eligible for cisplatin
      • Used in combination with cisplatin (preferred), or carboplatin for patients not eligible for cisplatin (preferred), or as a single agent (useful in certain circumstances) as first-line systemic therapy for (NCCN 1 and 2A)
          • unresectable clinical stage I-IIIA disease (if induction chemotherapy was not given) and epithelioid histology
          • resected clinical stage I-IIIA disease and epithelioid histology in patients not treated with induction chemotherapy
          • clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in patients with performance status (PS) 0-2
      • Subsequent systemic therapy as a single agent (preferred) (NCCN 1)
          • if not administered first-line
          • as rechallenge if good, sustained response at the time initial chemotherapy was interrupted (if administered first-line)
      • Induction chemotherapy in combination with cisplatin (preferred) (NCCN 1) or carboplatin (NCCN 2A) for patients not eligible for cisplatin (preferred) for medically operable clinical stage I-IIIA disease and epithelioid histology
      • Used in combination with bevacizumab and cisplatin followed by single-agent maintenance bevacizumab (preferred) as first-line systemic therapy for (NCCN 1)
          • unresectable clinical stage I-IIIA disease (if induction chemotherapy was not given) and epithelioid histology
          • clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in patients with performance status (PS) 0-2
 
Non-Small Cell Lung Cancer - Non-Small Cell Lung Cancer
      • For a diagnosis of recurrent, locally advanced, or metastatic non-squamous, non-small cell lung cancer (NSCLC); AND
          • Used as first-line therapy in combination with platinum based chemotherapy [carboplatin or cisplatin] with or without bevacizumab (or bevacizumab biosimilar) (NCCN 2A); OR  
          • Used as second-line therapy in combination with platinum-based chemotherapy with or without bevacizumab (or bevacizumab biosimilar) if tyrosine-kinase inhibitor (TKI/anaplastic lymphoma kinase (ALK) targeted agent was given as first-line therapy (NCCN 1); OR  
          • Used for maintenance therapy (single-agent) when disease has not progressed (following four cycles of platinum-based as a first-line therapy); OR  
          • Individual is using in combination with pembrolizumab (Keytruda) and platinum chemotherapy for initial treatment and without presence of actionable molecular markers (Label, NCCN 2A); OR
          • Individual is using as continuous maintenance therapy until disease progression, if given first-line as part of Keytruda (pembrolizumab)/platinum chemotherapy/and pemetrexed regimen (NCCN 1); OR  
          • Individual is using as first-line therapy in combination with nivolumab, ipilimumab, and platinum-based chemotherapy and without presence of actionable molecular markers (NCCN 2A); OR
          • Individual is using as adjuvant or neoadjuvant therapy in combination with platinum-based chemotherapy.
 
Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer - Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer, Carcinosarcoma (Malignant Mixed Müllerian Tumors), Clear Cell Carcinoma, Mucinous Carcinoma, Grade 1 Endometrioid Carcinoma, Low-Grade Serous Carcinoma/Ovarian Borderline Epithelial Tumors (Low Malignant Potential) with invasive implants
      • Single-agent therapy for persistent disease or recurrence (NCCN 2A) for:
          • Treatment of persistent or recurrent ovarian cancer, OR
          • Treatment of complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease), OR
          • Treatment of radiographic and/or clinical relapse in patients with previous complete remission and relapse ≥6 months after completing prior chemotherapy (platinum-sensitive disease)
 
Thymomas and Thymic Carcinomas - Thymomas and Thymic Carcinomas
      • Consider for postoperative treatment as a single agent for patients who cannot tolerate first-line combination regimens (NCCN 2A) for:
          • thymic carcinoma after R1 or R2 resection
          • thymoma after R2 resection
      • Consider as first-line therapy as a single agent for patients who cannot tolerate first-line combination regimens for
          • unresectable locally advanced disease in combination with radiation therapy
          • potentially resectable locally advanced disease
          • potentially resectable solitary metastasis or ipsilateral pleural metastasis
          • consideration following surgery for solitary metastasis or ipsilateral pleural metastasis
          • extrathoracic metastatic disease
      • Second-line therapy as a single agent (NCCN 2A) for
          • unresectable disease following first-line chemotherapy for potentially resectable locally advanced disease, solitary metastasis, or ipsilateral pleural metastasis
          • extrathoracic metastatic disease
 
Limitations of Use: Alimta in not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.
 
