Pemetrexed

Number: 0687

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

1. Criteria for Initial Approval

   Aetna considers pemetrexed (Alimta, Pemfexy, or generic pemetrexed) medically necessary for the treatment of the following:

   1. Bladder cancer - for treatment of locally advanced, metastatic, or relapsed transitional cell urothelium cancer, as second-line treatment;
   2. Cervical cancer - for treatment of persistent or recurrent cervical cancer;
   3. Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer - for treatment of persistent or recurrent epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, carcinosarcoma (malignant mixed Mullerian tumors), clear cell carcinoma of the ovary, grade 1 endometrioid carcinoma, low-grade serous carcinoma/ovarian borderline epithelial tumor (low malignant potential), or mucinous carcinoma of the ovary, as single agent therapy;
   4. Malignant pleural or peritoneal mesothelioma - for treatment of malignant pleural or peritoneal mesothelioma, including pericardial mesothelioma and tunica vaginalis testis mesothelioma, when any of the following criteria are met:
      
      
      1. The requested medication will be used as a single agent or in combination with cisplatin or carboplatin; or
      2. The requested medication will be used in combination with bevacizumab and either cisplatin or carboplatin;
   5. Non-small-cell lung cancer (NSCLC) (Non-squamous histology) - for treatment of non-squamous non-small cell lung cancer;
   6. Primary central nervous system (CNS) lymphoma - for treatment of primary CNS lymphoma, as a single agent;
   7. Thymomas and thymic carcinomas - for treatment of thymoma or thymic carcinoma, as a single agent.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of pemetrexed (Alimta, Pemfexy, or generic pemetrexed) medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Pemetrexed (Alimta) is supplied as 100 mg and 500 mg lyophilized powder in single-use vials and pemetrexed (Pemfexy) is supplied as 500 mg/20 mL (25 mg/mL) injection in a multi-dose vial for intravenous infusion.

The recommended dosing is as follows:

Non-squamous Non-small Cell Lung Cancer (NSCLC)

• Pemetrexed (Alimta) is administered as 500 mg/m² as an intravenous infusion over 10 minutes after pembrolizumab and prior to carboplatin or cisplatin on day 1 of each 21-day cycle for 4 cycles for initial treatment of metastatic non-squamous NSCLC in individuals with a creatinine clearance of 45 mL/min or greater. Following completion of platinum-based therapy, treatment with Alimta with or without pembrolizumab is administered until disease progression or unacceptable toxicity.
• Pemetrexed (Alimta, Pemfexy) is administered as 500 mg/m² as an intravenous infusion over 10 minutes prior to cisplatin on day 1 of each 21-day cycle for up to six cycles without disease progression or unacceptable toxicity for initial treatment of locally advanced or metastatic non-squamous NSCLC in individuals with a creatinine clearance of 45 mL/min or greater.
• Pemetrexed (Alimta, Pemfexy) is administered as 500 mg/m² as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle until disease progression or unacceptable toxicity after four cycles of platinum-based first-line chemotherapy for maintenance treatment of non-squamous NSCLC in individuals with a creatinine clearance of 45 mL/min or greater.
• Pemetrexed (Alimta, Pemfexy) is administered as 500 mg/m² as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle until disease progression or unacceptable toxicity for treatment of recurrent non-squamous NSCLC in individuals with a creatinine clearance of 45 mL/min or greater.

Mesothelioma

• Pemetrexed (Alimta, Pemfexy), when given with cisplatin, is administered as 500 mg/m² as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle until disease progression or unacceptable toxicity.

Source: Eli Lilly, 2019, Eagle Pharmaceuticals,2020b

Note: Pemetrexed is also available as a generic formulation.

Experimental and Investigational

Aetna considers pemetrexed (Alimta) experimental and investigational for the treatment of the following types of cancers (not an all-inclusive list) since its effectiveness for other malignancies has not been established:

• Acute leukemia (e.g., acute myeloid leukemia and acute lymphocytic leukemia)
• Biliary cancer
• Breast cancer
• Choriocarcinoma
• Colorectal cancer
• Esophageal cancer
• Extra-mammary Paget's disease
• Gastric cancer
• Neuroendocrine tumors
• Non-small cell lung cancer (Squamous cell histology)
• Pancreatic cancer
• Renal cell carcinoma
• Salivary cancer (e.g., parotid gland adenocarcinoma)
• Small cell lung cancer
• Squamous cell carcinoma of the head and neck, including the tongue
• Temporal bone squamous cell carcinoma.

Aetna considers MTHFR polymorphisms testing experimental and investigational for the prediction of pemetrexed effectiveness and toxicity in non-small cell lung cancer.

Note: Physician administration of vitamin B-12 injections is considered medically necessary for individuals receiving pemetrexed (see CPB 0536 - Vitamin B-12 Therapy)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96365, 96366, 96367, 96368, 96379, 96409, 96411, 96413, 96415, 96416, 96417	IV fusion therapy
HCPCS codes covered if selection criteria are met:
J9294	Injection, pemetrexed (hospira) not therapeutically equivalent to j9305, 10 mg
J9296	Injection, pemetrexed (accord) not therapeutically equivalent to j9305, 10 mg
J9297	Injection, pemetrexed (sandoz), not therapeutically equivalent to j9305, 10 mg
J9305	Injection, pemetrexed, 10 mg
J9314	Injection, pemetrexed (teva) not therapeutically equivalent to J9305, 10 mg
J9322	Injection, pemetrexed (bluepoint) not therapeutically equivalent to j9305, 10 mg
J9323	Injection, pemetrexed ditromethamine, 10 mg
Other HCPCS codes related to the CPB:
J9035	Injection, bevacizumab, 10 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9271	Injection, pembrolizumab, 1 mg
Q5107	Injection, bevacizumab-awwb, biosimilar, (Mvasi), 10 mg
ICD-10 codes covered if selection criteria are met:
C33 - C34.92	Malignant neoplasm of trachea, bronchus and lung [non-small-cell lung cancer (NSCLC) only- not small cell lung cancer] [covered for non squamous cell non-small cell lung cancer only]
C37	Malignant neoplasm of thymus [thymic carcinoma]
C38.4	Malignant neoplasm of pleura
C45.0	Mesothelioma of pleura
C45.1	Mesothelioma of peritoneum [persistent or recurrent]
C45.2	Mesothelioma of pericardium
C45.7	Mesothelioma of other sites [tunica vaginalis testis mesothelioma]
C45.9	Mesothelioma, unspecified
C48.2	Malignant neoplasm of peritoneum, unspecified [primary peritoneal cancer]
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.0 – C54.9	Malignant neoplasm of corpus uteri
C55	Malignant neoplasm of uterus, part unspecified
C56.1 - C57.02	Malignant neoplasm of ovary or fallopian tube
C67.0 - C67.9	Malignant neoplasm of bladder
C83.30 - C83.39	Diffuse large B-cell lymphoma [primary CNS lymphoma]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C01 - C02.9	Malignant neoplasm of tongue [squamous cell carcinoma]
C07 - C08.9	Malignant neoplasm of major salivary glands
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach [gastric]
C18.0 - C20	Malignant neoplasm of colon, rectosigmoid junction, and rectum [colorectal]
C21.0 - C21.8	Malignant neoplasm of anus and anal canal [Paget's disease]
C22.1	Intrahepatic bile duct carcinoma
C24.0	Malignant neoplasm of extrahepatic bile duct
C24.9	Malignant neoplasm of biliary tract, unspecified
C25.0 - C25.9	Malignant neoplasm of pancreas
C41.0	Malignant neoplasm of bones of skull and face [temporal bone squamous cell carcinoma]
C44.121 - C44.129, C44.221 - C44.229, C44.320 - C44.329, C44.42	Squamous cell carcinoma of skin
C44.590	Other specified malignant neoplasm of anal skin [Paget's disease]
C50.011 - C50.929	Malignant neoplasm of breast
C51.0 - C51.9	Malignant neoplasm of vulva [Paget's disease]
C58	Malignant neoplasm of placenta [choriocarcinoma]
C60.0 - C60.9	Malignant neoplasm of penis [Paget's disease]
C61	Malignant neoplasm of prostate [urothelial carcinoma]
C64.1 - C64.9	Malignant neoplasm of kidney, except renal pelvis
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of ureter
C68.0	Malignant neoplasm of urethra
C7A.010 - C7B.8	Neuroendocrine tumors
D03.0 - D03.9	Melanoma in situ
D3A.00 - D3A.8	Benign neuroendocrine tumors
MTHFR polymorphisms testing:
HCPCS codes not covered if selection criteria are met:
81291	MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C)
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C33 – C34.92	Malignant neoplasm of trachea, bronchus and lung [non-small-cell lung cancer (NSCLC)]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Non-squamous non-small cell lung cancer (NSCLC)
  
  
  • Alimta is indicated in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous NSCLC, with no EFGR or ALK genomic tumor aberrations.
  • Alimta/Pemfexy is indicated in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, non-small cell lung cancer (NSCLC).
  • Alimta/Pemfexy is indicated as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.
  • Alimta/Pemfexy is indicated as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.
     

