Clinical UM Guideline

 

Subject: Pemetrexed Disodium (Alimta®)
Guideline #:  CG-DRUG-38 Publish Date:    12/27/2017
Status: Revised Last Review Date:    11/02/2017

Description

This document addresses the use of pemetrexed disodium (Alimta, Eli Lilly & Company, Indianapolis, IN) in the treatment of oncologic conditions. Pemetrexed disodium is an antineoplastic agent that works as a folic acid antagonist by inhibiting folate-dependent metabolic processes which disrupts cell replication.

Note: Please see the following documents for additional information on combination therapy with the related products:

Clinical Indications

Medically Necessary:

  1. Pemetrexed disodium is considered medically necessary for the treatment of malignant mesothelioma when either of the following criteria are met:
    1. As combination therapy with cisplatin or carboplatin; or
    2. As a first-line of therapy in combination with cisplatin or carboplatin and bevacizumab in individuals who meet all the following criteria:
      1. Eastern Cooperative Oncology Group performance status of 0-2; and
      2. No history of hemoptysis or thrombosis; and
      3. Unresectable disease presentation.
  2. Pemetrexed disodium is considered medically necessary for the treatment of locally advanced or metastatic non-squamous, non-small cell lung cancer (NSCLC) when any of the following criteria are met:
    1. As a single agent after prior chemotherapy; or
    2. As a first-line of therapy in combination with platinum-based chemotherapy; or
    3. As a second-line therapy (first-line chemotherapy) in combination with platinum-based chemotherapy if tyrosine-kinase inhibitor (TKI)/anaplastic lymphoma kinase (ALK) targeted agent was given as first-line therapy.
  3. Pemetrexed disodium is considered medically necessary as maintenance therapy for locally advanced or metastatic non-squamous NSCLC when disease has not progressed following four cycles of platinum-based, first-line therapy.
  4. Pemetrexed disodium is considered medically necessary as a single-agent therapy for ovarian cancer for persistent disease or recurrence.
  5. Pemetrexed disodium is considered medically necessary as second-line therapy, and beyond, as a single-agent for metastatic urothelial carcinoma.
  6. Pemetrexed disodium is considered medically necessary as second-line therapy, and beyond, as a single-agent for thymic cancer and thymomas.

Not Medically Necessary:

Pemetrexed disodium is considered not medically necessary, when the above criteria are not met and for all other indications, including but not limited to:

  1. Primary central nervous system lymphoma (PCNSL);
  2. Squamous cell non-small cell lung cancer.
Coding

The following codes for treatments and procedures applicable to this guideline 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

 

J9305

Injection, pemetrexed, 10 mg

 

 

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

Secondary malignant neoplasm of pleura

D15.0

Benign neoplasm of thymus

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

Z85.238

Personal history of other malignant neoplasm of thymus

Discussion/General Information

Pemetrexed disodium is an antineoplastic agent that works as a folic acid antagonist. Pemetrexed’s effectiveness lies in its ability to disrupt cell replication by inhibiting folate-dependent metabolic processes. Synergistic effects are found in mesothelioma cell lines when pemetrexed is used in combination with cisplatin.

In 2004, pemetrexed disodium received U.S. Food and Drug Administration (FDA) approval for its intravenous use in malignant pleural mesothelioma as a first-line treatment in combination with cisplatin for individuals who are not eligible for surgery. Pemetrexed was the first FDA approved drug for this condition (Hazarika, 2004). In the same year, pemetrexed was also granted FDA approval for single agent use after previous chemotherapy treatment, in individuals with locally advanced or metastatic NSCLC (Cohen, 2005). Since then, the FDA has approved pemetrexed for first-line treatment of advanced NSCLC in combination with cisplatin and as single-agent, maintenance therapy in advanced NSCLC following first-line treatment with a platinum-based chemotherapy regimen (Cohen, 2010; Product Information [PI] Label, 2015). FDA approval of pemetrexed treatment in NSCLC was amended to exclude treatment of squamous cell histoligies (Peterson, 2008). Currently, the effectiveness and safety of pemetrexed is being investigated in a number of other oncologic conditions.

