Medication Policy Manual. Topic: Alimta, pemetrexed Date of Origin: May 12, 2010

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1 Medication Policy Manual Policy No: dru213 Topic: Alimta, pemetrexed Date of Origin: May 12, 2010 Committee Approval Date: February 17, 2015 Next Review Date: February 2016 Effective Date: March 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Pemetrexed (Alimta) is an intravenous chemotherapy medication that is used to treat certain types of cancer. It is an antifolate similar to methotrexate. dru213.5 Page 1 of 10

2 Policy/Criteria I. Most contracts require prior authorization approval of pemetrexed prior to coverage. Pemetrexed may be considered medically necessary when criterion A or B is met: A. Diagnosis of mesothelioma. OR B. Diagnosis of locally advanced (stage III or IV) or metastatic nonsquamous nonsmall cell lung cancer (NSCLC). (See Appendix A for NSCLC subtypes.) II. Administration, Quantity Limitations, and Authorization Period A. OmedaRx does not consider pemetrexed to be a self-administered medication. B. Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. III. Pemetrexed is considered not medically necessary when used concomitantly with bevacizumab (Avastin ) for the treatment of NSCLC. IV. Pemetrexed is considered investigational when: A. Used concomitantly with bevacizumab for all conditions other than NSCLC B. Used concomitantly with any targeted therapy, including but not limited to afatinib (Gilotrif ), cetuximab (Erbitux ), ceritinib (Zykadia ), crizotinib (Xalkori ), erlotinib (Tarceva ), gefitinib (Iressa ), nivolumab (Opdivo ), or ramucirumab (Cyramza ). C. Used for all other conditions, including but not limited to: 1. Bladder cancer. 2. Breast cancer. 3. Cervical cancer. 4. CNS Lymphoma 5. Ovarian cancer. 6. Squamous cell non-small cell lung cancer. 7. Thymic malignancies. dru213.5 Page 2 of 10

3 Position Statement - Pemetrexed is an intravenously administered cytotoxic chemotherapy medication approved for the treatment of advanced malignant pleural mesothelioma (MPM) and advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). - When given in combination with platinum chemotherapy, pemetrexed improved median overall survival in both MPM and NSCLC when used as a first-line therapy. - Pemetrexed has also been evaluated in the second-line NSCLC and MPM treatment settings and as maintenance therapy for nonsquamous NSCLC after first-line chemotherapy. - Pemetrexed was not effective when used in patients with squamous NSCLC. It is, therefore, only approved for use in the treatment of non-squamous NSCLC. - National Comprehensive Cancer Network (NCCN) guidelines list pemetrexed as an option for both MPM and nonsquamous NSCLC in various settings. - Use of bevacizumab (Avastin) in combination with pemetrexed-based chemotherapy has not been shown to improve clinically relevant outcomes such as survival or quality of life over pemetrexed regimens without bevacizumab. However, this combination is more costly. Therefore, the use of bevacizumab in combination with pemetrexed is considered not medically necessary. - Other cancers: The evidence in other cancer types is preliminary and evolving. Additional, well-controlled studies are necessary to establish potential for benefit with pemetrexed in the treatment other cancers such as breast, bladder, cervical, and ovarian cancers. - Pemetrexed, like methotrexate, blocks folate-dependent metabolic processes. Supplementation with folic acid and vitamin B12 are recommended to decrease the severity of adverse effects including serious bone marrow and gastrointestinal toxicity. Clinical Efficacy MALIGNANT PLEURAL MESOTHELIOMA - Two large, randomized controlled trials studied the use of pemetrexed in malignant pleural mesothelioma (MPM). [1,2] One trial evaluated its use in the first-line setting, while the other evaluated pemetrexed in the relapsed setting. Although pemetrexed appears to provide a clinical benefit in MPM, accurate quantification is difficult due to flaws that included lack of blinding (potential source of bias), erosion of randomization due to a large proportion of dropouts, and use of additional chemotherapy agents not specified in the study protocol, which may confound results. * One study evaluated the combination of cisplatin and pemetrexed versus cisplatin alone in the first-line treatment of MPM. The median overall survival in the cisplatin/pemetrexed and cisplatin alone treatment arms was 12.1 months and 9.3 months, respectively (p = 0.012). [1] dru213.5 Page 3 of 10