  Limitations of Use:

  Alimta/Pemfexy is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer (NSCLC).

• Mesothelioma - Alimta/Pemfexy is indicated, 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.

Compendial Uses

• Bladder cancer
• Cervical cancer
• Malignant peritoneal mesothelioma
• Malignant pleural mesothelioma
• Nonsquamous non-small cell lung cancer (NSCLC)
• Ovarian cancer, fallopian tube cancer, and primary peritoneal cancer: epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, carcinosarcoma (malignant mixed Mullerian tumors), clear cell carcinoma of the ovary, grade 1 endometrioid carcinoma, low-grade serous carcinoma/ovarian borderline epithelial tumor (low malignant potential), and mucinous carcinoma of the ovary
• Pericardial mesothelioma
• Primary central nervous system (CNS) lymphoma
• Thymomas and thymic carcinomas
• Tunica vaginalis testis mesothelioma

Alimta (pemetrexed) is a pyrimidine-based folate analog that suppresses tumor growth by inhibiting both DNA synthesis and folate metabolism at multiple target enzymes. The multiple enzyme inhibition is unique, as methotrexate inhibits only dihydrofolate reductase, and 5-fluorouracil and raltitrexed inhibit only thymidine synthetase. Thus, pemetrexed may be useful for 5-fluorouracil-, methotrexate- and raltitrexed-resistant cancers.

Pemetrexed acts as a 'multitargeted" antifolate compound by interrupting both purine synthesis via thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibition, and pyrimidine synthesis via glucinamide ribonucleotide formyl transferase (GARFT) and aminoimidazole carboxamide formyl transferase (AiCARFT) inhibition, which are all key enzymes involved in folate metabolism.

Alimta (pemetrexed) is FDA approved for mesothelioma and nonsquamous non-small cell lung cancer (NSCLC). Pemetrexed is not indicated for the treatment of squamous cell NSCLC.

To reduce the severity and frequency of possible adverse reactions, the following are recommended:

• Instruct patients to initiate folic acid 400 mcg to 1000 mcg orally once daily beginning 7 days before the first dose of Alimta (pemetrexed). Continue folic acid during the full course of therapy and for 21 days after the last dose of pemetrexed.
• Vitamin B12 injection (1000 mcg IM) during the week preceding the first dose of pemetrexed and every 3 cycles (i.e., every 9 weeks) thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with pemetrexed.
• To reduce cutaneous reactions, the following is recommended - dexamethasone (4 mg PO twice daily for 3 days) beginning the day before administration of pemetrexed.

On December 13, 2019, the U.S. Food and Drug Administration (FDA) moved the approval from tentative to final allowing initial limited entry of Pemfexy (pemetrexed) into the market on February 1, 2022 with subsequent uncapped entry on April 1, 2022.Pemfexy is considered as a branded alternative to Eli Lilly's Alimta (pemetrexed) (Eagle Pharmaceuticals, 2020a).

Monitoring

Complete blood cell counts, including platelet counts, should be performed on all patients receiving Alimta. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is greater than or equal to 1500 cells/mm3, the platelet count is greater than or equal to 100,000 cells/mm3, and creatinine clearance is greater than or equal to 45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function.

Refer to the Prescribing information for specific recommendations about dose adjustments.

Biliary Tract Cancer

Alberts et al (2007) determined the maximum tolerated dose (MTD) and effectiveness of pemetrexed and gemcitabine in patients with either biliary tract or gallbladder carcinoma.  Patients with unresectable previously untreated biliary tract cancers were eligible for participation.  An initial phase I trial was performed to determine the MTD using an every 2-week schedule.  The MTD was then used in the phase II portion of the trial.  The primary end-point for the phase II portion was 6-month survival with a planned accrual of 59 patients.  Overall, 63 eligible patients were enrolled.  The MTD was established as pemetrexed 500 mg/m² IV over 10 min and gemcitabine 800 mg/m² IV at 10 mg/m² per minute on days 1 and 15 of an every 4-week schedule with vitamin B12 and folate supplementation; 58 patients were included in the phase II portion.  Median age was 61 and median follow-up was 18.2 months.  A median of 3 cycles of treatment was given; 6-month survival was 55 % and the median survival was 6.6 months (95 % confidence interval [CI]: 5.4 to 8.7 months) with a median time to progression of 3.8 months (2.4 to 5.4); 47 (81 %) experienced at least 1 grade 3+ adverse event, and 28 patients (48 %) experienced at least 1 grade 4 adverse event, most of which were due to grade 4 neutropenia.  The authors concluded that the addition of pemetrexed to fixed-dose-rate gemcitabine, in a bi-weekly schedule, did not enhance the activity of gemcitabine in patients with biliary tract or gallbladder carcinoma.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2017) does not list biliary cancer as a recommended indication of pemetrexed.

Cervical Cancer and Vaginal Cancer

In a multi-center, phase II clinical trial, Miller and colleagues (2008) estimated the anti-tumor activity of pemetrexed in patients with advanced or recurrent carcinoma of the cervix that failed on higher priority treatment protocols and determined the nature and degree of toxicity.  Pemetrexed at a dose of 900 mg/m² was administered as an intravenous infusion over a 10-min period every 21 days.  A total of 29 patients were enrolled in this study.  Two patients did not receive treatment and thus were inevaluable.  A total of 128 cycles were administered with 37 % of patients receiving 6 or more cycles.  The treatment was well-tolerated.  More serious toxicities (grade 3 and 4) included anemia in 41 %, leukopenia in 30 %, neutropenia in 26 %, and infection in 26 %.  No treatment related deaths were reported.  Four patients (15 %) had partial responses with a median response duration of 4.4 months.  The response rate for non-radiated or radiated disease sites was 25 % and 7 % respectively.  A total of 16 patients (59 %) had stable disease and 7 (26 %) had increasing disease.  Median PFS was 3.1 months and OS was 7.4 months.  The authors concluded that pemetrexed at this dose and schedule showed moderate activity against advanced or recurrent cervical cancer that has failed prior chemotherapy.  Data from other tumor sites has suggested synergy between pemetrexed and cisplatin and should be considered for further study.

Carcinomas of the vagina are uncommon with tumors comprising about 1% of the cancers that arise in the female genital system. There is no standard treatment of proven efficacy for metastatic disease. The American Joint Committee on Cancer (AJCC) staging system indicates that tumors in the vagina that involve the cervix of women with an intact uterus are classified as cervical cancers, thus tumors that may have originated in the apical vagina but extend to the cervix would be classified as cervical cancers. Squamous cell cancer (SCC) of the vagina is associated with a high rate of infection with oncogenic strains of human papillomavirus (HPV) and has many risk factors in common with SCC of the cervix (NIH, 2018).