Mesothelioma

In 2003, Vogelzang and colleagues conducted a randomized, single-blind, multi-center, phase III trial to evaluate the efficacy and safety of pemetrexed combined with cisplatin versus single-agent cisplatin. Overall survival (OS) was the primary endpoint of interest in this clinical trial. A total of 448 individuals were enrolled and randomized into either the pemetrexed+cisplatin arm (n=226) or the cisplatin-only arm (n=222). Median OS times were 12.1 months and 9.3 months for the pemetrexed+cisplatin and cisplatin-only arms, respectively (p=0.020). After the first 117 participants, folic acid and vitamin B12 were added to reduce toxicities; a significant reduction in toxicities was seen in the pemetrexed+cisplatin arm. Authors concluded that treatment with pemetrexed and cisplatin with vitamin supplementation achieved superior response rates, time to progression (TTP) and survival time. FDA approval was based on the results of this study demonstrating superior survival as a clinical benefit of pemetrexed+cisplatin in the treatment of malignant pleural mesothelioma when compared to cisplatin alone (Hazarika, 2004).

The National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines (CPGs) in Oncology® for malignant pleural mesothelioma include a Category 1 recommendation for use of carboplatin in combination with pemetrexed for the treatment of mesothelioma (NCCN, 2017). In 2008, Santoro and colleagues published results of the International Expanded Access Program on the efficacy and safety of pemetrexed+cisplatin (PemC) versus pemetrexed+carboplatin (PemCar) as a first-line of therapy in malignant pleural mesothelioma. A total of 1704 participants were enrolled in this open-label, nonrandomized clinical trial; n=843 in the PemC arm and n=861 in the PemCar arm. The overall response rate (ORR), TTP, 1-year survival rates and toxicities were similar between both arms. Authors concluded that cisplatin and carboplatin demonstrate similar efficacy and safety as a component of a pemetrexed-based chemotherapy regimen in the treatment of malignant pleural mesothelioma.

The NCCN CPG (2017) includes a Category 1 off-label recommendation for use of pemetrexed as combination chemotherapy with bevacizumab and cisplatin for the treatment of unresectable malignant pleural mesothelioma. The evidence cited with this Category 1 recommendation includes published data from a multicenter, phase III, randomized, clinical trial (Zalcman, 2016). A total of 448 participants aged 18-75 years with unresectable malignant pleural mesothelioma who were chemotherapy naïve, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumor solid thickening) lesion confirmed by computerized tomography scan, and a life expectancy of at least 12 weeks, were randomly allocated 1:1 to receive pemetrexed+cisplatin (n=225 [PC]) or PC+bevacizumab (n=233 [PCB]) for up to six cycles, until progression or toxic effects. For grade 2 or higher cisplatin-induced renal toxic effects, participants were allowed a switch to carboplatin. The primary outcome was OS in the intention-to treat population. OS was reported as significantly extended in the PCB arm (median OS 18.8 months [95% CI, 15.9-22.6]; 164 [74%] of 223 died) than in the PC arm (median OS 16.1 months [14.0-17.9]; 178 [79%] of 225 died; Hazard Ratio [HR] 0.77 [0.62-0.95]; p=0.0167). PFS was also significantly improved with PCB (median PFS 9.2 months [8.5-10.5]; 198 [89%] of 223 died) compared to the PC arm (7.3 months [6.7-8.0]; 217 [96%] of 225 died; adjusted-HR 0.61 [0.50-0.75]; p<0.0001). More participants stopped first-line treatment for disease progression in the PC arm (189 [87.1%] of 217) than in the PCB arm (137 [62.8%] of 218; difference 24.3% [16.3-31.9]; p<0.0001). Grade 3-4 adverse events were reported in 158 (71%) of 222 participants in the PCB arm and 139 (62%) of 224 participants in the PC arm. Non-hematological adverse events in both groups included asthenia or fatigue, anorexia, constipation, and nausea or vomiting. There were more grade 3 or higher hypertension (51 [23%] of 222 vs. 0) and thrombotic events (13 [6%] of 222 vs. 2 [1%] of 224) in the PCB arm than in the PC arm. Limitations of this trial include the open-label design. Based on the 2.7 month OS improvement rate reported in this large, multicenter, phase III, randomized trial, the NCCN (category 2A) considers combination therapy with pemetrexed, cisplatin, and bevacizumab an acceptable chemotherapy regimen for individuals with unresectable malignant pleural mesothelioma.

NCCN CPGs for mesothelioma (2017) also include 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.

