Pemetrexed (Alimta)

Number: 0687

Policy

Aetna considers pemetrexed disodium (Alimta) medically necessary for the treatment of the following (see Appendix for selection criteria):

• Bladder, urethral and upper genitourinary tract cancers - second-line therapy as a single agent for metastatic disease
• Cervical cancer - second-line therapy as a single agent
• Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer - single agent therapy for persistent or recurrent disease
• Malignant peritoneal mesothelioma
• Malignant pleural mesothelioma
• Non-squamous non-small-cell lung cancer (NSCLC)
• Primary CNS lymphoma - as a single agent for progressive or recurrent disease
• Thymomas and thymic carcinomas - second-line therapy as a single agent
• Urothelial carcinoma of the prostate - second-line therapy as a single agent
• Vaginal cancer - second-line therapy as a single agent (see selection criteria for cervical cancer)

Alimta (pemetrexed) is considered not medically necessary for members with creatinine clearance (CrCl) less than 45 mL/min. 

Aetna considers pemetrexed 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
• Pancreatic cancer
• Renal cell carcinoma
• Small cell lung cancer
• Squamous cell carcinoma of the head and neck
• Squamous cell carcinoma of the tongue
• Squamous cell non-small cell lung cancer
• Temporal bone squamous cell carcinoma.

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

Background

Alimta (pemetrexed) is a pyrimidine-based folate analog that suppresses tumor growth by inhibitng 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.

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 perfomed to evaluate renal and hepatic function.

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

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.

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.

Thymoma and Thymic Carcinoma

Guidelines from the National Comprehensive Cancer Network (NCCN, 2018) 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" (v2.2018) list 6 combination chemotherapy regimens as first-line agents for thymic malignancies.

Cervical 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/m(2) 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.

Vaginal Cancer

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).

Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

The National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium (2018) recommends pemetrexed as a single agent therapy for persistent or recurrent epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (Category 2A for clinical relapse, 2B for immediate treatment of biochemical relapse). "In women with platinum-resistent disease, the response rate for pemetrexed is 21%" (NCCN, 2018).

Small Cell Lung Cancer

In an open-labe 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.

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.

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, 2018), and “Treatment protocols for renal cell cancer” (Brenner et al, 2016) do not mention the use of pemetrexed as a therapeutic option.

Furthermore, the NCCN clinical practice guideline on "Kidney cancer" (Version 2.2019) does not mention the use of pemetrexed; and the 2018 NCCN's Drugs & Biologics Compendium does not list renal cell carcinoma as an indication of pemetrexed.

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 (Brockstein et al, 2015a), “Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx” (Brockstein et al, 2015b), and “Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oropharynx” (Worden et al, 2015) 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, 2015) 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 2.2018) does not mention the use of pemetrexed; and the 2018 NCCN's Drugs & Biologics Compendium does not list head and neck cancers as an indication of pemetrexed. 

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 and Kindler, 2017) states that “For patients receiving systemic therapy, we suggest a pemetrexed-containing regimen over other chemotherapy options (Grade 2B).  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 is a very reasonable option that achieves similar results with less toxicity”.

Biliary 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.

Extra-Mammary Paget's Disease

Chen and colleagues (2018) 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.

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.

Appendix

Dosing recommendations

Pemetrexed is available as Alimta as 100 mg and 500 mg powder for injection in single-use vials.

Combination use in Non-Small Cell Lung Cancer and Mesothelioma: Recommended dose of pemetrexed 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 pemetrexed administration.

Single-Agent use in Non-Small Cell Lung Cancer: Recommended dose of pemetrexed is 500 mg/m2 i.v. on Day 1 of each 21-day cycle.

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.

Selection Criteria

The National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN, 2018) recommends the use of pemetrexed for the following indications (all recommendations NCCN Category I or 2A unless otherwise specified):

• Bladder Cancer - (urothelial carcinoma) - Used as subsequent systemic therapy post-platinum or post-checkpoint inhibitor as a single agent for 
   
  • stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy
  • stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy
  • stage IVB (any T, any N, M1b) disease
  • metastatic or local recurrence post cystectomy
     
    
• Primary Carcinoma of the Urethra - Used as a single agent as subsequent systemic therapy for recurrent or metastatic disease post-platinum or post-checkpoint inhibitor. Chemotherapy regimen based on histology. (Category 2B recommendation for recurrence of clinical stage T3-4 disease or palpable inguinal lymph nodes)
  
  
• Upper GU Tract Tumors - Used as a single agent as subsequent systemic therapy for metastatic disease post-platinum or post-checkpoint inhibitor
  