Extra-Mammary Paget's Disease

Chen and colleagues (2019) noted that advanced extra-mammary Paget's disease does not have a standardized treatment guideline as its incidence is low and has been rarely reported in literature.  These investigators reported a case of metastatic extra-mammary Paget's disease successfully treated with topical 5-fluorouracil (5-FU) and systemic pemetrexed.  The therapy was safe without any appreciable adverse effects like diarrhea, rash, neutropenia or fatigue; maintaining remission for more than 6 months.  The authors proposed 5-FU and pemetrexed as the 1st-line therapy for advanced extra-mammary Paget's disease, especially for aged patients with unresectable skin lesions.  This was a single-case study; and its findings were confounded by the combined use of 5-FU and pemetrexed.  These preliminary findings need to be further investigated.

Head and Neck Cancer

In a phase II clinical trial, Vermorken et al (2013) evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN).  Patients received cetuximab 250 mg/m2 (loading dose: 400 mg/m2) days 1, 8 and 15; pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 on day 1, q3w up to 6 cycles and folic acid, vitamin B12 and prophylactic medications.  After a minimum of 4 cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity.  Efficacy (primary end-point: PFS) and toxicity were evaluated.  A total of 66 patients received greater than or equal to 1 cycle of the triplet.  Most patients were male (80.3 %), with a median age of 62 years and ECOG performance status of 1 (71.2 %).  Diagnoses included oropharynx (45.5 %) and larynx (24.2 %) cancers, with loco-regional disease (51.5 %) alone, or combined with distant metastases (48.5 %).  Median (m) PFS was 4.4 months (95 % CI: 3.6 to 5.4); median OS was 9.7 months (95 % CI: 6.5 to 13.1).  Objective response rate was 29.3 %; 23 patients had stable disease (39.7 %).  Drug-related grade 3/4 toxicities included neutropenia (33.3 %), fatigue (24.2 %), anorexia (12.1 %) and infection (10.6 %).  Five treatment-related deaths (7.6 %) occurred.  The authors concluded that efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved.  Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.

UpToDate reviews on, “Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx” (Brockstein et al, 2022), and “Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oropharynx” (Worden et al, 2022) do not mention pemetrexed as a therapeutic option. 

Also, an UpToDate review on “Treatment of metastatic and recurrent head and neck cancer” (Brockstein and Vokes, 2022) states that “Cisplatin plus pemetrexed -- Although the combination of cisplatin plus pemetrexed may have activity in some patient subsets, this regimen is not recommended for the initial treatment of patients with recurrent or metastatic head and neck cancer”.

Furthermore, the NCCN clinical practice guideline on "Head and neck cancers" (Version 2.2022) does not mention the use of pemetrexed. 

Kidney Cancer

In a phase II clinical study, Thodtmann et al (2003) evaluated the effects of pemetrexed (multi-targeted anti-folate, Alimta) for the treatment of metastatic renal cell carcinoma (RCC).  Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy.  In addition, patients were required to have a World Health Organization (WHO) performance status of 0 to 2 and adequate bone marrow reserve.  Patients received pemetrexed at a dose of 600 mg/m2 as a 10-min infusion every 3 weeks.  Patients did not receive folic acid or vitamin B12 supplementation.  A total of 39 patients were enrolled and 32 were evaluable for response.  Three patients had a partial response for a response rate of 9 % (95 % confidence interval (CI): 2 to 25 %).  The median time to progressive disease was 10.5 months.  Of the non-responders, 22 had stable disease (median duration was 5.8 months; range of 1.5 to 27.7) and 7 had progressive disease (median time to progression was 5.4 months).  Median time to progression for all qualified patients was 5.7 months.  Common toxicities experienced were diarrhea and infection.  Fatigue, stomatitis, and rash were also reported.  The most common hematologic toxicity was grade 3/4 lymphopenia in 76 % of patients.  Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported.  The authors concluded that single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.

Dasanu et al (2012) stated that many of the risk factors and pathogenesis of urothelial carcinoma of the renal pelvis are similar to the ones of the more common urothelial bladder cancer.  In addition, 2 endemic nephropathies and 2 inherited syndromes have been linked with the development of upper urologic cancer.  Multiple synchronous or metachronous lesions throughout urinary tract are rather common and should always be sought in the management of this entity.  Surgical resection is the treatment of choice in early-stage tumors.  The role of adjuvant radiation and chemo-radiation for carcinoma of the renal pelvis remains to be redefined, given the advent of conformal approaches and intensity modulation.  In non-surgical candidates, chemotherapy remains the mainstay.  Metastatic urothelial renal pelvic cancer is usually treated with combination platinum-based chemotherapy.  Definitive radiation therapy should be considered in persons with locally advanced/unresectable disease, multiple comorbidities, and/or severely compromised performance status.  Recently, the anti-folate agent pemetrexed has demonstrated an overall response rate of circa 30 % in urothelial carcinoma.  New targeted agents, alone or in combination with cytotoxic drugs, are currently being tested in clinical trials and may lead to new and exciting avenues for the therapy of this disease.

UpToDate reviews on "Overview of the treatment of renal cell carcinoma" (Atkins, 2022), and “Treatment protocols for kidney cancer” (Brenner et al., 2022) do not mention the use of pemetrexed as a therapeutic option.

Furthermore, the NCCN clinical practice guideline on "Kidney cancer" (Version 3.2023) does not mention the use of pemetrexed.

Leptomeningeal Metastasis from NSCLC

Choi and colleagues (2019) noted that leptomeningeal metastasis (LM), still an area of unmet need, has frequently been observed in patients with EGFR-mutant NSCLC.  Because the anti-tumor efficacy of systemic cytotoxic agents against LM is unclear, these researchers examined the role of pemetrexed in the treatment of patients with LM from EGFR-mutant NSCLC.  They retrospectively reviewed the medical records of patients with LM from EGFR-mutant NSCLC treated between 2006 and 2016.  Post-LM survival was evaluated as well as clinical factors.  In this patient cohort with EGFR-mutant NSCLC (n = 631), 17.4 % (n = 110) developed LM.  Their median post-LM survival was 5.7 months (95 % CI: 0.0 to 12.0 months).  Post-LM survival was significantly longer with pemetrexed use after LM (median of 13.7 months; 95 % CI: 4.1 to 23.2 months) than without pemetrexed use after LM (median of 4.0 months; 95 % CI: 2.2 to 5.7 months; p = 0.008).  In the multi-variate analyses, no pemetrexed use after LM (versus use) and no EGFR tyrosine kinase inhibitor (TKI) use after LM (versus use) were independently associated with a poor post-LM survival with a HR of 3.1 (95 % CI: 1.5 to 6.3; p = 0.002) and 3.0 (95 % CI: 1.6 to 5.8; p = 0.001), respectively.  The authors concluded that pemetrexed use after LM was independently associated with a longer post-LM survival in patients with EGFR-mutant NSCLC with LM.  Moreover, these researchers stated that prospective studies are needed to validate this finding.

Leukemia and Lymphoma

Norris and Adamson (2010) noted that renewed interest in antifols for the treatment of childhood cancers has resulted from identification of novel antifols with broad spectrums of anti-cancer activity and from re-evaluation of the original clinical antifol, aminopterin.  In this pre-clinical study, these researchers evaluated the in-vitro activity of both traditional antifols (e.g., methotrexate, aminopterin) and novel antifols (e.g., pemetrexed, talotrexin) in childhood acute leukemias and lymphomas.  These researchers compared the in-vitro cytotoxicity of methotrexate, aminopterin, pemetrexed, and talotrexin in a panel of 6 pediatric leukemia and lymphoma cell lines using the sulforhodamine B assay.  In addition to defining a 50 % growth inhibitory concentration (IC50) for a 120-hr drug exposure, these researchers contrasted the activity of the drugs in the context of clinically achievable (tolerable) drug exposures using the area under the plasma concentration-time curve (AUC).  They defined each agent's clinical potency index (CPI) as the AUC achieved with standard pediatric dosing regimens divided by the in-vitro IC50.  Across all cell lines, talotrexin (median IC50 7 nM) and aminopterin (median IC50 17 nM) had lower IC50's than methotrexate (median IC50 78 nM) and pemetrexed (median IC50 155 nM).  However, the CPI for methotrexate (median 0.9) was significantly greater than that for aminopterin (median 0.4).  In contrast, pemetrexed had a significantly better CPI (median 13) than the traditional antifols.  The authors concluded that aminopterin does not appear to offer any advantage over methotrexate for the treatment of childhood ALL.  They stated that further study of pemetrexed in childhood leukemias is warranted.

