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PubMed2004

Pemetrexed in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a disease with a poor prognosis, related in part to the aggressiveness of this disease, and in part due to the lack of drugs that have demonstrated tumor activity. Historically, antifolates such as methotrexate have been the most active drugs in the treatment of mesothelioma. Newer antifolates have recently demonstrated higher efficacy than older regimens in the treatment of this rare disease. One of these agents, pemetrexed (Alimta), has been evaluated both as a single agent and as part of a combination regimen. Pemetrexed has been studied in three trials in patients with MPM, and two phase I trials included patients with MPM. In a phase II trial, pemetrexed was studied as a single agent in patients with MPM. Seven of 64 patients achieved partial responses, with a median overall survival of 10.7 months. A large, randomized, phase III trial was conducted to compare pemetrexed/cisplatin with cisplatin. The response rate was 41.3% compared with 16.7%, median survival was 12.1 months compared with 9.3 months, and 1-year survival was 50.3% vs 38% in the pemetrexed/cisplatin and cisplatin arms, respectively. The combination of pemetrexed/cisplatin also demonstrated superiority in quality of life and pulmonary functioning analysis when compared with cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Pemetrexed in front-line chemotherapy for advanced non-small-cell lung cancer.

Pemetrexed (Alimta) possesses broad antitumor activity. It has been evaluated in non-small-cell lung cancer (NSCLC) as front-line chemotherapy in a comprehensive phase II evaluation. While various antifolates have been previously evaluated in clinical trials, drug development was stopped or delayed in light of their lack of efficacy or occurrence of life-threatening toxicities. While similar trends were observed with pemetrexed early in development, investigators instituted folic acid and vitamin B12 supplementation to minimize these toxicities without hampering drug efficacy. This article briefly summarizes the current evidence that supports the role of pemetrexed-based combinations in clinical trials for chemonaive patients with advanced NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Pemetrexed in transitional cell carcinoma of the urothelium.

Currently, the four-drug combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) or the two-drug combination of gemcitabine and cisplatin (GC) represents the standard of care for patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. Recently, there has been a plethora of data from other chemotherapeutic regimens. Promising new agents, such as the multitargeted antifolate pemetrexed (Alimta), and new drug combinations have demonstrated increased efficacy and/or decreased toxicity compared with current regimens. Currently, data are available from three phase II studies utilizing pemetrexed or the combination of pemetrexed/gemcitabine (Gemzar) in patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. Further investigation of combinations of pemetrexed and other active drugs in the treatment of patients with locally advanced and metastatic disease is warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

The evolving role of gemcitabine and pemetrexed (Alimta) in the management of patients with malignant mesothelioma.

Malignant mesothelioma is a refractory malignancy. Treatment for unresectable disease may provide a palliative benefit, but survival duration is impacted only minimally, if at all. Several newer agents, including difluorodeoxycytidine (gemcitabine) and pemetrexed disodium (LY231514, Alimta) appear to have activity against this neoplasm. Phase II data for combination regimens of gemcitabine and a platinum in mesothelioma patients have been encouraging. However, no phase III data are available to place these phase II results in true perspective. In phase I studies of a cisplatin/pemetrexed combination, objective responses occurred in several mesothelioma patients. This led to a phase II trial of pemetrexed alone in untreated mesothelioma patients and a randomized phase III trial of cisplatin alone versus pemetrexed/cisplatin. Phase II activity (15% partial response) was seen with single-agent pemetrexed. The phase III trial accrued over 450 patients. Primary analysis of the phase III data set has been completed and the results will be presented at the American Society of Clinical Oncology Meeting in May 2002.

Journal Article↗
PubMed2005

Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer.

BACKGROUND: The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed-carboplatin combination as first-line therapy in patients with advanced nonsmall cell lung cancer. METHODS: Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration-time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis. RESULTS: Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety-six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1-year survival 56.0%, and median survival 13.5 months. CONCLUSIONS: This is an active, very well-tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted.