4 * The other study evaluated single-agent pemetrexed versus best supportive care in relapsed MPM. There was no statistical difference noted in median overall survival; however, the median progression-free survival in the pemetrexed and BSC arms was 3.6 months and 1.5 months, respectively (p = 0.015). [2] - Subjects were required to have a good Karnofsky Performance Score (KPS > 70) to be included in the studies. [1,2] - Both trials used pemetrexed in a dose of 500 mg/m 2 on day 1 of each 21-day cycle. [1,2] - NCCN guideline recommendation for malignant pleural mesothelioma: Pemetrexed in combination with cisplatin is listed as a first-line therapy for malignant pleural mesothelioma. [3] - Pemetrexed has not been compared with other options recommended in the NCCN treatment guideline for MPM, such as cisplatin/gemcitabine or vinorelbine. ADVANCED NON-SQUAMOUS, NON-SMALL CELL LUNG CANCER - First-line treatment: Two large, randomized controlled trials studied the use of pemetrexed in the first-line treatment of advanced non-small cell lung cancer (NSCLC). [4,5] Although pemetrexed appears to provide a clinical benefit in advanced nonsquamous NSCLC, accurate quantification is difficult due to flaws that included lack of blinding (potential source of bias), use of post hoc analysis (erosion of randomization), and use of additional chemotherapy agents not specified in the study protocol, which may confound results. * A large RCT (n = 1,725) in chemotherapy-naïve adults with advanced NSCLC compared the combination of cisplatin and pemetrexed with the combination of cisplatin and gemcitabine (standard of care). The study was designed to show that the two regimens were similar with regard to their effect on median overall survival. The two regimens were found to be similar; however, a post hoc analysis found that the combination of cisplatin and pemetrexed was superior in the subset of patients with non-squamous NSCLC. [5] * A second RCT (n =436) in chemotherapy-naïve adults with advanced NSCLC compared the combination of carboplatin and pemetrexed with the combination of carboplatin and gemcitabine. Both regimens were found to be similar with regard to their effect on median overall survival. [4] - NCCN Guideline recommendation for first-line therapy in advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): Cisplatin in combination with gemcitabine, docetaxel, pemetrexed, or bevacizumab are endorsed by the NCCN guideline as preferred first-line chemotherapy in this setting. A lower level recommendation includes the combination of cisplatin, vinorelbine, and cetuximab. [6] dru213.5 Page 4 of 10

5 - Maintenance: A single trial studied the use of single-agent pemetrexed as a maintenance therapy in patients with advanced NSCLC. [7] Although pemetrexed appears to provide a clinical benefit as a maintenance therapy in advanced, nonsquamous NSCLC, accurate quantification is difficult due to flaws that included a high proportion of study dropouts which erodes randomization and use of additional chemotherapy agents not prespecified in the study protocol, which may confound results. * A large RCT (n = 663) in patients with advanced NSCLC who did not have disease progression on their initial platinum-based regimen compared pemetrexed with best supportive care. In this setting, pemetrexed was superior to best supportive care (BSC). Patients on pemetrexed versus those on BSC had a median progression-free survival of 4.3 months and 2.6 months, respectively (p < ). Median overall survival was 13.4 months and 10.6 months in the pemetrexed and BSC groups, respectively (p = 0.012). [7] - NCCN Guideline recommendation for maintenance therapy in advanced or metastatic non-squamous non-small cell lung cancer (NSCLC): Maintenance therapy refers to continuation of at least one of the agents used in the first-line setting, beyond the initial 4 to 6 cycles, if there has been no disease progression. Continuation of bevacizumab, cetuximab, or pemetrexed for an additional 4 to 6 cycles is listed as a category 1 (high level) recommendation in the NCCN NSCLC guideline. A switch to pemetrexed after induction with a non-pemetrexed-containing chemotherapy regimen is given a lower level of recommendation. [6] - Second-line treatment: A single trial studied the use of single-agent pemetrexed in patients with advanced NSCLC in the second-line setting. [8] Although pemetrexed appears to provide a clinical benefit as a second-line therapy for advanced, nonsquamous NSCLC, accurate quantification is difficult due to flaws that included omission of a high proportion of subjects from the final efficacy analysis, which erodes randomization and may introduce bias, and use of additional chemotherapy agents not prespecified in the study protocol, which may confound results. * A large RCT (n = 571) in patients with advanced NSCLC who had progression of their disease after first-line therapy compared single-agent pemetrexed with docetaxel (standard of care). The two regimens were found to be similar with regard to their effect on median overall survival. [8] - NCCN Guideline recommendation for second-line treatment of advanced or metastatic non-squamous non-small cell lung cancer (NSCLC): Single-agent docetaxel, erlotinib, a platin doublet, or pemetrexed are among recommendations for second-line therapy in the second-line treatment setting. [6] dru213.5 Page 5 of 10