In a phase I study, Abdel-Karim and colleagues (2011) examined the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia.  Patients with refractory or relapsed acute leukemia were eligible.  Pemetrexed was infused intravenously over 25 mins with vitamin B-12 supplementation.  Courses were repeated every 3 to 4 weeks according to toxicity and efficacy.  The starting dose of 900 mg/m2 was escalated by approximately 33 % until the dose-limiting toxicity (DLT) was determined.  A total of 20 patients with acute myeloid (AML) or lymphocytic (ALL) leukemia received therapy.  The main non-hematologic adverse event was liver dysfunction at several dose levels, including 2 DLTs at 3,600 mg/m2.  One patient with ALL (3,600 mg/m2 dose level) achieved a partial response.  Pemetrexed pharmacokinetics were linear with escalated dosing.  Elevated plasma deoxyuridine was observed in a subset of patients following pemetrexed infusion, but was not correlated with dose levels.  Changes in the nucleotide pools of circulating mononuclear cells were observed, but were variable.  The authors concluded that recommended phase II dose of pemetrexed for future leukemia studies is intravenous 2,700 mg/m2 over 25 mins every 3 to 4 weeks with vitamin B-12 supplementation.  Deoxyuridine levels did not increase with increasing pemetrexed dose, suggesting pemetrexed inhibition of thymidylate synthase (TS) may be saturated by the 900 mg/m2 dose level.  However, no firm conclusion can be made regarding TS saturation in tumor cells.  While tolerable, pemetrexed monotherapy had limited activity in this highly refractory population.  These researchers noted that exploration of pemetrexed in combination with other active agents in leukemia is a reasonable future endeavor.

Raizer et al (2012) evaluated the anti-tumor activity and safety of pemetrexed in recurrent primary central nervous system lymphoma (PCNSL).  Patients with relapsed/refractory PCNSL were enrolled in this trial.  Treatment consisted of pemetrexed 900 mg/m(2) given every 3 weeks with low-dose dexamethasone, folate, and B12 supplementation.  Each cycle was 6 weeks, and follow-up imaging was done before each new cycle.  Treatment was continued until complete remission, progression, or toxicity.  A total of 11 patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70 %; 10 of 11 patients had failed prior high-dose methotrexate.  The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55 % and disease control rate of 91 %.  The 6-month PFS was 45 %, median PFS was 5.7 months, and median OS was 10.1 months.  Toxicities were primarily hematologic and infectious.  The authors concluded that pemetrexed has single-agent activity in relapsed/refractory PCNSL.  Toxicities were seen likely because of the higher than standard dose used.  They stated that further investigation of this agent or other multi-targeted anti-folates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population.

MTHFR Polymorphisms for Prediction of Pemetrexed Effectiveness and Toxicity in Non-Small cell Lung Cancer

In a meta-analysis, Bai et al (2021) examined if MTHFR polymorphisms are effective biomarkers for NSCLC patient survival and pemetrexed (PEM) treatment toxicity. Because of data heterogeneity, fixed or random effects models were chosen, and pooled HRs and 95 % CIs were calculated. No correlation between MTHFR 677 C > T polymorphism and PFS or OS was detected in NSCLC patients; however, patients with the T allele benefited more than those with the wild-type allele. Two studies reported hematologic toxicity of single-agent PEM treatment in patients with the MTHFR 677 C > T polymorphism. However, data on MTHFR polymorphisms and toxicity could not be combined, even though publication bias and sensitivity analysis results were stable and reliable. The authors concluded that the MTHFR 677 C > T polymorphism could not predict PEM effectiveness in NSCLC patients; however, the T allele may increase the risk of hematological toxicity. Moreover, these researchers stated that a large clinical trial is recommended.

Mesothelioma

Mesothelioma refers to cancer of the mesothelium, a membrane that covers and protects most of the internal organs of the body.  Mesothelioma is rare; approximately 2,000 new cases are diagnosed each year.  Malignant mesothelioma is an aggressive malignancy that may be caused by environmental carcinogens (e.g., asbestos and erionite), viruses (SV40), and genetic predisposition.  Malignant pleural mesothelioma is far more common than the peritoneal variants;  it is a rapidly progressing malignancy with a median survival time of 6 to 9 months.

Most patients with mesothelioma are not candidates for radiation therapy or surgical treatment, and cytotoxic agents are the only options.  Historically, no classes or combinations of cytotoxic agents consistently yielded response rates over 20 %.  Recently, pemetrexed, a new multi-targeted anti-folate that inhibits several enzymes involved in the folate pathway, has been reported to exhibit broad anti-tumor activity in clinical trials in various solid tumors, including mesothelioma, non-small cell lung, breast, cervical, colorectal, head and neck, and bladder cancers.  In particular, pemetrexed in combination with platinum compounds, have produced response rates of up to 45 %.  Pemetrexed is a potent inhibitor of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.

In a phase III clinical trial, Vogelzang et al (2003) examined whether treatment with pemetrexed and cisplatin results in better survival time than treatment with cisplatin alone.  Chemotherapy-naive patients who were ineligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day-1, or cisplatin 75 mg/m2 on day-1.  Both regimens were given intravenously every 21 days.  A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and 8 never received therapy.  Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm.  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 group treated with the pemetrexed/cisplatin combination.  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.

Pemetrexed disodium (Alimta) was approved by the FDA on February 5, 2004.  It is the first drug approved for mesothelioma.  The recommended dose of Alimta is 500 mg/m2 administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle.  Patients must take daily doses of folic acid and vitamin B-12 to reduce the severity of side effects such as low white blood cell count, nausea, vomiting, fatigue, rash, and diarrhea.

The FDA-approved labeling of Alimta has the following recommendations for dosing and administration in mesothelioma:

• Combination use in Non-Small Cell Lung Cancer: Recommended dose of Alimta is 500 mg/m2 i.v. on Day 1 of each 21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning 30 minutes after Alimta administration.
• Prior to initiating Alimta, initiate supplementation with oral folic acid and intramuscular vitamin B12. Continue folic acid and vitamin B12 supplementation throughout treatment.
• Administer corticosteroids the day before, the day of, and the day after Alimta administration.
• Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy.

Malignant Peritoneal Mesothelioma 

Peitl and associates (2017) stated that diffuse malignant peritoneal mesothelioma (DMPM) is generally an under-studied disease, largely because most molecular and clinical studies of mesothelioma have been conducted in patients with the more common malignant pleural mesothelioma.  These researchers presented the case of a 45-year old male who initially presented with abdominal discomfort and ascites.  Diagnostic work-up revealed advanced DMPM.  Bi-modal treatment was started with cyto-reductive surgery (CRS) and hyperthermic intra-peritoneal perfusion with chemotherapy (HIPEC) procedure, followed by pemetrexed systemic monotherapy.  After the disease progression, and because of a very good previous treatment response to pemetrexed, these investigators decided to re-challenge systemic pemetrexed, along with the introduction of cisplatin.  Although the intent behind systemic treatment was at first solely palliative, OS after the initial diagnosis was 50 months.  The authors concluded that treatment based on re-challenging pemetrexed with or without cisplatin in patients with advanced DMPM can result in a quite satisfactory disease control and symptom management.

Fujimoto and colleagues (2017) evaluated the effectiveness of 1st-line systemic pemetrexed and cisplatin chemotherapy in the treatment of patients with aggressive MPM.  A total of 24 patients with histologically proven MPM were treated with pemetrexed plus cisplatin as a 1st-line systemic chemotherapy.  The response was evaluated radiologically according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria; 22 patients underwent 18F-fluorodeoxyglucose positron emission tomography/(FDG-PET)/computed tomography(CT) at baseline, and 13 were eligible for metabolic assessment.  Two complete responses and 9 partial responses were achieved.  Overall response rate and disease control rate were 45.8 % and 91.7 %, respectively.  Median PFS and median OS were 11.0 months and 15.8 months, respectively.  Wet-type MPM had significantly longer survival (median of 40.9 months) than other clinical types (15.5 months; p = 0.045).  The baseline maximum standardized uptake value in 22 patients was 8.93 (range of 2.5 to 16.77).  The authors concluded that systemic pemetrexed plus cisplatin was active for MPM.  Disparity with the outcome of CRS/HIPEC needs to receive more emphasis, since peritoneal mesothelioma has a 5-year survival rate of 50 %.