Adult↗
PubMed2003

Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma.

Regimens with antimetabolites such as gemcitabine administered alone or in combination with cisplatin have shown promising phase II study data. Accordingly, antifolate agents are of considerable interest. Pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN), a folate-based inhibitor of thymidylate synthase., is currently under phase III investigation. The Evaluation of Mesothelioma in a Phase III Trail of Pemetrexed with Cisplatin (EMPHACIS) trial is the first phase III randomized study in mesothelioma with survival as the primary end point; it showed statistically significant superiority of the pemetrexed/cisplatin combination over cisplatin low-dose folic acid and vitamin B12 supplementation significantly reduced the toxicity observed with the use of pemetrexed/cisplatin will soon be recommended for malignant pleural mesothelioma as first-line standard chemotherapy.

Antimetabolites, Antineoplastic↗
PubMed2005

Pemetrexed plus carboplatin or oxaliplatin in advanced non-small cell lung cancer.

Over the past decade many large randomized trials have been conducted in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC); however, no single regimen has shown clear superiority. Typical response rates of 17% to 32%, median survival times of 7 to 10 months, and 1-year survival rates of 30% to 45% are common in such studies. Nevertheless, metastatic NSCLC remains an incurable disease, with the development of drug resistance as a major impediment. New treatment regimens, such as the broadly used antifolate antimetabolites, target multiple metabolic functions and may lead to improvements in clinical outcome. Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel antifolate, distinguished by a unique nuclear structure and its ability to inhibit multiple folate-dependent enzymatic pathways. Typically, vitamin B 12 and folic acid supplementation are incorporated into the treatment regimen to ameliorate untoward toxicities. When used either as a single agent or in combination with cis-diamine platinums (eg, cisplatin, carboplatin) or diaminocyclohexane platinums (eg, oxaliplatin), pemetrexed has shown significant antitumor activity, with mild, manageable toxicity in patients with advanced NSCLC.

Antimetabolites, Antineoplastic↗
PubMed2002

Future directions in the development of pemetrexed.

Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. Such a drug may have theoretical advantages over fluoropyrimidines and specifically acting antifolates. Phase I studies identified a preferred schedule of an intravenous dose once every 3 weeks. Phase II studies showed a broad spectrum of activity in solid tumors (ie, non-small cell lung, colorectal, and pancreatic cancers) usually considered refractory to most antimetabolites. Binary combinations with cisplatin, carboplatin, and gemcitabine have proven feasible and show encouraging activity in lung cancer and mesothelioma. Problems of sporadic life-threatening toxicity identified in early studies of this and other antifolates have been resolved by the discovery that they were caused by functional folate deficiency and may be avoided by a low-dose nutritional supplement of folic acid and vitamin B(12). Pemetrexed is a promising new drug that should make a contribution to solid tumor oncology.

Antimetabolites, Antineoplastic↗
PubMed2002

Preclinical and clinical studies with combinations of pemetrexed and gemcitabine.

The novel antimetabolite pemetrexed inhibits the folate-dependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent is broadly active in a wide variety of solid tumors, including non-small cell lung, breast, bladder, head and neck, and ovarian cancers, as well as mesothelioma. Gemcitabine is a pyrimidine nucleoside antimetabolite that is approved worldwide for the treatment of pancreatic and non-small cell lung cancers, and bladder cancer outside the United States. In addition, gemcitabine is active against a broad range of tumors including breast, ovarian, and other cancers. Preclinical studies have shown cytotoxic synergy when pemetrexed is combined with gemcitabine. Based on these data, a phase I study of this combination was performed that showed striking activity. Phase II studies of this combination are being performed in breast and non-small cell lung cancer. In addition, a phase III study in pancreatic cancer is ongoing.

Animals↗
PubMed2005

[Second-line treatment of malignant pleural mesothelioma with Pemetrexed (Alimta) -- a case report].