6 - Use of pemetrexed in combination with bevacizumab (Avastin): There is currently no published evidence that the addition of bevacizumab (Avastin) to pemetrexed- based chemotherapy improves survival or quality of life over the same pemetrexed-based chemotherapy without bevacizumab or other any other chemotherapy regimen used for NSCLC. However, costs are increased. Because the use of this combination is not superior to less costly treatment options, the use of bevacizumab in combination with pemetrexed is considered not medically necessary. * There are no published, well-controlled studies demonstrating superiority of bevacizumab in combination with pemetrexed versus other chemotherapy regimens, including pemetrexed-based regimens without bevacizumab. The claims of superiority are based on preliminary (Phase 2 trial) evidence. * The POINTBREAK study compared overall survival with pemetrexed plus carboplatin plus bevacizumab followed by maintenance therapy with pemetrexed plus bevacizumab versus paclitaxel plus carboplatin plus bevacizumab followed by maintenance therapy with bevacizumab. No difference in median overall survival (OS) was shown between the two treatment arms. [9] * Additionally, there is no evidence that bevacizumab plus pemetrexed-based chemotherapy is better than bevacizumab plus any other chemotherapy doublet used for NSCLC. * There is currently no evidence that the addition of bevacizumab (Avastin) to pemetrexed maintenance therapy improves survival or quality of life over pemetrexed monotherapy. The AVAPERL study compared maintenance therapy with cisplatin plus bevacizumab versus bevacizumab alone after first-line induction therapy in patients with nonsquamous NSCLC. Final overall survival analysis (OS) failed to demonstrate a statistically significant difference in median overall survival between the two treatment arms.. [10,11] - Use of pemetrexed in combination with other targeted therapies: - There is currently no evidence that the combination of pemetrexed plus erlotinib improves survival or quality of life relative to either medication used alone. * A small, phase II trial studied the combination of pemetrexed and erlotinib as a second-line treatment in patients with nonsquamous NSCLC. There was no difference in overall survival between the pemetrexed-erlotinib treatment arm and either the pemetrexed-alone or erlotinib-alone treatment arms. Greater toxicity was reported in the combination arm. [12] - Use of pemetrexed in early stage NSCLC: * Neoadjuvant and adjuvant chemotherapy may be used for patients with stage II or IIIa (resectable NSCLC). There is no evidence to support the use of pemetrexed over other chemotherapy options. * The use of adjuvant chemotherapy in earlier stage IB NSCLC remains controversial. Although platinum-based chemotherapy has a definite role in stage II and IIIa disease, the NCCN guideline gives adjuvant chemotherapy in dru213.5 Page 6 of 10

7 stage IB lung cancer a 2B recommendation, which indicates there is disagreement among members of the panel regarding use in this setting. Chemotherapy may have a role in this stage if there are significant risk factors such as a poorly differentiated tumor, vascular invasion, wedge resection rather than lobectomy, incomplete lymph node sampling, or for tumors over 4 cm. [6] OTHER CANCER TYPES - Pemetrexed has been studied in other types of cancer including, but not limited to, breast cancer [13], bladder cancer, cervical cancer, and thymic cancer. These trials are small, uncontrolled, and employ overall response rates as endpoints. Larger, wellcontrolled trials are necessary to confirm potential for clinical benefit in these settings. - A phase III trial in patients with recurrent or metastatic squamous cell cancer of the head and neck (SCCHN) failed to demonstrate any difference in survival between cisplatin plus pemetrexed and cisplatin alone. Authors reported a survival improvement with the combination in the subgroup of patients with better ECOG performance status. - NCCN guidelines list pemetrexed among several potential treatment options for CNS lymphoma [14], bladder [15], ovarian [16], cervical [17], and thymic malignancies [18]. The evidence is these settings is of poor quality and there is no comparative evidence showing that pemetrexed is superior to other treatment alternatives for these conditions. - Use of concomitant pemetrexed and bevacizumab in cancers other than NSCLC: * No sufficiently large, well-designed studies evaluating concomitant use of pemetrexed and bevacizumab were identified. * There was a single, small (n = 34) observational study evaluating 6-month progression-free survival in patients receiving pemetrexed plus bevacizumab for relapsed or refractory ovarian, fallopian tube, or primary peritoneal cancer. [19] However, the study was too small to establish the safety and efficacy of this combination in this population. * Additionally, there is no evidence to suggest that concomitant pemetrexed and bevacizumab is superior to any other cytotoxic chemotherapy agent used in combination with bevacizumab. OmedaRx performs independent analyses of oncology medications. The OmedaRx analysis and coverage policy may differ from NCCN guidelines. Safety - Supplementation of folic acid and vitamin B12 is recommended during treatment with pemetrexed to help reduce hematologic and gastrointestinal side effects. [20] - The most common (> 20% incidence) adverse effects with single-agent pemetrexed include fatigue, nausea, and anorexia. When used in combination with cisplatin, additional common adverse effects may occur. They include vomiting, bone marrow suppression (neutropenia, anemia, thrombocytopenia), stomatitis, and constipation. [20] dru213.5 Page 7 of 10