Furthermore, an UpToDate review on “Malignant peritoneal mesothelioma: Treatment” (Alexander et al., 2022) states that “Pemetrexed plus cisplatin is an active regimen if the patient's performance status and general health are adequate to tolerate it.  Particularly in the palliative setting, pemetrexed plus carboplatin might be preferred given that achieves similar results with less toxicity”.

Non-Small Cell Lung Cancer

Pemetrexed has also demonstrated clinical activity in non-small-cell lung cancer (NSCLC).  In a randomized, controlled study (n = 571), Hanna et al (2004) compared the effectiveness and toxicity of pemetrexed versus docetaxel in patients with advanced NSCLC previously treated with chemotherapy.  Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function.  Patients received pemetrexed 500 mg/ m2 intravenously day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 intravenously day 1 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 (40.2 % versus 5.3 %; p < 0.001), febrile neutropenia (12.7 % versus 1.9 %; p < 0.001), neutropenia with infections (3.3 % versus 0.0 %; p = 0.004), hospitalizations for neutropenic fever (13.4 % versus 1.5 %; p < 0.001), hospitalizations due to other drug related adverse events (10.5 % versus 6.4 %; p = 0.092), use of granulocyte colony-stimulating factor support (19.2 % versus 2.6 %, p <. 0001) and all grade alopecia (37.7 % versus 6.4 %; p < 0.001) compared with patients receiving pemetrexed.  The authors 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.

On August 20, 2004, the FDA approved Alimta (pemetrexed for injection) for the treatment of advanced NSCLC patients who have undergone chemotherapy.  In October 2008, FDA-approved indications for Alimta were expanded to include use in combination with cisplatin, in the first-line treatment of locally-advanced and metastatic NSCLC, for patients with nonsquamous histology.  According to available guidelines, pemetrexed is indicated for persons who have histological or cytological confirmation of NSCLC with stage III or IV disease not amenable to curative therapy, and who have had prior chemotherapy for advanced disease.  According to these guidelines, candidates for pemetrexed should have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, and have adequate bone marrow, renal and hepatic function.

The approval of Alimta in first-line advanced NSCLC for nonsquamous cell histology was based on a phase III, open-label randomized study (1,725 patients) that evaluated pemetrexed plus cisplatin (AC arm) versus gemcitabine plus cisplatin (GC arm) (Eli Lilly, 2008).  The median survival was 10.3 months in the AC arm and 10.3 months in the GC arm [adjusted hazard ratio 0.94 (95 % confidence interval [CI]: 0.84 to 1.05)] (Scagliotti et al, 2008).  The median progression-free survival was 4.8 and 5.1 months for the AC and GC arms, respectively [adjusted hazard ratio [HR] 1.04 (95 % CI: 0.94 to 1.15)]. The overall response rates were 27.1% and 24.7% for the AC and GC arms, respectively.  The investigators reported that, in a pre-specified analysis, the impact of NSCLC histology on overall survival was examined.  Clinically relevant differences in survival according to histology were observed. In the nonsquamous cell NSCLC subgroup, the median survival was 11.0 and 10.1 months in the AC and GC groups, respectively [unadjusted HR 0.84 (95 % CI: 0.74 to 0.96)].  However, in the squamous cell histology subgroup, the median survival was 9.4 versus 10.8 months in the AC and GC groups, respectively [unadjusted HR1.22 (95 % CI: 0.99 to 1.50)].  The investigators reported that this unfavorable effect on overall survival associated with squamous cell histology observed with pemetrexed was also noted in a retrospective analysis of the single-agent trial of pemetrexed versus docetaxel in patients with stage III/IV NSCLC after prior chemotherapy (citing Peterson et al, 2007).

In a phase II study, Patel and colleagues (2009) evaluated the safety and effectiveness of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naive stage IIIB (effusion) or stage IV non-squamous NSCLC.  Patients received pemetrexed 500 mg/m(2), carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for 6 cycles.  For patients with response or stable disease, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity.  A total of 50 patients were enrolled and received treatment.  The median follow-up was 13.0 months, and the median number of treatment cycles was 7 (range of 1 to 51).  Thirty patients (60 %) completed greater than or equal to 6 treatment cycles, and 9 (18 %) completed greater than or equal to 18 treatment cycles.  Among the 49 patients assessable for response, the objective response rate was 55 % (95 % CI: 41 % to 69 %).  Median progression-free and overall survival rates were 7.8 months (95 % CI: 5.2 to 11.5 months) and 14.1 months (95 % CI: 10.8 to 19.6 months), respectively.  The authors concluded that this regimen, involving a maintenance component, was associated with acceptable toxicity and relatively long survival in patients with advanced non-squamous NSCLC.  These results justify a phase III comparison against the standard-of-care in this patient population.

Mok and Ramalingam (2009) noted that systemic chemotherapy with platinum-based regimens provides modest improvements in survival and quality of life for patients with advanced-stage NSCLC.  Extended first-line chemotherapy with combination regimens for more than 4 to 6 cycles is not recommended because of cumulative toxicities and lack of proven advantage in survival with the increased duration of therapy.  The early use of an anti-cancer agent as maintenance therapy after disease stabilization or maximal response with platinum-based regimens is, therefore, being recognized as a new treatment paradigm in NSCLC.  Maintenance therapy can extend first-line treatment and provide an acceptable balance between efficacy and toxicity.  The essential prerequisites for maintenance therapy include good tolerability, ability to administer extended cycles of therapy without cumulative toxicity, and an increase in the duration of progression-free survival (PFS).  Pemetrexed has recently been shown to improve the median PFS in the maintenance setting.

On July 2, 2009, the FDA approved pemetrexed as maintenance therapy of patients with locally advanced or metastatic non-squamous NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy.  The FDA approval was based on a double-blind study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care.  The study was designed to show superior PFS and overall survival (OS) of pemetrexed over placebo.  The FDA-specified primary study objective was OS.  Pemetrexed (500 mg/m2) was given as an intravenous infusion over 10 mins on day 1 of each 21‑day cycle until disease progression.  Folic acid, vitamin B12, and a corticosteroid were also given to all patients to reduce pemetrexed toxicity.  There were 663 randomized patients (pemetrexed arm = 441 patients; placebo arm = 222 patients).  Treatments were well-balanced with respect to the baseline disease characteristics and randomization factors.  The majority of patients had ECOG Performance Status (PS) of 1 (60.2 %) and stage IV disease (80.8 %).  Adenocarcinoma (49.6 %) was the predominant histologic subtype, followed by squamous cell histology (27.3 %).

The median OS for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo [HR of 0.79 (95 % CI: 0.65 to 0.95, p = 0.012)].  Median OS was 15.5 months versus 10.3 months for patients with non-squamous histologies receiving pemetrexed and placebo, respectively [HR of 0.70 (95 % CI: 0.56 to 0.88)].  The median OS in patients with squamous histology receiving pemetrexed was 9.9 months versus 10.8 months for those receiving placebo [HR of 1.07 (95 % CI: 0.77 to 1.50)].  A significant improvement in PFS for the ITT patient population receiving pemetrexed maintenance therapy compared to placebo was observed.  The median PFS was 4.0 months for the pemetrexed-treated patients compared to 2.0 months for patients in the placebo arm [HR of 0.60 (95 % CI: 0.49 to 0.73, p < 0.00001)].  A treatment-by-histology interaction was also observed for PFS.  The PFS for patients with non-squamous histologies receiving pemetrexed versus placebo was 4.4 months and 1.8 months, respectively [HR of 0.47 (95 % CI: 0.37 to 0.60)].  The PFS for pemetrexed therapy in patients with squamous cell histology was 2.4 months versus 2.5 months for placebo treatment [HR of 1.03 (95 % CI: 0.71 to 1.49)].