Malignant Pleural Mesothelioma is regarded as a tumour, which lacks chemo-sensitivity. However, patients are able to benefit from a first line chemotherapy, as indicated in a currently published randomised study. Here the case of a 75 year old patient will be reported, who has been diagnosed with malignant pleural mesothelioma for 4 years. After a first line therapy with Gemcitabine/Oxaliplatin, partial remission was assessed. 15 months later a distinct progress was detected. After a second line therapy with Pemetrexed a sound partial response could be determined radiologically and clinically. This case history is supposed to exemplify that patients with malignant pleural mesothelioma should not only be considered for a first line therapy, but that a second line therapy may also be offered to a certain group of patients. The new substance Pemetrexed (Alimta) offers an excellent alternative with a very good efficacy profile and a favourable spectrum of side effects.

Aged↗
PubMed2006

Pemetrexed and malignant pleural mesothelioma.

Malignant Pleural Mesothelioma (MPM) continues to be a challenging problem; because few patients may be treated with radical surgery and conventional chemotherapy have achieved very dismal results. Pemetrexed is a new drug with multitarget antifolate activity which seems to be particularly active in many solid tumors and also in MPM. The principal clinical experiences of pemetrexed alone or in combination with other compounds, chiefly platinum and its derivative, are reported. The Italian study on 1114 cases of MPM treated over 30 months is discussed and the definitive results will be available after a complete external review of all responsive patients.

Antimetabolites, Antineoplastic↗
PubMed2007

Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial.

BACKGROUND: A standard second-line chemotherapy regimen has yet to be defined for patients with gemcitabine (Gem)-refractory advanced pancreatic cancer (PC). PATIENTS AND METHODS: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m(2) as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity. The primary end point was the 3-month survival rate. RESULTS: A total of 192 treatment cycles were given to 52 patients. The overall response rate was 3.8% (two partial responses); 10 patients (19.2%) experienced stable disease, nine of them for >12 weeks. At least one CA 19-9 reduction > or =50% occurred in 12 patients (23.1%). The 3-month survival rate was 75% (95% confidence interval 63.2% to 86.8%), the median time to tumor progression was 7 weeks (range 1-62 weeks) and the median overall survival time was 20 weeks (range 1-84 weeks). Grade 3/4 hematological toxic effects included (percent of patients): neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). The most frequent non-hematological toxic effects were diarrhea, nausea and stomatitis/pharyngitis (23.1% each). CONCLUSION: Pemetrexed is a safe treatment option with moderate activity in patients with advanced PC after failure of Gem.

Adult↗
PubMed2006

Can pemetrexed help in malignant mesothelioma?

Mesothelioma is a cancer that originates in the pleura or, more rarely, the peritoneum, and is almost always due to exposure to asbestos fibres. It is typically fatal, with a median survival of about 8-14 months after diagnosis. Conventional treatment options have not improved this poor outlook. Also, the number of deaths attributable to malignant mesothelioma has been rising rapidly in the UK since the late 1960s, and is set to peak at about 1,950-2,450 per year between 2011 and 2015. It is against this background that pemetrexed (pronounced pe-me-treks-ed) (Alimta - Lilly) has recently become available for use with cisplatin for the treatment of patients with unresectable malignant pleural mesothelioma who have not previously been treated with chemotherapy. Currently, this is the only chemotherapy regimen licensed for patients with malignant pleural mesothelioma in the UK. Here we review the care of patients with malignant pleural mesothelioma, focusing on what, if anything, pemetrexed might offer such individuals.

Antineoplastic Agents↗
PubMed2006

Dramatic tumour response to pemetrexed single-agent in an elderly patient with malignant peritoneal mesothelioma: a case report.

