Anthem Blue Cross California Pemetrexed Agents (Alimta, Pemfexy) Form

Overview Clinical criteria Overview Coding Document history References This document addresses the use of pemetrexed agents, including Alimta (pemetrexed disodium) and Pemfexy (pemetrexed), which are folate analog metabolic inhibitors. They work by inhibiting folate-dependent metabolic processes which disrupts cell replication. The FDA approved indications for Alimta and Pemfexy include non-squamous (NSCLC) and malignant pleural mesothelioma. Non-Small Lung Cancer • In combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non- squamous NSCLC, with no EGFR or ALK genomic tumor aberrations (Alimta only*). • In combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous, (NSCLC). • As a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. • As a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. Malignant Pleural Mesothelioma • In initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The FDA states neither Alimta nor Pemfexy are indicated for the treatment of patients with squamous cell, non-small cell lung cancer. The National Comprehensive Cancer Network (NCCN) provides additional recommendations with a category 2A level of evidence for the use of pemetrexed in ovarian cancer, and thymomas and thymic carcinomas, and additional uses in NSCLC. The NCCN panel includes category 1 recommendations for nonsquamous NSCLC continuation maintenance therapy for use of pembrolizumab in combination with pemetrexed if given first-line as part of pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed regimen. The NCCN panel also gives a category 1 and 2A recommendation for use of pemetrexed in combination with platinum-based therapy as adjuvant or neoadjuvant therapy in NSCLC (Kenmotsu 2020, Kreuter 2013, Zhang 2014). The NCCN panel also gives a category 1 recommendation for use of pemetrexed in malignant mesothelioma as single agent, subsequent therapy. The NCCN panel recommends that individuals with NSCLC be tested for actionable molecular markers, such as EGFR, ALK, ROS1, BRAF, NTRK, MET and RET mutations, before initiating first line therapy to help guide treatment. If there is insufficient tissue to allow testing for all of these markers, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes. *The NCCN panel does not differentiate between Alimta and Pemfexy for any indication, including the use in NSCLC in combination with pembrolizumab and platinum therapy for initial treatment. Other Uses The NCCN also provides a category 2A recommendation for use in thymic cancer and thymomas as first-line therapy when preferred first-line combination regimens are not tolerated. At this time, there is insufficient data to support such use. The NCCN CPGs in Oncology for primary CNS lymphoma include a recommendation for the use of pemetrexed in the treatment of recurrent or progressive primary CNS lymphoma. The 2A recommendation is based on a single study conducted by Raizer and 1 colleagues (2012) which enrolled 11 participants with relapsed/refractory PCNSL to assess for single agent activity based on OS, PFS and response rates. Ten of the 11 participants had previously been treated with high-dose methotrexate. The 6-month PFS was 45%, median PFS was 5.7 months and median OS was 10.1 months. Toxicities experienced were largely infectious and hematologic. Authors conclude that pemetrexed demonstrated single-agent activity in relapsed/refractory PCNSL. At this time, the published data does not demonstrate the efficacy of pemetrexed in the treatment of PCNSL. NCCN CPG for mesothelioma also includes a 2A recommendation for pemetrexed-based chemotherapy for unresectable malignant peritoneal mesothelioma or tunica vaginalis testis mesothelioma, relatively rarer forms of mesothelioma. Evidence for peritoneal mesothelioma, which accounts for about 30% of mesothelioma cases, consists of results from two open-label, expanded-access programs that found pemetrexed safe and active for this indication (Carteni, 2009; Jänne, 2005). To date, there are no published studies on pemetrexed’s efficacy in tunica vaginalis testis which accounts for less than 1% of mesothelioma cases, though NCCN endorses it as a reasonable treatment approach for unresectable disease based on expert consensus. Definitions and Measures Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals. ECOG or Eastern Cooperative Oncology Group Performance Status: A scale and criteria used by doctors and researchers to assess how an individual’s disease is progressing, assess how the disease affects the daily living abilities of the individual, and determine appropriate treatment and prognosis. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale: • • • • • • 0 = Fully active, able to carry on all pre-disease performance without restriction 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 5 = Dead Immune checkpoint inhibitor: A type of drug that blocks certain proteins made by some types of immune system cells, such as T cells, and some cancer cells. When these proteins are blocked, the “brakes” on the immune system are released and T cells are able to kill cancer cells better. Examples of checkpoint proteins found on T cells or cancer cells include programmed death (PD)-1, PD-ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen (CTLA)-4/B7-1/B7-2. Line of Therapy: • First-line therapy: The first or primary treatment for the diagnosis, which may include surgery, chemotherapy, radiation therapy or a combination of these therapies. • Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression. • Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression. Maintenance therapy: Designed to maintain a condition to prevent a relapse. Metastasis: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread. Non-small cell lung cancer: A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Programmed death (PD)-1 proteins: PD-1 proteins are found on T-cells and attach to PD ligands (PD-L1) found on normal (and cancer) cells (see immune checkpoint inhibitor above). Normally, this process keeps T-cells from attacking other cells in the body. However, this can also prevent T-cells from attacking cancer cells in the