The safety results for patients treated with pemetrexed are consistent with the known safety profile of single-agent pemetrexed previously described in product labeling.  The most common (greater than 5 %) adverse reactions in patients receiving pemetrexed were hematologic toxicity, increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy and skin rash.

The FDA-approved labeling of Alimta has the following recommendations for dosing and administration in NSCLC:

• Combination use in Non-Small Cell Lung Cancer: Recommended dose of Alimta is 500 mg/m2 i.v. on Day 1 of each 21-day cycle in combination with cisplatin 75 mg/m2 i.v. beginning 30 minutes after Alimta administration.
• Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose of Alimta is 500 mg/m2 i.v. on Day 1 of each 21-day cycle.
• Prior to initiating Alimta, initiate supplementation with oral folic acid and intramuscular vitamin B12. Continue folic acid and vitamin B12 supplementation throughout treatment.
• Administer corticosteroids the day before, the day of, and the day after Alimta administration.
• Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy.

Salivary Cancer (e.g., Parotid Gland Adenocarcinoma)

Viscuse and Price (2019) stated that there are no proven systemic therapies for metastatic adenocarcinoma of the salivary glands.  Pemetrexed use in adenocarcinoma of the salivary glands has not been previously described.  In a retrospective, case reports and literature review, these researchers described the findings of 2 patients with metastatic salivary gland adenocarcinoma who were treated with single-agent pemetrexed with marked response and clinical benefit.  Case 1 described a sustained clinical response for 8 months after failing several lines of chemotherapy.  Case 2 described a marked interval response of diffuse metastatic disease at 2 months with resolution of bone pain and sustained response at 8 months.  The authors concluded that to their  knowledge, this was the first report of efficacy of single-agent pemetrexed for metastatic salivary gland adenocarcinoma. These researchers stated that given the significant and sustained responses in heavily pre-treated patients, further investigation of pemetrexed for salivary cancer may be warranted.

Small Cell Lung Cancer

In a phase III clinical trial, Socinski et al (2009) compared pemetrexed-carboplatin with etoposide-carboplatin for the treatment of extensive-stage small-cell lung cancer (ES-SCLC).  Chemotherapy-naive patients with ES-SCLC and an ECOG performance status of zero to 2 were randomly assigned to receive

1. pemetrexed-carboplatin (pemetrexed 500 mg/m(2) on day 1; carboplatin at area under the serum concentration-time curve [AUC] 5 on day 1) or
2. etoposide-carboplatin (etoposide 100 mg/m(2) on days 1 through 3; carboplatin AUC 5 on day 1) every 3 weeks for up to 6 cycles.

The primary objective of the study was non-inferiority of pemetrexed-carboplatin overall survival with a 15 % margin.  Accrual was terminated with 908 of 1,820 patients enrolled after results of a planned interim analysis.  In the final analysis, pemetrexed-carboplatin was inferior to etoposide-carboplatin for OS (median, 8.1 versus 10.6 months; HR,1.56; 95 % CI: 1.27 to 1.92; log-rank p < 0.01) and PFS (median, 3.8 versus 5.4 months; HR, 1.85; 95 % CI: 1.58 to 2.17; log-rank p < 0.01).  Objective response rates were also significantly lower for pemetrexed-carboplatin (31 % versus 52 %; p < 0.001).  Pemetrexed-carboplatin had lower grade 3 to 4 neutropenia, febrile neutropenia, and leukopenia than etoposide-carboplatin; grade 3 to 4 thrombocytopenia was comparable between arms and anemia was higher in the pemetrexed-carboplatin arm.  The authors concluded that pemetrexed-carboplatin is inferior for the treatment of ES-SCLC.  Planned translational research and pharmacogenomic analyses of tumor and blood samples may help explain the study results and provide insight into new treatment strategies.

In an open-label phase II study, Che et al (2010) attempted to confirm the efficacy and to assess the tolerability of a pemetrexed plus carboplatin combination in previously untreated patients with ES-SCLC.  Subjects received pemetrexed 500 mg/m(2) and carboplatin (ACU of 5) every 21 days for a maximum 6 cycles.  The primary end point for this trial was the confirmed response rate and the accrual goal was 70 patients.  A total 46 eligible patients (29 aged less than 70 years, 17 aged greater than or equal to 70 years) were accrued to this study.  The efficacy outcomes were similar between the 2 age groups.  Overall, the confirmed response rate was 35 % (16 of 46; 95 % CI: 21 % to 50 %), where all 16 were partial responses.  These results provided strong evidence that the study would not meet the preset efficacy criteria and thus this study closed before full accrual.  The median duration of response was 4.4 months (95 % CI: 2.9 to 5.2).  Median OS for patients aged less than 70 years and aged greater than or equal to 70 years was 9.2 months (95 % CI: 5.4 to 11.6) and 10.8 months (95 % CI: 2.2 to14.3), respectively.  Grade 3 or higher toxicity rates were similar between the younger and older patients.  Grade 3/4 and grade 4 hematological toxicities were observed in 46 % and 26 % of patients, respectively.  The authors concluded that although well-tolerated, the combination of pemetrexed and carboplatin is not as effective as standard therapy in patients with untreated ES-SCLC.

Temporal Bone Squamous Cell Carcinoma

Wei and colleagues (2017) stated that high recurrence rates and poor survival rates for late stage/advanced temporal bone SCC with the standard treatments continues to be a significant challenge to otolaryngologists.  Targeted therapy for temporal bone SCC after relapse has not been reported.  These investigators presented the case of a 58-year old man who was diagnosed with recurrent temporal bone SCC and treated with a regimen developed using whole exome sequencing.  Somatic mutations in genes encoding catenin beta 1 and vascular endothelial growth factor (VEGF) receptor 2 were identified in the patient's tumor sample compared to the normal tissue.  The patient was then treated with bevacizumab in combination with pemetrexed.  After 2 weeks of treatment, tumor volume was reduced by 95 % measured by MRI, and the visual analog scale (VAS) headache scores went down from 10/10 to 2/10.  These findings revealed novel gene mutations of temporal bone SCC and demonstrated, for the first time, an effective targeted therapy for temporal bone SCC.  The authors concluded that the successful treatment regimen of bevacizumab and pemetrexed may provide a new therapeutic option for treating recurrent temporal bone SCC that failed to respond to conventional tumor resection, radiotherapy, and/or chemotherapy.  Moreover, these researchers stated that follow-up care has been established for the patient and an update of clinical outcomes is needed.  They noted that as temporal bone SCC is a rare disease, collaborative efforts for a cohort study is desirable to further prove the effectiveness of this approach.  These investigators stated that surgery followed by chemo-radiotherapy is the current standard of care for temporal bone SCC and fails frequently with a high risk of recurrence and adverse effects.  Genome-based targeted therapy for recurrent and late stage temporal bone SCC is potentially an option in terms of its promising clinical response, and hence deserves further investigation in a prospective clinical trial.

Thymoma and Thymic Carcinoma

Guidelines from the National Comprehensive Cancer Network (NCCN, 2022) recommend pemetrexed, with or without prednisone, gemcitabine, 5-FU, etoposide, and ifosfamide as second-line systemic therapy for thymic malignancies. NCCN panel members "feel that pemetrexed and paclitaxel are more efficacious as second-line therapy for thymomas than the other agents."  NCCN guidelines on "Thymomas and thymic carcinomas" (v.2.2022) list 6 combination chemotherapy regimens as first-line agents for thymic malignancies.