  
• Urothelial Carcinoma of the Prostate - Used as a single agent as subsequent systemic therapy for metastatic disease post-platinum or post-checkpoint inhibitor
  
  
• Primary CNS Lymphoma 
   
  • Single-agent treatment for relapsed or refractory disease 
     
    • may be considered in persons who received prior whole brain radiation therapy
    • in persons who received a prior high-dose methotrexate-based regimen without prior radiation therapy (RT) after previous response with long duration (≥12 months) to prior regimen
    • in combination with whole brain RT or involved field RT in persons 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 persons who received prior high-dose chemotherapy with stem cell rescue after previous response with long duration (≥12 months)
       
      
• Cervical Cancer - Second-line therapy as a single agent for
   
  • local/regional recurrence (2B recommendation)
  • stage IVB or distant metastases (2B recommendation)
     
• Malignant Pleural Mesothelioma
   
  • Induction therapy in combination with cisplatin for medically operable clinical stage I-III disease
  • Used as a single agent or in combination with cisplatin or carboplatin as treatment of
     
    • unresectable clinical stage I-III disease and tumors of epithelial or mixed histology
    • resected clinical stage I-III disease in persons not treated with induction chemotherapy
    • clinical stage IV disease, tumors of sarcomatoid or mixed histology, or medically inoperable tumors in persons with performance status (PS) 0-2
       
  • Used in combination with bevacizumab and cisplatin, or bevacizumab and carboplatin, followed by single agent maintenance bevacizumab as treatment of
     
    • unresectable clinical stage I-III disease and tumors of epithelial histology
    • clinical stage IV disease, tumors of sarcomatoid or mixed histology, or medically inoperable tumors in persons with performance status (PS) 0-2
      
      
  • Subsequent systemic therapy a single agent
     
    • 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 (NSCLC) (adenocarcinoma (with mixed subtypes), large cell carcinoma)
   
  • initial systemic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PD-L1 <50% or unknown
  • first-line or subsequent therapy for BRAF V600E-mutation positive tumors
  • subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, osimertinib, or dacomitinib therapy
  • subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy
  • subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy
  • subsequent therapy for PD-L1 expression-positive (≥50%) tumors and EGFR, ALK negative or unknown and no prior platinum-doublet chemotherapy
    (2B recommendation for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease)
  • Preoperative concurrent chemoradiation for nonsquamous cell histology in combination with cisplatin or carboplatin for
     
    • resectable or possibly resectable superior sulcus tumors (T3 invasion or T4 extension, N0-1)
    • T3 invasion or resectable T4 extension, N0-1 disease in the chest wall, proximal airway, or mediastinum
    • stage IIA (T4, N0-1) disease
       
      
  • For nonsquamous cell histology in combination with cisplatin or carboplatin (for persons who have comorbidities or are unable to tolerate cisplatin)
     
    • may be used as induction chemotherapy for operable stage IB (peripheral T2a, N0), stage I (central T1abc-2a, N0), stage II (T1abc-2ab, N1 or T2b, N0), stage IIB (T3, N0), or stage IIIA (T3, N1) with negative mediastinal nodes as an alternative for persons likely to receive adjuvant chemotherapy
    • as neoadjuvant chemotherapy for T3 invasion or resectable T4 extension, N0-1 disease in the chest wall, proximal airway, or mediastinum
    • as induction chemotherapy with or without radiation for T1-2 or T3 (other than invasive) N2, M0
    • may be used as induction chemotherapy for T1-3, N0-1 (including T3 with multiple nodules in the same lobe) as an alternative for persons likely to receive adjuvant chemotherapy
       
  • Initial treatment as definitive concurrent chemoradiation for nonsquamous cell histology in combination with carboplatin or cisplatin (with or without an additional 4 cycles of pemetrexed after concurrent chemoradiation if given with cisplatin) for
     
    • medically inoperable stage IB (peripheral T2a, N0), stage I (central T1abc-2a, N0), stage II (T1abc-2ab, N1 or T2b, N0), stage IIB (T3, N0), or stage IIIA (T3, N1) with negative mediastinal nodes and N1 disease
    • unresectable superior sulcus tumors (T4 extension, N0-1)
    • unresectable stage IIIA (T4, N0-1)
    • T1-2 or T3 (other than invasive), N2 nodes positive, M0
    • T3 invasion, N2 nodes positive, M0
    • stage IIIB (T1-2, N3 positive, M0)
    • contralateral or ipsilateral mediastinal node-positive stage IIIB (T4,, N2) and stage IIIC (T4, N3)
    • stage IVA, M1b (T1-3, N1-2 or T4, N0-2) disease and limited non-brain metastases confirmed, if definitive therapy for thoracic disease is feasible
       