Non-small cell lung cancer

In 2004, Hanna and colleagues conducted a non-blinded, randomized phase III trial to examine efficacy and toxicity of pemetrexed versus docetaxel in the treatment of advanced or metastatic NSCLC. A total of 571 participants were randomly assigned to 1 of the 2 treatment arms. Eligible participants had a performance status of 2 or better, previous chemotherapy treatment regimen for NSCLC, and satisfactory organ function. Once enrolled, the remaining 541 participants (30 participants dropped out, 18 and 12 from the pemetrexed and docetaxel arms, respectively, for a variety of unrelated reasons) either received 500 mg/m2 of pemetrexed on day 1 with vitamin B12, folic acid and dexamethasone (n=265), or standard treatment of docetaxel 75 mg/m2 on day 1 with dexamethasone (n=266). The primary outcome of interest was OS. ORR was 9.1% and 8.8% for pemetrexed and docetaxel, respectively (not statistically significant). Median progression-free survival (PFS) was 2.9 months in each arm and median OS was 8.3 months versus 7.9 months for pemetrexed and docetaxel, respectively (not statistically significant). In this large, randomized controlled trial, authors concluded that pemetrexed treatment provided equivalent clinical efficacy to docetaxel but side effects, such as grade 3 or 4 neutropenia, febrile neutropenia and hospitalizations, were significantly reduced with pemetrexed. Initial FDA approval for the treatment of NSCLC with pemetrexed was based on this trial (Cohen, 2005). A recent meta-analysis of four randomized controlled trials, representing 1084 participants, confirmed that pemetrexed, single-agent, remains the safest and most efficacious approach after prior chemotherapy, compared to treatment with a platinum-based doublet (Sun, 2014).

In 2007, a retrospective study was performed by Peterson and colleagues examining the histology of the previously described randomized phase III trial which determined the OS rates of pemetrexed versus docetaxel in the treatment of advanced or metastatic NSCLC were comparable. Peterson’s investigation identified a statistically significant treatment-by-histology interaction (p=0.001); those with squamous cell NSCLC had significantly better survival when treated with docetaxel rather than pemetrexed (p=0.018). For the non-squamous sub-group, pemetrexed was statistically superior to docetaxel (p=0.048). Based on the results of this study, the FDA revised its approval of pemetrexed treatment to include only non-squamous histology of NSCLC.

Scagliotti and colleagues (2008) conducted a multi-center, randomized phase III, open-label study of pemetrexed with cisplatin (AC) versus gemcitabine plus cisplatin (GC) in chemotherapy-naïve individuals diagnosed with stage IIIB/IV non-squamous NSCLC. A total of 1725 individuals were enrolled and randomly assigned to either the AC (n=862) or GC (n=863) arm. The primary outcome of interest was OS. Median OS was 10.3 months in both the AC and GC arm (adjusted HR not statistically significant) and median PFS times were 4.8 months and 5.1 months for the AC and GC arms, respectively (HR not statistically significant). Although noninferiority could not be conclusively demonstrated, the FDA’s opinion was that there is substantial evidence that pemetrexed is sufficiently active as a first-line treatment in non-squamous NSCLC and in 2008 it was approved for use in combination with cisplatin for this indication (Cohen, 2009).

A systematic review and meta-analysis was published by Xiao and colleagues (2016) on the efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced non-squamous NSCLC. A total of 2551 individuals were enrolled from 10 clinical trials, 1565 of which had received pemetrexed as first-line treatment with a platinum-based doublet and the remaining 986 received a chemotherapy other than pemetrexed with a platinum doublet as a first-line of treatment. Pooled OS was significantly longer in those treated with pemetrexed and a platinum doublet versus another chemotherapy and a platinum doublet (p=0.01), further confirming the efficacy and safety of this regimen in advanced non-squamous NSCLC.

Langer and colleagues (2016) conducted the phase I/II KEYNOTE-021 trial, an open-label, multicenter, multi-cohort study that evaluated tumor response and progression-free survival in individuals with nonsquamous NSCLC. Individuals with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC were randomly assigned (1:1) to receive pemetrexed every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexedmaintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion who achieved an objective response (percentage of patients with radiologically confirmed complete or partial response). A total of 123 individuals were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. At the time of analysis, 33 (55%; 95% CI, 42-68) of 60 study participants in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18-41) of 63 study participants in the chemotherapy alone group (estimated treatment difference 26% [95% CI, 9-42%]; p=0.0016). The incidence of grade 3 or worse treatment-related adverse events was similar between the two groups. The NCCN has given a category 2A recommendation for the combination treatment of NSCLC with pemetrexed, a platinum-based therapy and pembrolizumab. This combination therapy regimen is continuing to be investigated in a phase III, manufacture-sponsored clinical trial.

Both the NCCN CPGs in Oncology for NSCLC (2017) and the American Society of Clinical Oncology (ASCO) guidelines on ‘Systemic Therapy for Stage IV NSCLC’ recommend treatment with pemetrexed for second-line of therapy in combination with platinum-based chemotherapy if a tyrosine-kinase inhibitor (TKI)/targeted agent was given as first-line therapy (Hanna, 2017). The recommendations are based on consensus but considered appropriate in the less conventional treatment approach necessitated by sensitizing epidermal growth factor receptor (EGFR) mutations.