Combined Therapies

Combined Pemetrexed and Bevacizumab for the Treatment of Non-Squamous Non-Small Cell Lung Cancer

Zhao and associates (2018) stated that platinum-based doublet chemotherapy with or without bevacizumab is the standard treatment for untreated advanced non-squamous NSCLC (NS-NSCLC).  However, adding bevacizumab to chemotherapies other than paclitaxel-carboplatin is, though widely applied clinically, largely unjustified due to the lack of head-to-head data.  These investigators performed a Bayesian network meta-analysis (NMA) to address this important issue.  Data of 8,548 patients from 18 randomized controlled trials (RCTs) receiving 6 treatments, including taxane-platinum (Taxane-Pt), gemcitabine-platinum (Gem-Pt), pemetrexed-platinum (Pem-Pt), taxane-platinum + bevacizumab (Taxane-Pt + B), gemcitabine-platinum + bevacizumab (Gem-Pt + B) and pemetrexed-platinum + bevacizumab (Pem-Pt + B), were incorporated into the analyses.  Direct and indirect evidence of OS and PFS were synthesized at the HR scale and evidence of objective response rate (ORR) and serious adverse events (SAE) were synthesized at the odds ratio (OR) scale.  Taxane-Pt + B showed significant advantages in OS (HR = 0.79, p < 0.001), PFS (HR = 0.54, p < 0.001) and ORR (OR = 2.7, p < 0.001) over Taxane-Pt with comparable tolerability (OR = 3.1, p = 0.08).  Gem-Pt + B showed no OS benefit compared to any other treatment.  No significant differences were detected between Pem-Pt + B and Pem-Pt in four outcomes. I n terms of the benefit-risk ratio, Pem-Pt and Taxane-Pt + B were ranked the first and second, respectively.  The authors concluded that in the 1st-line treatment for advanced NS-NSCLC, Taxane-Pt and Gem-Pt are the most and least preferable regimens to be used with bevacizumab, respectively.  These researchers stated that adding bevacizumab to Pem-Pt remains unjustified because it failed to improve efficacy or tolerability.  In terms of the benefit-risk ratio, Pem-Pt and Taxane-Pt + B were the best and 2nd-best treatment for this population.

Kaira and co-workers (2019) noted that it remains unclear which chemotherapeutic regimens are better for the addition of bevacizumab.  These researchers performed an exploratory, randomized, phase-II clinical trial comparing 1st-line S-1 plus cisplatin with bevacizumab and pemetrexed plus cisplatin with bevacizumab in patients with advanced NS-NSCLC.  Chemotherapy-naïve patients received S-1 (80 mg/m2) from day 1 to day 14 plus cisplatin (80 mg/m2) on day 1 with bevacizumab (15 mg/kg) on day 1, followed by maintenance with bevacizumab plus S-1 (SCB) on day 1 every 3 weeks and pemetrexed (500 mg/m2) on day 1 plus cisplatin (75 mg/m2) on day 1 with bevacizumab (15 mg/kg) on day 1 followed by maintenance bevacizumab plus pemetrexed (PCB) on day 1 every 3 weeks.  The expression of thymidylate synthase (TS) was analyzed using immunohistochemistry.  A total of 48 patients were enrolled in this study, and eligible patients were randomly assigned at 1:1 ratio to receive SCB (n = 24) or PCB (n = 24).  The median number of chemotherapy and maintenance therapy for SCB and PCB was 4 (range of 1 to 6 cycles) and 4 (range of 2 to 6 cycles), and 5 (range of 0 to 39 cycles) and 5 (range of 0 to 28 cycles), respectively.  The ORR for PCB and SCB were 54.2 % and 83.3 %, respectively (p = 0.06).  The median PFS and OS for PCB and SCB were 406 and 351 days, (p = 0.96), and 678 and 1,190 days, respectively (p = 0.23); mild AEs were observed in both regimens; TS expression was more predictive of the chemotherapeutic response in SCB compared to PCB, but not for PFS.  The authors concluded that the combination regimen of SCB was identified as having a similar activity and tolerability to that of PCB in patients with advanced NS-NSCLC.

In a randomized, phase-II clinical trial, Fukuda and colleagues (2019) examined the safety and efficacy of pemetrexed (Pem) versus Pem + bevacizumab (Bev) for elderly patients with NS-NSCLC.  The eligibility criteria were as follows: NS-NSCLC, no prior therapy, stage IIIB/IV disease or post-operative recurrence, age of greater than or equal to 75 years, PS of 0 to 1, and adequate bone marrow function.  The patients were randomly assigned (1:1 ratio) to receive Pem or Pem + Bev.  The primary end-point was PFS; the secondary end-points were the RR, OS, toxicities, and cost-effectiveness.  A total of 41 patients were enrolled and 40 (20 from each group) were assessable.  Their characteristics were as follows: male/female = 23/17; median age (range) of 78 (75 to 83) years; stage IIIB / IV / post-operative recurrence = 1/30/9; PS 0/1 = 11/29.  All cases involved adenocarcinoma.  There was no significant inter-group difference in PFS and the median PFS (95 % CI values of the Pem and Pem + Bev groups were 5.4 (3.0 to 7.4) and 5.5 (3.6 to 9.9) months, respectively (p = 0.66).  The RR was significantly higher in the Pem + Bev group (15 % versus 55 %, p = 0.0146), and there was no significant difference in OS (median of 16.0 versus 16.4 months, p = 0.58).  Grade 3 and 4 leukopenia, neutropenia, and thrombocytopenia were observed in 10 and 30, 20 and 55, and 5 and 5 cases, respectively.  Drug costs were higher in the Pem + Bev group (median of 1,522,008 versus 3,368,428 JPY, p = 0.01).  No treatment-related deaths occurred.  The authors concluded that adding Bev to Pem did not result in improved survival in the elderly NS-NSCLC patients.  Compared with Pem + Bev, Pem monotherapy had similar effects on survival, a more favorable toxicity profile, and was more cost-effective in elderly NS-NSCLC patients.

Bagley and associates (2019) stated that despite recent advances in targeted therapy and immunotherapy for advanced NSCLC, carboplatin/pemetrexed/bevacizumab remains a commonly used 1st-line regimen.  However, it is unknown whether the addition of bevacizumab to carboplatin/pemetrexed improves OS.  Using nationally representative curated electronic health record data from Flatiron Health, these researchers performed a retrospective cohort study of patients diagnosed with advanced NS-NSCLC who received greater than or equal to 1 cycle of carboplatin/pemetrexed ± bevacizumab as initial systemic therapy for stage IV or metastatic/recurrent disease . The OS impact of adding bevacizumab to carboplatin/pemetrexed was assessed using a Cox proportional hazards model to adjust for age, sex, race, original tumor stage, time between diagnosis of metastatic disease and start of chemotherapy, and PS.  In a secondary analysis of patients at a single academic institution, these investigators also adjusted for the presence of brain metastases, hemoptysis, and anti-coagulation.  A total of 4,724 patients were included, of which 2,759 patients (58 %) received carboplatin/pemetrexed and 1,965 (42 %) received carboplatin/pemetrexed/bevacizumab.  Median OS was 12.1 months (95 % CI: 11.2 to 12.9 months) in the carboplatin/pemetrexed/bevacizumab group compared with 8.6 months (95 % CI: 8.1 to 9.1 months) in the carboplatin/pemetrexed group (p < 0.001).  Bevacizumab use remained associated with improved OS in a multi-variate model (HR, 0.80; 95 % CI: 0.75 to 0.86; p < 0.001).  In the secondary, institutional analysis (n = 539), the effect of bevacizumab was unchanged (HR 0.75; 95 % CI: 0.59 to 0.96; p = 0.02).  The authors concluded that this was the first adequately powered study to address whether the addition of bevacizumab to carboplatin/pemetrexed is associated with OS in advanced NS-NSCLC.  These researchers stated that it is unlikely that an RCT to address this question will ever be performed due to the size and cost that such a trial would entail, and the higher priority of other clinical questions in thoracic oncology.  They stated that findings of this real-world study provided essential information that can be incorporated into the complex clinical decision-making necessary for this large population of patients with cancer.