BACKGROUND: To date, there is no standard treatment for unresectable malignant peritoneal mesothelioma; either best supportive care or systemic chemotherapy with palliative intent are accepted options. CASE PRESENTATION: Here, we report the case of a 79-year old patient with malignant peritoneal mesothelioma who was treated with pemetrexed single-agent and obtained an impressive long-lasting response. CONCLUSION: Single-agent pemetrexed is a treatment option for malignant peritoneal mesothelioma in selected elderly patients or in patients with unpaired performance status.

Aged↗
PubMed2005

Pemetrexed-cisplatin combination in mesothelioma.

Despite the desperate struggle for improvement in the therapy of malignant pleural mesothelioma in previous decades, no standard therapy could be established. Pemetrexed (Alimta), a new multitargeted antifolate, showed significant antitumor activity in combination with cisplatin compared with cisplatin alone in patients with unresectable pleural mesothelioma. Furthermore, this improved efficacy was transformed into a significant symptomatic benefit. These data led to the approval of the drug by the US Food and Drug Administration and recently by the European Medicines Evaluation Agency for this combination in malignant pleural mesothelioma, and consequently founded the first standard of treatment in this disease. This review reflects the development of chemotherapy in malignant pleural mesothelioma, discusses the results of the EMPHACIS trial, and outlines further developments for pemetrexed-containing regimens in malignant pleural mesothelioma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Three emerging new drugs for NSCLC: pemetrexed, bortezomib, and cetuximab.

Despite advances made in cytotoxic chemotherapy, the prognosis for patients with non-small cell lung cancer (NSCLC) continues to be poor. New, more effective drugs must be identified and developed to improve the outcome of these patients. Three drugs with promising activity in NSCLC are pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com), bortezomib (Velcade; Millennium Pharmaceuticals, Inc., Cambridge, MA, http://www.mlnm.com), and cetuximab (Erbitux; ImClone Systems, Inc., New York, NY, http://www.imclone.com). Pemetrexed inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase, enzymes necessary for purine and pyrimidine synthesis, thus causing cell-cycle arrest in the S phase. Bortezomib, a proteasome inhibitor, interferes with the cytosolic protein degradation machinery, namely the ubiquitin-proteasome complex, causing breakdown of cell-cycle regulators and cell-cycle arrest. Cetuximab is a chimeric mouse-human antibody that inhibits ligand-dependent activation of the epidermal growth factor receptor, resulting in receptor internalization and inhibition of downstream pathways that, in turn, causes cell growth and progression. All three drugs are approved for different tumor types, and studies defining their role in NSCLC are under way.

Antibodies, Monoclonal↗
PubMed2001

Gemcitabine and Pemetrexed disodium in treating breast cancer.

Pemetrexed disodium (Alimta, LY231514) is a novel, multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. This agent is broadly active in a wide variety of solid tumors, including breast cancer. Pemetrexed disodium has also shown clinically relevant activity in combination with gemcitabine (Gemzar). This combination is being evaluated for the treatment of metastatic breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Pemetrexed in previously treated non-small-cell lung cancer.

Several decades of chemotherapy trials in non-small-cell lung cancer (NSCLC) have clearly shown a survival benefit for chemotherapy over best supportive care. However, only short-lived responses are attained, with an average of four cycles of chemotherapy, before tumor progression is observed. Second-line chemotherapy has been demonstrated to improve outcome, with docetaxel (Taxotere) as the predominant cytotoxic drug. A recent randomized trial in second-line NSCLC indicated that the novel drug pemetrexed (Alimta) attained the same response, time to progression, and survival as docetaxel. This finding ushers in a new age in second-line treatment that can be further invigorated by the addition of targeted agents. Accumulated evidence indicates that overexpression of epidermal growth factor receptor and HER2/neu, which occurs frequently in NSCLC, leads to the deregulation of PI3K and MAPK, activating Akt and enhancing chemoresistance. Future clinical trials in NSCLC will include tailored and multitargeted therapy and pemetrexed represents a significant step forward in this direction.

Antineoplastic Combined Chemotherapy Protocols↗