body. Examples of FDA approved anti-PD-1 agents include Keytruda (pembrolizumab), Opdivo (nivolumab), and Libtayo (cemiplimab). Programmed death ligand (PD-L)-1: The ligands found on normal (and cancer) cells to which the PD-1 proteins attach (see immune checkpoint inhibitor above). Cancer cells can have large amounts of PD-L1 on their surface, which helps them to avoid immune attacks. Examples of FDA approved anti-PD-L1 agents include Bavencio (avelumab), Tecentriq (atezolizumab), and Imfinzi (durvalumab). Refractory Disease: Illness or disease that does not respond to treatment. Clinical Criteria 2 When a drug is being reviewed for coverage under a member’s medical benefit plan or is otherwise subject to clinical review (including prior authorization), the following criteria will be used to determine whether the drug meets any applicable medical necessity requirements for the intended/prescribed purpose. Pemetrexed Agents (Alimta, Pemfexy) Requests for Pemetrexed Agents (Alimta, Pemfexy) may be approved if the following criteria are met: I. Individual has a diagnosis of malignant mesothelioma; AND A. Individual is using in combination with cisplatin or carboplatin (Label, NCCN 2A); OR B. OR C. D. Individual is using as a first-line therapy in combination with cisplatin or carboplatin AND bevacizumab (or bevacizumab biosimilar) (Label, NCCN 2A); AND 1. 2. 3. Disease presentation is unresectable; Individual has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; AND Individual does not have a history of hemoptysis or thrombosis; AND Individual is using as single agent for subsequent therapy (NCCN 1); AND 1. Pemetrexed was not administered as first-line; OR 2. Pemetrexed was used as first-line with good sustained response; Individual is using as single agent for first line systemic therapy; OR II. OR III. IV. Individual has a diagnosis of recurrent, locally advanced, or metastatic non-squamous, non-small cell lung cancer (NSCLC); AND A. B. Individual is using as a single agent after prior chemotherapy; OR Individual is using as a first-line therapy in combination with platinum based chemotherapy with or without bevacizumab (or bevacizumab biosimilar) (NCCN 2A); OR Individual is using as second-line therapy (first-line chemotherapy) in combination with platinum-based chemotherapy with or without bevacizumab (or bevacizumab biosimilar) if tyrosine-kinase inhibitor (TKI/anaplastic lymphoma kinase (ALK) targeted agent was given as first-line therapy (NCCN 1) ; OR Individual is using for maintenance therapy when disease has not progressed following four cycles of platinum-based, first-line therapy; OR Individual is using in combination with pembrolizumab (Keytruda) and platinum chemotherapy for initial treatment and without presence of actionable molecular markers* (Label, NCCN 2A); OR Individual is using as continuous maintenance therapy until disease progression, if given first-line as part of Keytruda (pembrolizumab)/platinum chemotherapy/and pemetrexed regimen (NCCN 1); OR Individual is using in combination with cemiplimab and platinum chemotherapy; OR Individual is using in combination with tremelimumab, durvalumab, and platinum chemotherapy; OR Individual is using in combination with bevacizumab as continuous maintenance therapy, if given first-line as part of bevacizumab/ platinum/and pemetrexed regimen (NCCN 2A); OR Individual is using in combination with cemiplimab as continuous maintenance therapy, if given first-line as part of cemiplimab/ platinum/and pemetrexed regimen (NCCN 2A); OR Individual is using in combination with durvalumab as continuous maintenance therapy if given first-line as part of tremelimumab/durvalumab/platinum/and pemetrexed regimen (NCCN 2A); OR Individual is using as first-line therapy in combination with nivolumab, ipilimumab, and platinum-based chemotherapy and without presence of actionable molecular markers* (NCCN 2A); OR Individual is using as adjuvant or neoadjuvant therapy in combination with platinum-based chemotherapy; C. D. E. F. G. H. I. J. K. L. M. Individual is using as a single-agent therapy; AND Individual has one of the following (NCCN 2A): A. B. Individual has a diagnosis for persistent or recurrent ovarian cancer; OR Individual has a diagnosis for thymic cancer and thymomas and using as second-line therapy and beyond. *Note: Actionable molecular markers include EGFR, ALK, ROS1, BRAF, NTRK, MET and RET mutations. The NCCN panel recommends testing prior to initiating therapy to help guide appropriate treatment. If there is insufficient tissue to allow testing for all of these markers, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these patients are treated as though they do not have driver oncogenes (NCCN 2A). Pemetrexed Agents (Alimta, Pemfexy) may not be approved for the following: I. Individual has a diagnosis of squamous cell non-small cell lung cancer; OR 3 II. When the above criteria are not met and for all other indications. Coding The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. HCPCS J9304 J9305 J9314 J9322 J9323 J9324 J9294 J9296 J9297 Injection, pemetrexed, 10 mg [Pemfexy] Injection, pemetrexed, NOS, 10 mg [Alimta] Injection, pemetrexed [Teva] Injection, pemetrexed (bluepoint) Injection, pemetrexed (hospira) Injection, pemetrexed (pemrydi rtu), 10 mg Injection, pemetrexed (Hospira) Injection, pemetrexed (Accord) Injection, pemetrexed (Sandoz) ICD-10 Diagnosis C34.00-C34.92 Malignant neoplasm of bronchus and lung C37 Malignant neoplasm of thymus C38.0-C38.8 Malignant neoplasm of heart, mediastinum and pleura C45.0-C45.9 Mesothelioma C48.0-C48.8 Malignant neoplasm of retroperitoneum and peritoneum C56.1-C56.9 Malignant neoplasm of ovary C57.00-C57.9 Malignant neoplasm of other and unspecified female genital organs C61 Malignant neoplasm of prostate C65.1-C65.9 malignant neoplasm of renal pelvis C66.1-C68.0 Malignant neoplasm of ureter, bladder, urethra C78.00-C78.02 Secondary malignant neoplasm of lung C78.2 D15.0 Z85.118 Z85.238 Secondary malignant neoplasm of pleura Benign neoplasm of thymus Personal history of other malignant neoplasm of bronchus and lung Personal history of other malignant neoplasm of thymus Document History Reviewed: 02/24/2023