Off Label
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosing and Administration
Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
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 January 2022 to July 12, 2022
 
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:
 
Central Nervous System Cancers - Primary CNS Lymphoma
      • Induction therapy as a single agent (useful in certain circumstances) if patient is unsuitable for or intolerant to high-dose methotrexate (NCCN 2A)
      • Treatment as a single agent for relapsed or refractory disease (NCCN 2A)
          • considered in patients who received prior whole brain radiation therapy;
          • In patients who received a prior high-dose methotrexate-based regimen without prior radiation therapy (rt);
          • In combination with whole brain rt or involved field rt in patients who received a prior high-dose methotrexate-based regimen without prior rt after no response or short response duration (<12 months) to prior regimen;
          • In patients who received prior high-dose chemotherapy with stem cell rescue.
 
Malignant Pleural Mesothelioma - Malignant Pleural Mesothelioma
      • Induction chemotherapy in combination with cisplatin (preferred) for medically operable clinical stage I-IIIA disease and epithelioid or biphasic histology (NCCN 1); or
      • Induction chemotherapy in combination with carboplatin (in patients not eligible for cisplatin) for medically operable clinical stage I-IIIA disease and epithelioid or biphasic histology (NCCN 2A);
      • Used in combination with cisplatin (preferred) (NCCN1) or carboplatin (in patients not eligible for cisplatin) (NCCN 2A), or as a single agent (useful in certain circumstances) (NCCN 2A) as first-line systemic therapy for:
          • Unresectable clinical stage I-IIIA disease and epithelioid or biphasic histology;
          • Resected clinical stage I-IIIA disease and epithelioid or biphasic histology in patients not treated with induction chemotherapy;
          • Clinical stage IIIB or IV disease, sarcomatoid, or medically inoperable tumors in patients with performance status (PS) 0-2;
      • Used in combination with bevacizumab and cisplatin followed by single-agent maintenance bevacizumab (preferred) as first-line systemic therapy (NCCN 1) for:
          • Unresectable clinical stage I-IIIA disease and epithelioid or biphasic histology;
          • Clinical stage IIIB or IV disease, sarcomatoid, or medically inoperable tumors in patients with performance status (PS) 0-2;
      • Used in combination with bevacizumab and cisplatin followed by single-agent maintenance bevacizumab (preferred) as first-line systemic therapy (NCCN 2A) for:
          • Unresectable clinical stage I-IIIA disease and epithelioid or biphasic histology;
          • Clinical stage IIIB or IV disease, sarcomatoid, or medically inoperable tumors in patients with performance status (PS) 0-2;
      • Subsequent systemic therapy as a single agent (preferred) (NCCN 1):
          • If not administered first-line;
          • As rechallenge if good, sustained response at the time initial chemotherapy was interrupted (if administered first-line).
 
Non-Small Cell Lung Cancer - Non-Small Cell Lung Cancer
      • For a diagnosis of recurrent, locally advanced, or metastatic non-squamous, non-small cell lung cancer (NSCLC); AND
        • Used as first-line therapy in combination with platinum based chemotherapy [carboplatin or cisplatin] with or without bevacizumab (or bevacizumab biosimilar) (NCCN 2A); OR  
        • Used as second-line therapy (first-line chemotherapy) in combination with platinum-based chemotherapy with or without bevacizumab (or bevacizumab biosimilar) if tyrosine-kinase inhibitor (TKI/anaplastic lymphoma kinase (ALK) targeted agent was given as first-line therapy (NCCN 1); OR  
        • Used for maintenance therapy (single-agent) when disease has not progressed (following four cycles of platinum-based as a first-line therapy); OR  
        • Individual is using in combination with pembrolizumab (Keytruda) and platinum chemotherapy for initial treatment and without presence of actionable molecular markers (Label, NCCN 2A); OR
        • Individual is using as continuous maintenance therapy until disease progression, if given first-line as part of Keytruda (pembrolizumab)/platinum chemotherapy/and pemetrexed regimen (NCCN 1); OR  
        • Individual is using as first-line therapy in combination with nivolumab, ipilimumab, and platinum-based chemotherapy and without presence of actionable molecular markers (NCCN 2A); OR
        • Individual is using as adjuvant or neoadjuvant therapy in combination with platinum-based chemotherapy.
 
Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer - Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer, Carcinosarcoma (Malignant Mixed Müllerian Tumors), Clear Cell Carcinoma, Mucinous Carcinoma, Grade 1 Endometrioid Carcinoma, Low-Grade Serous Carcinoma/Ovarian Borderline Epithelial Tumors (Low Malignant Potential) with invasive implants
 
      • Single-agent therapy for persistent disease or recurrence (NCCN 2A) for:
        • Treatment of persistent or recurrent ovarian cancer, OR
        • Treatment of complete remission and relapse <6 months after completing chemotherapy (platinum-resistant disease), OR
        • Treatment of radiographic and/or clinical relapse in patients with previous complete remission and relapse 6 months after completing prior chemotherapy (platinum-sensitive disease)
 
Thymomas and Thymic Carcinomas - Thymomas and Thymic Carcinomas
 
      • Consider for postoperative treatment as a single agent for patients who cannot tolerate first-line combination regimens (NCCN 2A) for:
        • thymic carcinoma after R1 or R2 resection
        • thymoma after R2 resection
      • Consider as first-line therapy as a single agent for patients who cannot tolerate first-line combination regimens for
        • unresectable locally advanced disease in combination with radiation therapy
        • potentially resectable locally advanced disease
        • potentially resectable solitary metastasis or ipsilateral pleural metastasis
        • consideration following surgery for solitary metastasis or ipsilateral pleural metastasis
        • extrathoracic metastatic disease
      • Second-line therapy as a single agent (NCCN 2A) for
        • unresectable disease following first-line chemotherapy for potentially resectable locally advanced disease, solitary metastasis, or ipsilateral pleural metastasis
        • extrathoracic metastatic disease
 
Limitations of Use: Alimta in not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.
 
Off Label
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosing and Administration
Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
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 November 2021 through December 31, 2021
 
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 pembrolizumab and platinum chemotherapy, for the initial treatment of patients 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, 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.
 
Limitations of Use: Alimta in not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.
 
Off Label
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosing and Administration
Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
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 June 2021 to October 31, 2021
 
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 pembrolizumab and platinum chemotherapy, for the initial treatment of patients 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, 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.
 
Limitations of Use: Alimta in not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.
 
Off Label
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, 2A, and 2B recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosing and Administration
Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
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 June 2019 to May 2021
 
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 pembrolizumab and platinum chemotherapy, for the initial treatment of patients 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, 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.
 
Limitations of Use: Alimta in not indicated for the treatment of patients with squamous cell, non-small cell lung cancer.
 
Off Label
NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
 
Dosing and Administration
Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
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 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.
 
2019 Update
The efficacy of ALIMTA 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:
 
• ALIMTA 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 ALIMTA 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. ALIMTA was administered after pembrolizumab and prior to platinum chemotherapy on Day 1.
• Placebo, ALIMTA 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 ALIMTA 500 mg/m2 intravenously every 3 weeks.
 
Treatment with ALIMTA 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, ALIMTA, 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 ALIMTA, pembrolizumab, and platinum chemotherapy arm and 206 to the placebo, ALIMTA, 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 Reference ID: 4383136 percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo, ALIMTA, 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 ALIMTA in combination with pembrolizumab and platinum chemotherapy compared with placebo, ALIMTA, and platinum chemotherapy.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS).
 
The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49–0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64–1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71–1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively.
 
IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified. (Nishio M, Barlesi F, West H, et. al., 2020)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J9304Injection, pemetrexed (pemfexy), 10 mg
J9305Injection, pemetrexed, not otherwise specified, 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

Gandhi, Leena, et. al.(2018) Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.” The New England Journal of Medicine, U.S. National Library of Medicine, 31 May 2018.

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.

Nishio M, Barlesi F, West H, et. al.(2021) Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. doi: 10.1016/j.jtho.2020.11.025. Epub 2020 Dec 14. PMID: 33333328.

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.


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