Non-small cell lung cancer-maintenance therapy

In 2009, Ciuleanu and colleagues published results of a randomized, double-blind phase III study to assess the efficacy and safety of pemetrexed with best supportive care (BSC) compared to placebo with BSC in individuals with locally advanced or metastatic NSCLC whose disease had not progressed following four cycles of platinum-based, doublet induction chemotherapy. OS was the primary outcome of interest. In total, 663 participants were randomized into 1 of each arms (pemetrexed, n=441; placebo, n=222). The median OS in the treatment arm was 15.5 months versus 10.3 months in the placebo arm for those participants with non-squamous cell histology (HR=0.70; 95% confidence interval [CI], 0.65-0.88). Based on the superior outcome of the pemetrexed arm in non-squamous cell NSCLC participants, the FDA approved pemetrexed for use in maintenance treatment of this population when their disease has not progressed after four cycles of platinum-based doublet induction therapy. Paz-Ares (2013) replicated the study design in another randomized, double-blind phase III study of 939 individuals. Randomization was 2:1 in the pemetrexed+BSC arm (n=359) and placebo+BSC arm (n=180), respectively. Similarly, pemetrexed treatment was found superior to BSC based on OS of 13.9 months versus 11.0 months in the non-treatment arm (HR=0.78, 95% CI, 0.64-0.96; p=0.0195). The treatment regimen was relatively well tolerated and authors conclude that the study findings further support the efficacy and safety of pemetrexed as a single-agent maintenance therapy in advanced non-squamous NSCLC. Long-term study results continue to affirm these findings (Pujol, 2014).

The NCCN CPGs in Oncology for NSCLC include a 2A recommendation for the use of pemetrexed and platinum-based therapy in combination with bevacizumab, followed by pemetrexed with bevacizumab as maintenance therapy if bevacizumab was a component of the first-line regimen (NCCN, 2017). In 2009, Patel and colleagues conducted a nonrandomized, phase II trial evaluating the safety and efficacy of cisplatin, pemetrexed and bevacizumab in chemotherapy-naïve, advanced non-squamous NSCLC. Pemetrexed and bevacizumab therapy were continued until treatment failure occurred; 60% received greater than 6 cycles. In total, 49 participants were enrolled and available for evaluation; 55% experienced an objective response. PFS and OS were 7.8 months and 14.1 months, respectively. Incidence of grade 3-4 toxicities were modest and based on the findings of this study, a Phase III trial was recommended. In 2013, Patel and colleagues reported findings from a randomized, open-label, phase III trial evaluating the safety and efficacy of induction therapy with carboplatin, pemetrexed and bevacizumab, followed by maintenance with pemetrexed plus bevacizumab (PemCBev) versus paclitaxel, carboplatin and bevacizumab, followed by bevacizumab alone (PacCBev; standard of care for first-line therapy), in advanced non-squamous NSCLC. The primary endpoint was OS; secondary endpoints included PFS, ORR, disease control rate (partial response [PR] + complete response [CR] + stable disease), TTP and toxicities. In total, 939 participants were enrolled and randomized, 1:1 to the PemCBev arm (n=472) or the PacCBev arm (n=467); 292 and 298 participants were eligible for and received maintenance therapy with PemCBev and PacCBev, respectively. OS and survival at 12 and 24 months was not statistically different between the PemCBev and PacCBev arms in this study. Secondary endpoints of PFS (6.0 vs 5.6 months; HR=0.83, 95% CI, 0.71-0.96; p=0.012) and TTP (7.0 vs 6.0 months; HR=0.79, 95% CI, 0.67 to 0.94; p=0.006) were significantly better in the PemCBev arm. Grade 3-4 toxicities of neutropenia, alopecia and neuropathy were significantly lower in the PemCBev arm while thrombocytopenia, anemia and fatigue were lower in the PacCBev arm. The trial’s primary endpoint was not met, but authors concluded that the treatment options explored in this trial were comparably safe and efficacious as induction and maintenance therapies in advanced NSCLC.