The authors stated that the principal drawback of this study, based on its retrospective and non-randomized nature, was the potential for unmeasured confounding.  Although these investigators adjusted for ECOG PS, which may address this issue to some extent, PS data were missing for approximately 50 % of the patients.  This was a direct result of electronic health record (EHR)-derived data, because PS was only available if recorded by the patient’s providers.  These researchers attempted to address this drawback using sensitivity analyses, in which the beneficial effect associated with bevacizumab was maintained.  In addition, the survival benefit associated with bevacizumab persisted in the University of Pennsylvania cohort after adjusting for brain metastases, hemoptysis, and anti-coagulation use, which were 3 important potential confounders in this analysis.  Nonetheless, these researchers could not rule out the possibility that unmeasured confounders, particularly other medical co-morbidities not available in the national cohort data, were responsible for the association between bevacizumab use and improved OS.  In addition, the University of Pennsylvania cohort was younger in general compared with the national cohort, which may have mitigated the impact of brain metastases, hemoptysis, and anti-coagulation use on outcomes in the institutional analysis.  Another drawback was that these investigators did not seek to examine the impact of the number of chemotherapy cycles received, the duration of bevacizumab treatment, or the use of maintenance therapy, all of which could impact outcomes in this population.  However, this was an ITT analysis, and the primary objective was to ascertain the real-world effectiveness of the addition of bevacizumab to carboplatin/pemetrexed.  It is debatable whether the median OS advantage of 3.5 months (HR, 0.80) associated with bevacizumab in this study is clinically meaningful.  Although this degree of incremental benefit is considered “clinically meaningful” according to prior ASCO guidance, and exceeds the median survival increment observed in ECOG 4599, the financial cost and increased toxicity associated with bevacizumab must also be considered when deciding whether to use bevacizumab both in individual patients and for society as a whole.

Combined Pemetrexed and Nintedanib for the Treatment of Malignant Pleural Mesothelioma

Scagliotti and colleagues (2019) stated that nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis.  These investigators reported the final results of the phase-III part of the LUME-Meso Trial, which examined the safety and efficacy of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma.  This double-blind, randomized, placebo-controlled, phase-III clinical trial was carried out at 120 academic medical centers and community clinics in 27 countries across the world.  Chemotherapy-naive adults (aged greater than or equal to 18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0 to 1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to 6 21-day cycles of pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) on day 1, then nintedanib (200 mg twice-daily) or matched placebo on days 2 to 21.  Patients without disease progression after 6 cycles received nintedanib or placebo maintenance on days 1 to 21 of each cycle.  The primary end-point was PFS (investigator-assessed according to mRECIST) in the ITT population.  Safety was assessed in all patients who received at least 1 dose of their assigned study drug.  Between April 14, 2016, and January 5, 2018, a total of 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n = 229) or the placebo group (n = 229).  Median treatment duration was 5.3 months (IQR 2.8 to 7.3) in the nintedanib group and 5.1 months (2.7 to 7.8) in the placebo group.  After 250 events, PFS was not different between the nintedanib group (median of 6.8 months [95 % CI: 6.1 to 7.0]) and the placebo group (7.0 months [6.7 to 7.2]; HR 1.01 [95 % CI: 0.79 to 1.30], p = 0.91).  The most frequently reported grade 3 or worse adverse event (AE) in both treatment groups was neutropenia (73 [32 %] in the nintedanib group versus 54 [24 %] in the placebo group).  Serious AEs were reported in 99 (44 %) patients in the nintedanib group and 89 (39 %) patients in the placebo group.  The only serious AE occurring in at least 5 % of patients in either group was pulmonary embolism (13 [6 %] versus 7 [3 %]).  The authors concluded that the primary PFS end-point of the phase-III part of LUME-Meso was not met and phase-II findings were not confirmed.  No unexpected safety findings were reported.

Combined Pemetrexed and Radiotherapy for the Treatment of Lung Adenocarcinoma Brain Metastasis

Zhang and colleagues (2019) examined the clinical efficacy and adverse reactions of pemetrexed combined with stereotactic gamma-ray radiotherapy in the treatment of patients with lung adenocarcinoma brain metastasis in the First People's Hospital of Yunnan Province.  A total of 67 patients with lung adenocarcinoma brain metastasis (experimental group) were treated with simple pemetrexed chemotherapy, and then with radiotherapy, followed by pemetrexed chemotherapy.  Their treatment results were compared with those of 53 patients treated with simple gamma knife (control group).  The results were analyzed by comparing the clinical efficacy, side reactions, serum level changes, and survival between the 2 groups.  Among 67 patients in the experimental group, there were 16 cases of complete response (CR), 39 cases of partial response (PR), 7 cases of stable disease (SD) and 5 cases of progressive disease (PD), with an effective rate of 82.09 % (55/67) and a tumor local control rate of 92.54 % (62/67).  Among 53 patients in the control group, there were 13 cases of CR, 20 cases of PR, 9 cases of SD and 11 cases of PD, with an effective rate of 62.26 % (33/53) and a tumor local control rate of 79.25 % (42/53).  There were statistically significant differences in the effective rate and local control rate between the 2 groups (p < 0.05). The 6-, 12- and 24-month survival rates in experimental group were higher than those in control group (p < 0.05).  The main adverse reactions after pemetrexed combined with radiotherapy were lower than those after simple radiotherapy (p < 0.05).  The expression levels of the tumor markers carcino-embryonic antigen (CEA) and cytokeratin fragment antigen 21-1 (CYFRA21-1) in the 2 groups of patients after treatment were lower than those before treatment (p < 0.05).  After treatment, the expression levels of serum CEA and CYFRA21-1 in the experimental group were significantly lower than those in the control group (p < 0.05).  The authors concluded that pemetrexed combined with radiotherapy in the treatment of lung adenocarcinoma brain metastasis was more effective than simple radiotherapy, with lighter adverse reactions, worthy of clinical application and promotion.  These findings need to be validated by well-designed studies.

The authors stated that in the screening of lung adenocarcinoma patients and collection of relevant data, subjective factors were inevitable.  Furthermore, there was a limitation in the design.  These researchers stated that 4 further experimental groups should be included in future experiments to validate the data.  Frist -- simple gamma-knife only; second -- whole body gamma knife only; third -- pemetrexed only, and fourth -- a combination of pemetrexed and whole body gamma knife.  In addition, these investigators stated that in subsequent studies, the staging of lung adenocarcinoma brain metastasis should be studied, to compare the efficacy difference between pemetrexed combined with radiotherapy and simple gamma knife and the incidence of adverse reactions in the staging.

Combined Pemetrexed and TroVax Vaccine for the Treatment of Malignant Pleural Mesothelioma

Lester and colleagues (2018) stated that vaccines in combination with chemotherapy have been shown to be safe in different tumor types.  These investigators examined the immunological activity of the TroVax vaccine in combination with pemetrexed-cisplatin chemotherapy in malignant pleural mesothelioma (MPM).  In an open-label, single-arm, phase-II clinical trial, patients with locally advanced or metastatic MPM were enrolled.  Eligible patients received up to 9 intra-muscular injections of TroVax, starting 2 weeks before chemotherapy and continuing at regular intervals during and after chemotherapy to 24 weeks.  The primary end-point was the induction of cellular or humoral anti-5T4 immune response (defined as a doubling of either response at any of 6 follow-up time-points), with a target response rate of 64 %.  Of 27 patients, enrolled between February 2013 and December 2014, 23 (85 %) received at least 3 doses of TroVax and 1 cycle of chemotherapy and were included in the per-protocol analysis (PPA); 22/23 patients (95.6 %) developed humoral or cellular immune response to 5T4.  Thus, the study reached its primary end-point.  Disease control was observed in 87 % of patients (PR: 17.4 %, SD: 69.6 %).  The median PFS was 6.8 months and median OS was 10.9 months.  Treatment-related AEs were comparable to those observed in patients with chemotherapy alone.  Translational immunology studies revealed a circulating baseline immune signature that was significantly associated with long-term (greater than 20 months in n = 8/23, 34.8 %) survival.  The authors concluded that in this phase-II clinical trial, TroVax with pemetrexed-cisplatin chemotherapy showed robust immune activity, acceptable safety and tolerability to warrant further investigation in a phase-III clinical trial setting.

Dosage Adjustments

Prior to initiating pemetrexed, initiate supplementation with oral folic acid and intramuscular vitamin B12. Continue folic acid and vitamin B12 supplementation throughout treatment. Administer corticosteroids the day before, the day of, and the day after pemetrexed administration.

Dose Reductions: Dose reductions or discontinuation may be needed based on toxicities from the preceding cycle of therapy.

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References