8 - Skin rashes were reported in pemetrexed clinical trials. The incidence and severity of cutaneous reactions may be reduced by pre-treating with corticosteroids (e.g. dexamethasone). [20] Dosing Considerations - The recommended dose of pemetrexed is 500 mg/m 2 administered as an IV infusion over 10 minutes on the first day of each 21-day cycle. [20] - Dose reductions for subsequent cycles are based on the severity of hematologic and gastrointestinal toxicities. [20] - Pemetrexed should not be administered to patients with a creatinine clearance below 45 ml/min (calculated using the standard Cockcroft and Gault formula). [20] - Patients with mild to moderate renal insufficiency (creatinine clearance of 45 to 79 ml/min) should not receive concomitant non-steroidal anti-inflammatory medications (NSAIDs) because they may delay excretion of pemetrexed, thereby increasing its toxicity. [20] Appendix A: Lung cancer histological subtypes (and approximate incidence, %) Lung cancer (162.0, , 162.8, 162.9) A. Non-small cell lung cancer (NSCLC) (85-90%) 1) Squamous cell (epidermoid) carcinoma (25-30%) 2) Non-squamous cell (55%) - Adenocarcinoma (40%) - Large cell (undifferentiated) carcinoma (10-15%) - Other B. Small cell lung cancer (SCLC) (10-15%) A. Unspecified lung cancer (< 5%) American Cancer Society. What is non-small cell lung cancer?;16dec2010. Available at: dru213.5 Page 8 of 10

9 Cross References Maximum Drug Dosage, Medication Policy Manual, Policy No. dru237 Avastin, bevacizumab, Medication Policy Manual, Policy No. dru215 Cyramza, ramucirumab, Medication Policy Manual, Policy No. dru355 Erbitux, cetuximab, Medication Policy Manual, Policy No. dru187 Gilotrif, afatinib, Medication Policy Manual, Policy No. dru317 Opdivo, nivolumab, Medication Policy Manual, Policy No. dru390 Tarceva, erlotinib, Medication Policy Manual, Policy No. dru118 Xalkori, crizotinib, Medication Policy Manual, Policy No. dru265 Zykadia, ceritinib, Medication Policy Manual, Policy No. dru354 Codes Number Description HCPCS J9305 Injection, pemetrexed, 10 mg ICD , 163.0, 163.1, 163.8, Malignant Pleural Mesothelioma ICD , , 162.8, Non-small Cell Lung Cancer References 1. Vogelzang, NJ, Rusthoven, JJ, Symanowski, J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol Jul 15;21(14): PMID: Jassem, J, Ramlau, R, Santoro, A, et al. Phase III trial of pemetrexed plus best supportive care compared with best supportive care in previously treated patients with advanced malignant pleural mesothelioma. J Clin Oncol Apr 1;26(10): PMID: NCCN Clinical Practice Guidelines in Oncology. Malignant Pleural Mesothelioma v [cited 1/14/2015]; Available from: 4. Gronberg, BH, Bremnes, RM, Flotten, O, et al. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol Jul 1;27(19): PMID: Scagliotti, GV, Parikh, P, von Pawel, J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advancedstage non-small-cell lung cancer. J Clin Oncol Jul 20;26(21): PMID: NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer v [cited 1/14/2015]; Available from: 7. Ciuleanu, T, Brodowicz, T, Zielinski, C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet Oct 24;374(9699): PMID: dru213.5 Page 9 of 10

10 8. Hanna, N, Shepherd, FA, Fossella, FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol May 1;22(9): PMID: Patel, JD, Socinski, MA, Garon, EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol Dec 1;31(34): PMID: Barlesi, F, Scherpereel, A, Rittmeyer, A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol Aug 20;31(24): PMID: Barlesi, F, Scherpereel, A, Gorbunova, V, et al. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol May;25(5): PMID: Lee, DH, Lee, JS, Kim, SW, et al. Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer. Eur J Cancer Oct;49(15): PMID: Dittrich, C, Solska, E, Manikhas, A, et al. A phase II multicenter study of two different dosages of pemetrexed given in combination with cyclophosphamide as first-line treatment in patients with locally advanced or metastatic breast cancer. Cancer Invest May;30(4): PMID: NCCN Clinical Practice Guidelines in Oncology. Central Nervous System Cancers v [cited 1/14/2015]; Available from: NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer v [cited 1/14/2015]; Available from: NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer v [cited 1/14/2015]; Available from: NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer v [cited 1/14/2015]; Available from: NCCN Clinical Practice Guidelines in Oncology. Thymomas and Thymic Carcinomas v [cited 1/14/2015]; Available from: Hagemann, AR, Novetsky, AP, Zighelboim, I, et al. Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer. Gynecologic oncology Dec;131(3): PMID: Alimta (pemetrexed) [package insert]. Indianapolis, IN: Eli Lilly and Company; September dru213.5 Page 10 of 10