Similarly, Barlesi and colleagues (2013) conducted a randomized, open-label, phase III trial evaluating the safety and efficacy of maintenance therapy with pemetrexed, with and without bevacizumab in advanced non-squamous NSCLC. In total, 376 individuals were enrolled and received four cycles of induction therapy with pemetrexed, cisplatin and bevacizumab. The study’s primary endpoint was PFS. If a CR, PR or stable disease (SD) was achieved (n=253; 72%), participants were randomized 1:1 to receive bevacizumab (n=125) or bevacizumab+pemetrexed (n=128) as maintenance therapy. Investigators found that bevacizumab+pemetrexed (7.4 months) achieved a superior PFS to bevacizumab alone (3.7 months) as maintenance therapy (HR=0.48, 95% CI, 0.35-0.66; p=0.001). Investigators conclude from this trial’s results that bevacizumab+pemetrexed demonstrated improved clinical benefit when compared to bevacizumab alone in the maintenance treatment of advanced NSCLC in those who had achieved disease control with pemetrexed, cisplatin and bevacizumab. Barlesi and colleagues (2014) continued this investigation in a subsequent publication evaluating overall survival in this same clinical trial cohort and found that after a median follow-up of 14.8 months from randomization, individuals in the bevacizumab+pemetrexed arm continued to have statistically longer PFS; however, 1-year and 2-year OS differences did not reach statistical significance. There was an increase in grade 3 and 4 adverse events in the bevacizumab+pemetrexed arm, and a separately published study from the same cohort noted that health-related quality of life (HRQOL) was not improved in the combination bevacizumab+pemetrexed arm (Rittmeyer, 2013). An additional, smaller clinical trial (n=110) also investigated maintenance bevacizumab+pemetrexed versus pemetrexed alone in non-squamous NSCLC and similarly found no differences in the superiority of PFS between these treatments and increased adverse events with the combination therapy (Karayama, 2016). Consequently, there is a lack of evidence in the peer-reviewed literature supporting the efficacy and safety of this chemotherapy combination, over single-agent treatment, as maintenance therapy in NSCLC.

Neoadjuvant and Adjuvant Treatment for NSCLC

There are a number of randomized controlled trials investigating the role of pemetrexed in the neoadjuvant, adjuvant and chemoradiation settings. At this time, only Phase I and II studies have been published with mixed findings. A randomized phase II trial conducted to assess the efficacy and safety of pemetrexed with thoracic radiation concluded that, “We should await the results of … large trials before incorporating pemetrexed or cetuximab in routine clinical practice for the treatment of patients with locally advanced NSCLC” (Govindan, 2011). In 2016, results were published from the PROCLAIM trial, a Phase III randomized trial evaluating the efficacy of pemetrexed-cisplatin doublet as a component of chemoradiation therapy for locally advanced non-squamous NSCLC compared to the standard of care, etoposide-cisplatin doublet in this setting. The trial randomly enrolled 599 individuals 1:1 into the two study arms with a primary objective of identifying superiority in OS. The trial was halted early due to futility (HR, 0.98; 95% CI, 0.79-1.20; p=0.831). Superiority of pemetrexed-cisplatin doublet, over standard of care etoposide-cisplatin with thoracic radiation therapy, was not demonstrated in unresectable NSCLC. The pemetrexed arm did however consistently demonstrate fewer grade 3 and 4 neutropenic and thrombocytopenic events. Further research is needed to more definitely determine the efficacy and safety of pemetrexed in neoadjuvant, adjuvant and chemoradiation settings over current standard of care chemotherapy regimens.

Ovarian cancer

The current NCCN CPG in Oncology for ovarian cancer includes a recommendation for the use of pemetrexed for the second-line treatment of platinum-resistant, recurrent or progressive ovarian cancer (NCCN, 2017). The 2A recommendation is based on a phase II trial conducted by Miller and colleagues (2009) designed to estimate antitumor activity of pemetrexed in women with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer. A total of 51 women were enrolled in the study and treatment was continued until disease progression or intolerable toxicities. The study also sought to identify the extent of toxicities. The study successfully identified antitumor activity and median PFS was 2.9 months with an OS of 11.4 months. Vergote and colleagues (2009) conducted a randomized Phase II trial in 102 women with platinum-resistant disease. Study participants were treated with standard versus high-dose pemetrexed; the ORR was 9.3% and 10.4%, respectively. Similar to Miller and colleagues, PFS was 2.8 months in both arms with the standard-dose arm experiencing more favorable toxicities. A small number of additional phase II trials have appeared in the literature assessing safety and efficacy of pemetrexed combination chemotherapies in the treatment of recurrent or persistent ovarian cancer (Hagemann, 2013; Matulonis, 2008; Sehouli, 2012).

Bladder cancer

The NCCN CPGs in Oncology for bladder cancer include a recommendation for the use of pemetrexed as a second-line treatment for metastatic bladder cancer (NCCN, 2017). The 2A recommendation is based on two phase II studies. In 2006, Sweeney and colleagues enrolled 47 participants with a performance status of one or better, satisfactory organ function, and previous treatment with one prior chemotherapy regimen for advanced transitional cell carcinoma (TCC) of the urothelium or relapsed within 1 year of treatment. The median TTP of disease was 2.9 months and median OS was 9.6 months. Incidence of grade 3 or 4 hematologic and nonlaboratory toxicities was relatively low in this clinical trial. The authors conclude that pemetrexed is safe and active as a second-line treatment in participants with advanced TCC of the urothelium. The other study cited by the NCCN was conducted by Galsky and colleagues (2007). Similarly, this phase II study sought to determine the activity of pemetrexed administered as a second-line treatment in individuals with advanced urothelial carcinoma. A total of 13 participants were enrolled and an objective response was achieved in 1 participant, resulting in an ORR of 8%.

Primary central nervous system (CNS) lymphoma

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 (PCNSL; NCCN, 2017). The 2A recommendation is based on a single study conducted by Raizer and colleagues (2012) which enrolled 11 participants with relapsed/refractory PCNSL to asses 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.

Thymomas and thymic carcinomas

The NCCN CPGs in Oncology for thymomas and thymic carcinomas include a recommendation for the use of pemetrexed as a second-line treatment of thymomas and thymic carcinomas (NCCN, 2017). This is a rare neoplasm with an incidence in the United States of approximately 0.15 per 100,000 person-years; approximately 30% of new diagnoses are locally advanced or metastatic and inoperable. The 2A recommendation is based on two studies. The first, a phase II clinical trial conducted by Loehrer and colleagues (2006) evaluated the clinical activity of pemetrexed in individuals with thymomas and thymic carcinoma who had been previously treated. A total of 27 participants were enrolled with treatments scheduled every 3 weeks for a total of 6 cycles, or until disease progression or intolerable toxicities. A total of 2 participants had a CR and 2 others had PRs. Median time to progression for all participants was 45 weeks (thymomas = 45.5 weeks and thymic carcinomas = 45.1 weeks). This trial data was presented at a 2006 ASCO meeting but was not subsequently published in the peer-reviewed literature. In 2015, a small retrospective study was conducted by Liang and colleagues and evaluated 16 individuals diagnosed with thymic malignancies (n=10 with thymic carcinoma and n=6 with thymoma). All study enrollees had previously treated, unresectable, histologically confirmed invasive, recurrent or metastatic disease and received pemetrexed either as monotherapy (n=14) or combination therapy (n=2). Among the 6 individuals with thymoma, best response was 1 (17%) with a PR and 5 (83%) had SD. At a median follow-up of 21.2 months, the median PFS for those with thymomas was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 individuals with thymic carcinoma, best response was 1 (10%) PR, 5 (50%) SD, and 4 (40%) had progressive disease. At a median follow-up of 13.5 months, the median PFS in those with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months). Pemetrexed has demonstrated modest activity in this rare, difficult to treat malignancy.

Warnings and Adverse Events

The FDA Product Information Label (2015) includes the following information and recommendations:

Adverse Events

Other Warnings and Precautions

Definitions

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone, or biological therapy.

Line of therapy:

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.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to a specific substance in the body.

Off-label drug use: Utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved labeling.

Partial response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.

Progression free survival (PFS): The length of time during and after treatment that an individual lives but does not get worse (usually measured by the size of a tumor or amount of cancer in the body).

Refractory disease: Illness or disease that does not respond to treatment.

References

Peer Reviewed Publications:

  1. 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. 2014; 25(5):1044-1052.
  2. 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. 2013; 31(24):3004-3011.
  3. Branden E, Hillerdal G, Kolbeck K, Koyi H. Pemetrexed and gemcitabine versus carboplatin and gemcitabine in non-small cell lung cancer: a randomized noninferiority phase II study in one center. Oncologist. 2015; 20(4):365.
  4. Carteni G, Manegold C, Garcia GM, et al. Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer. 2009; 64(2):211-218.
  5. 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. 2009; 374(9699):1432-1440.
  6. Cohen MH, Cortazar P, Justice R, Pazdur R. Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC). Oncologist. 2010; 15(12):1352-1358.
  7. Cohen MH, Johnson JR, Wang YC, et al. FDA drug approval summary: pemetrexed for injection (Alimta) for the treatment of non-small cell lung cancer. Oncologist. 2005; 10(6):363-368.
  8. Cohen MH, Justice R, Pazdur R. Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer. Oncologist. 2009; 14(9):930-935.
  9. Galsky MD, Mironov S, Iasonos A, et al. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007; 25(3):265-270.
  10. Govindan R, Bogart J, Stinchcombe T, et al. Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B trial 30407. J Clin Oncol. 2011; 29(23):3120-3125.
  11. 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. Gynecol Oncol. 2013; 131(3):535-540.
  12. 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. 2004; 22(9):1589-1597.
  13. Hazarika M, White RM, Johnson JR, Pazdur R. FDA drug approval summaries: pemetrexed (Alimta). Oncologist. 2004; 9(5):482-488.
  14. Hu X, Pu K, Feng X, et al. Role of gemcitabine and pemetrexed as maintenance therapy in advanced NSCLC: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2016; 11(3):e0149247.
  15. Jänne PA, Wozniak AJ, Belani CP, et al. Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program. Clin Lung Cancer. 2005; 7(1):40-46.
  16. Karayama M, Inui N, Fujisawa T, et al. Maintenance therapy with pemetrexed and bevacizumab versus pemetrexed monotherapy after induction therapy with carboplatin, pemetrexed, and bevacizumab in patients with advanced non-squamous non-small cell lung cancer. Eur J Cancer. 2016; 58:30-37.
  17. Kulkarni S, Vella ET, Coakley N, et al. The use of systemic treatment in the maintenance of patients with non-small cell lung cancer: a systematic review. J Thorac Oncol. 2016; 11(7):989-1002.
  18. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016; 17(11):1497-1508.
  19. Li X, Wang H, Lin W, Xu Q. Efficacy of combining targeted therapy with pemetrexed or docetaxel as second-line treatment in patients with advanced non-small-cell lung cancer: a meta-analysis of 14 randomized controlled trials. Curr Med Res Opin. 2014; 30(11):2295-2304.
  20. Liang Y, Padda SK, Riess JW, et al. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung Cancer. 2015; 87(1):34-38.
  21. Loehrer P, Yiannoutsos C, Dropcho S, et al. A phase II trial of pemetrexed in patients with recurrent thymoma or thymic carcinoma. J of Clin Onco, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006:7079.
  22. Matulonis UA, Horowitz NS, Campos SM, et al. Phase II study of carboplatin and pemetrexed for the treatment of platinum-sensitive recurrent ovarian cancer. J Clin Oncol. 2008; 26(35):5761-5766.
  23. Miller DS, Blessing JA, Krasner CN, et al. Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol. 2009; 27(16):2686-2691.
  24. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer. J Clin Oncol. 2009; 27(20):3284-3289.
  25. 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. 2013; 31(34):4349-4357.
  26. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013; 31(23):2895-2902.
  27. Paz-Ares L, Mezger J, Ciuleanu TE, et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015; 16(3):328-337.
  28. Peterson P, Park K, Fossella F, et al. Is Pemetrexed more effective in adenocarcinoma and large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2012 World Conference on Lung Cancer. 2007; 2(8):S8510.
  29. Pilkington G, Boland A, Brown T, et al. A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer. Thorax. 2015; 70(4):359-367.
  30. Pujol JL, Paz-Ares L, de Marinis F, et al. Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2014; 15(6):418-425.
  31. Raizer JJ, Rademaker A, Evens AM, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer. 2012; 118(15):3743-3748.
  32. Rittmeyer A, Gorbunova V, Vikström A, et al. Health-related quality of life in patients with advanced nonsquamous non-small-cell lung cancer receiving bevacizumab or bevacizumab-plus-pemetrexed maintenance therapy in AVAPERL (MO22089). J Thorac Oncol. 2013; 8(11):1409-1416.
  33. Santoro A, O'Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008 3(7):756-763.
  34. 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 advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008; 26(21):3543-3551.
  35. Sehouli J, Alvarez AM, Manouchehrpour S, et al. A phase II trial of pemetrexed in combination with carboplatin in patients with recurrent ovarian or primary peritoneal cancer. Gynecol Oncol. 2012; 124(2):205-209.
  36. Senan S, Brade A, Wang LH, et al. PROCLAIM: Randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016; 34(9):953-962.
  37. Shi SB, Wang M, Tian J, et al. MicroRNA 25, microRNA 145, and microRNA 210 as biomarkers for predicting the efficacy of maintenance treatment with pemetrexed in lung adenocarcinoma patients who are negative for epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations. Transl Res. 2016; 170:1-7.
  38. Sio T, Ko J, Gudena V, et al. Chemotherapeutic and targeted biologic agents for metastatic bladder cancer: a comprehensive review. Int J Urol. 2014; 21(7):630-637.
  39. Sun CT, Xu X, Sheng W, et al. A meta-analysis of pemetrexed-based doublet compared with pemetrexed alone for the second-line treatment of advanced non-small-cell lung cancer. Bratisl Lek Listy. 2014; 115(4):233-237.
  40. Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006; 24(21):3451-3457.
  41. Tong S, Fan K, Jiang K, et al. Increased risk of severe infections in non-small-cell lung cancer patients treated with pemetrexed: a meta-analysis of randomized controlled trials. Curr Med Res Opin. 2017; 33(1):31-37.
  42. Vergote I, Calvert H, Kania M, et al. A randomised, double-blind, phase II study of two doses of pemetrexed in the treatment of platinum-resistant, epithelial ovarian or primary peritoneal cancer. Eur J Cancer. 2009; 45(8):1415-1423.
  43. 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. 2003; 21(14):2636-2644.
  44. Xiao HQ, Tian RH, Zhang ZH, et al. Efficacy of pemetrexed plus platinum doublet chemotherapy as first-line treatment for advanced nonsquamous non-small-cell-lung cancer: a systematic review and meta-analysis. Onco Targets Ther. 2016; 9:1471-1476.
  45. Zalcman G, Mazieres J, Margery J, et al.; French Cooperative Thoracic Intergroup (IFCT). Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016; 387(10026):1405-1414.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Alimta [Product Information], Indianapolis, IN. DailyMed. Updated September, 2015. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5a860f3-37ec-429c-ae04-9c88d7c55c08.  Accessed on October 01, 2017.
  2. Burdett S, Pignon JP, Tierney J, et al. Adjuvant chemotherapy for resected early-stage non-small cell lung cancer. Cochrane Database Syst Rev. 2015;(3):CD011430.
  3. Hanna N, Johnson D, Temin S, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Aug 14:[Epub ahead of print].
  4. Masters GA, Temin S, Azzoli CG, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015; 33(30):3488-3515.
  5. Pemetrexed Disodium (Alimta). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated August 30, 2017. Available at: http://www.micromedexsolutions.com. Accessed on October 01, 2017.
  6. Pemetrexed Disodium (Alimta). Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised November 1, 2004.  http://online.lexi.com/lco/action/login. Accessed on October 01, 2017.
  7. National Cancer Institute (NCI). Pemetrexed Disodium. Last updated on October 25, 2011. Available at: http://www.cancer.gov/cancertopics/druginfo/pemetrexeddisodium. Accessed on October 01, 2017.
  8. NCCN Clinical Practice Guidelines in Oncology®. © 2017 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on October 01, 2017
    • Bladder Cancer (V5.2017). Revised May 25, 2017.
    • Central Nervous System Cancers (V1.2017). Revised August 18, 2017.
    • Malignant Pleural Mesothelioma (V2.2017). Revised July 07, 2017.
    • Non-Small Cell Lung Cancer (V9.2017). Revised September 28, 2017.
    • Ovarian Cancer (V3.2017). Revised August 30, 2017.
    • Thymomas and Thymic Carcinomas (V1.2017). Revised March 02, 2017.
Websites for Additional Information
  1. American Cancer Society (ACS). Available at: http://www.cancer.org/. Accessed on October 01, 2017.
  2. National Cancer Institute (NCI). Available at: http://www.cancer.gov/. Accessed on October 01, 2017.
    • Bladder Cancer Treatment (PDQ). Revised June 5, 2017.
    • Malignant Mesothelioma Treatment (PDQ). Revised October 14, 2016.
    • Non-Small Cell Lung Cancer Treatment (PDQ). Revised March 31, 2017.
    • Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment (PDQ). Revised September 13, 2017.
    • Primary CNS Lymphoma Treatment (PDQ). Revised January 5, 2017.
    • Thymomas and Thymic Carcinomas Treatment (PDQ). Revised February 04, 2015.
Index

Pemetrexed
Alimta
Antifolate

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Expanded MN criteria for urothelial carcinoma. Updated Rationale, References and Websites sections.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Updated formatting in Clinical Indications section. Updated Medically Necessary Criteria with the addition of thymic cancers and thymomas and combination therapy with bevacizumab for mesothelioma. Updated Coding, Discussion/General Information and Reference sections.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Updated Medically Necessary Criteria with the addition of all sub-types of mesothelioma, treatment of NSCLC after TKIs/ALK targeted therapy, urothelial cancer and ovarian cancer and removal of ‘with or without bevacizumab.’ Removed ovarian and bladder cancer from not Medically Necessary Criteria. Updated Coding, Discussion/General Information, and Reference sections. Removed ICD-9 codes from Coding section.

New

11/13/2014

MPTAC review.

New

11/12/2014

Hematology/Oncology Subcommittee review. Initial document development.