  • Adjuvant chemotherapy for nonsquamous cell histology in combination with cisplatin or carboplatin (for persons with comorbidities or who are unable to tolerate cisplatin)
     
    • may be considered following definitive radiation therapy in medically inoperable high-risk stage IB (peripheral T2a, N0), stage I (central T1abc-2a, N0), stage II (T1abc- 2ab, N1; T2b, N0), stage IIB (T3, N0) with negative mediastinal nodes and N0 disease
    • for high-risk, margin-negative stage IB (T2a, N0) and IIA (T2b, N0)
    • for margin-positive stage IB (T2a, N0) and IIA (T2b, N0)
    • for margin-positive stage IIA (T2b, N0) following radiation
    • for stage IIB (T1abc-2a, N1; T3, N0; T2b, N1)
    • for margin-negative stage IIIA (T1-2, N2; T3, N1) and stage IIIB (T3, N2)
    • for resectable superior sulcus tumors (T3 invasion or T4 extension, N0-1)
    • for T3 invasion or resectable T4 extension, N0-1 tumors in the chest wall, proximal airway, or mediastinum if not given as initial treatment
    • for stage IIIA (T4, N0-1) disease if not given as initial treatment
    • for clinical stage IIIA disease (T1-3, including T3 with multiple nodules in the same lobe) that was clinically N2 but has negative N2, N3 nodes on mediastinal biopsy and negative margins post-surgery
    • for clinical stage IIIA disease (T1-2, T3 other than invasive, N2 nodes positive, M0) with no apparent progression or local progression after induction chemotherapy 
    • for separate pulonary nodule(s) in the same lobe (T3) or ipsilateral non-primary lobe (T4), N0-1
    • for margin-negative separate pulmonary nodule(s) in the same lobe (T3) or ipsilateral non-primary lobe (T4), N2 (Category 2B for high-risk medically inoperable stages IB-IIB with negative mediastinal nodes and for T1-2, T3 (other than invasive), N2 nodes positive, M0 with no apparent progression)
       
  • Adjuvant concurrent chemoradiation for nonsquamous cell histology in combination with cisplatin or carboplatin (with or without an additional 4 cycles of pemetrexed after concurrent chemoradiation if given with cisplatin) for
     
    • margin-positive stage IIB (T1abc-2a, N1; T3, N0; T2b, N1)
    • margin-positive stage IIIA (T1-2, N2) and stage IIIB (T3, N2)
    • margin-positive T3 invasion or resectable T4 extension, N0-1 tumors in the chest wall, proximal airway, or mediastinum if not given as initial treatment
    • margin-positive stage IIIA (T4, N0-1) disease if not given as initial treatment
    • clinical stage IIIA disease (T1-3, including T3 with multiple nodules in the same lobe) that was clinically N2 but has negative N2, N3 nodes on mediastinal biopsy and positive margins post-surgery
    • margin-positive separate pulmonary nodule(s) in the same lobe (T3) or ipsilateral nonprimary lobe (T4), N2
       
  • Concurrent chemoradiation for nonsquamous cell histology in combination with carboplatin or cisplatin (with or without an additional 4 cycles of pemetrexed after concurrent chemoradiation if given with cisplatin) if radiation not previously given for locoregional recurrence in the mediastinal lymph nodes or for superior vena cava obstruction with or without SVC stent
  • Sequential chemoradiation for nonsquamous cell histology in combination with cisplatin or carboplatin (for persons with comorbidities or who are unable to tolerate cisplatin) as
     
    • initial definitive therapy for medically inoperable stage IB (peripheral T2a, N0), stage I (central T1abc-2a, N0), stage II (T1abc-2ab, N1 or T2b, N0), stage IIB (T3, N0), or stage IIIA (T3, N1) with negative mediastinal nodes and N1 disease
    • adjuvant therapy for margin-positive, R1 stage IIB (T1abc-2a, N1; T3, N0; T2b, N1)
    • adjuvant therapy for margin-negative stage IIIA (T1-2, N2) and stage IIIB (T3, N2) 
    • adjuvant therapy for margin-positive, R1 stage IIIA (T1-2, N2) and stage IIIB (T3, N2)
    • adjuvant therapy for margin-positive, R1 T3 invasion or resectable T4 extension, N0-1 tumors in the chest wall, proximal airway, or mediastinum if not given as initial treatment
    • adjuvant therapy for margin-positive, R1 stage IIIA (T4, N0-1) disease if not given as initial treatment
    • adjuvant therapy for clinical stage IIIA disease (T1-3, including T3 with multiple nodules in the same lobe) that was clinically N2 but has negative N2, N3 nodes on mediastinal biopsy and R1 positive margins post-surgery
    • adjuvant therapy for margin-positive, R1 separate pulmonary nodule(s) in the same lobe (T3) or ipsilateral non-primary lobe (T4), N2
       
  • Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (≥50%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab or atezolizumab and performance status 0-2 in combination with pembrolizumab and either carboplatin or cisplatin for nonsquamous cell histology (2B recommendation for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease)
  • Continuation maintenance therapy in combination with pembrolizumab for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥50%) tumors that are EGFR, ALK negative or unknown and no contraindications to the addition of pembrolizumab or atezolizumab in persons with performance status 0-2 who achieve a response or stable disease following first-line therapy with pembrolizumab/pemetrexed and either cisplatin or carboplatin for nonsquamous cell histology (2B recommendation for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease)
  • Treatment for recurrent, advanced or metastatic disease of nonsquamous cell histology as a single agent for persons with performance status (PS) 2, in combination with either cisplatin or carboplatin and pembrolizumab for PS 0-1 (as preferred regimens if no contraindications to the addition of pembrolizumab or atezolizumab) or in combination with cisplatin for PS 0-1 (if contraindications to the addition of pembrolizumab or atezolizumab), or in combination with carboplatin for PS 0-2 (if contraindications to the addition of pembrolizumab or atezolizumab for PS 0-1) as
  • Treatment for recurrent, advanced or metastatic disease in combination with bevacizumab and either cisplatin or carboplatin for persons with performance status 0-1, tumors of nonsquamous cell histology, and no history of recent hemoptysis as
     
    • initial systemic therapy for EGFR, ALK, ROS1, BRAF negative or unknown, and PD-L1 <50% or unknown
    • first-line or subsequent therapy for BRAF V600E-mutation positive tumors
    • subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, osimertinib, or dacomitinib therapy
    • subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy
    • subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib or ceritinib therapy
    • subsequent therapy for PD-L1 expression-positive (≥50%) tumors and EGFR, ALK negative or unknown and no prior platinum-doublet chemotherapy 
      (2B recommendation for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease)
       
  • Treatment for recurrent, advanced or metastatic disease of nonsquamous cell histology in persons with performance status 0-2 who achieve tumor response or stable disease following initial systemic therapy
     
    • as a single agent for continuation maintenance therapy
    • in combination with bevacizumab for continuation maintenance therapy if bevacizumab previously used with a first-line pemetrexed/platinum chemotherapy regimen
    • in combination with pembrolizumab for continuation maintenance therapy if previously used first-line as part of a pembrolizumab/pemetrexed and either cisplatin or carboplatin regimen
    • as a single agent for switch maintenance
      (2B recommendation for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease)
       
  • Single agent (if not already given) as subsequent systemic therapy for recurrent, advanced or metastatic disease in persons with performance status 0-2 and tumors of nonsquamous cell histology (2B recommendation for progression after subsequent systemic therapy)
     
• Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer - Single-agent therapy for persistent disease or recurrence (2B recommendation for immediate treatment of biochemical relapse)
• Thymomas and Thymic Carcinomas- Second-line therapy as a single agent
  
  

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
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:
J9305	Injection, pemetrexed, 10 mg
ICD-10 codes covered if selection criteria are met:
For Mesothelioma (malignant) - see Neoplasm, by site, malignant
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]
C48.2	Malignant neoplasm of peritoneum, unspecified [primary peritoneal cancer]
C52	Malignant neoplasm of vagina
C53.0 - C53.9	Malignant neoplasm of corpus uteri
C56.1 - C57.02	Malignant neoplasm of ovary or fallopian tube [persistent or recurrent] [epithelial ovarian cancer]
C61	Malignant neoplasm of prostate [urothelial carcinoma]
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of ureter
C67.0 - C67.9	Malignant neoplasm of bladder
C68.0	Malignant neoplasm of urethra
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]
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 neoplasom 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]
C51.0 - C51.9	Malignant neoplasm of vulva [Paget's disease]
C60.0 - C60.9	Malignant neoplasm of penis [Paget's disease]
C64.9	Malignant neoplasm of unspecified kidney, except renal pelvis [renal cell carcinoma]
C50.011 - C50.929	Malignant neoplasm of breast
C58	Malignant neoplasm of placenta [choriocarcinoma]
C7A.010 - C7B.8	Neuroendocrine tumors
D03.0 - D03.9	Melanoma in situ
D3A.00 - D3A.8	Benign neuroendocrine tumors

The above policy is based on the following references: