Therapy of advanced non-small-cell lung cancer with irinotecan and gemcitabine in combination

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.     

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.     

The role of gemcitabine in the treatment of malignant mesothelioma

Gemcitabine is broadly active in a variety of solid tumors, including malignant mesothelioma. In vitro, gemcitabine demonstrates activity against mesothelioma cell lines. The role of single-agent gemcitabine in patients with mesothelioma is unclear, since three phase II trials treated a total of 60 patients and achieved response rates of 0%, 7%, and 31%. The combination of gemcitabine and cisplatin is synergistic against mesothelioma cell lines in vitro. Gemcitabine in combination with cisplatin or carboplatin shows definite activity in phase II trials. The trial by Byrne and colleagues that demonstrated a response rate of 48% established the combination of gemcitabine plus cisplatin as a standard therapy for this disease in the United States. Subsequent multicenter trials have achieved lower response rates of 26% and 16% for this combination. Gemcitabine plus carboplatin also has activity. Future roles for gemcitabine in malignant mesothelioma patients include incorporating a gemcitabine/platinum regimen for neoadjuvant or adjuvant therapy, combining it with other cytotoxic chemotherapy agents such as pemetrexed or vinorelbine, or adding novel cytostatic agents such as the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, to the gemcitabine and platinating agent combination.     

The emerging role of antifolates in the treatment of malignant pleural mesothelioma

Clinicians have long regarded malignant pleural mesothelioma as a chemoresistant neoplasm and as a result no standard chemotherapy regimen has emerged. Antifolates such as methotrexate are among the most active compounds in mesothelioma, albeit based only on phase II data. Recently two antifolate-based combinations with apparently higher efficacy than older regimens have emerged: the pemetrexed/cisplatin regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials with pemetrexed combined with either cisplatin or carboplatin responses occurred in five of 11 and nine of 29 patients, respectively. In a phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with mesothelioma achieved a partial response. In a phase II trial of raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72 patients (25%) with malignant pleural mesothelioma. Indeed, responses were seen in cisplatin-refractory patients. Based on the promising results from these combination trials, two large phase III studies have begun. The first study was a multicenter, multinational trial sponsored by Eli Lilly and Company, which randomized more than 430 patients with malignant pleural mesothelioma to cisplatin with or without pemetrexed. That trial completed enrollment in February 2001 and is the largest trial ever conducted in mesothelioma. The second trial is being conducted by the European Organization for the Research and Treatment of Cancer (EORTC) and compares cisplatin with or without raltitrexed with planned accrual of 240 patients. In both trials, survival is the main endpoint. These trials will help to define the role of these new antifolates in malignant pleural mesothelioma.     

Overview on ongoing or planned clinical trials in Europe

Malignant pleural mesothelioma (MPM) is a locally invasive malignancy, but only a minority of patients can benefit by surgical resection. Among chemotherapeutic agents only vinorelbine, edatrexate, gemcitabine and raltitrexed have demonstrated response rates >20%. The largest randomised trial in MPM showed an improved median survival with cisplatin and pemetrexed versus cisplatin alone from 9.3 to 12.1 months. For the present overview about 70 requests of information were sent to the major European centres of thoracic oncology. The most widespread study treatment in Europe is an 'Extended Access Program (EAP)' evaluating pemetrexed alone or combined with cisplatin or carboplatin with about 1500 enrolled patients. Two other international randomized studies compare pemetrexed plus best supportive care (BSC) versus BSC alone, and the role of Ranpirnase (Onconase) in MPM. Important national trials are ongoing: in the UK the addressed questions were the role of radical surgery (MARS Trial), the role of chemotherapy (MS-01 trial) and the role of VATS on active treatment of pleural effusion. In Switzerland the SAKK group phase III study explores in a comparative way the value of hemithoracic radiotherapy after primary treatment with cisplatin/pemetrexed followed by surgery. In Italy, 2 phase II trials of neoadjuvant chemotherapy (pemetrexed plus cisplatin in Rome, pemetrexed plus carboplatin in Padua) followed by surgery and radiotherapy are active. With the important exception of UK, the most evident element is the overwhelming presence of pemetrexed in the ongoing and future clinical trials. Pemetrexed has influenced not only the clinical practice, but also the patient enrolment in clinical trials.     

Chemotherapy for malignant pleural mesothelioma

This paper covers the outcome of previously conducted clinical trials on chemotherapy for malignant pleural mesothelioma and presents data from recent phase II and phase III trials. In contrast to conventional cytotoxic drugs, which have barely produced response rates exceeding 30%, recently introduced chemotherapeutic agents and their combinations promise to be more effective. Especially pemetrexed has yielded response rates of up to 45% in combination with platinum compounds. Furthermore, raltitrexed-oxaliplatin has shown promising activity and gemcitabine was found to improve quality of life in patients with malignant pleural mesothelioma when applied as a single agent or in combination with cisplatin. Based on robust phase III study results, pemetrexed-cisplatin may soon be considered with chemotherapy for this aggressive disease.     

Pemetrexed in the treatment of advanced non-small-cell lung cancer: a review of the clinical data

Pemetrexed is a novel multitargeting antimetabolite that has first-line and second-line activity against non-small cell lung cancer (NSCLC). Phase II studies have shown significant efficacy and a favorable toxicity profile of the combination of pemetrexed plus platinum as first-line therapy for NSCLC. Second-line activity against NSCLC was demonstrated in a phase III trial comparing single-agent pemetrexed with docetaxel; in that trial, survival was comparable between these agents but side effects were significantly less for patients who received pemetrexed. Pemetrexed is also an active agent against mesothelioma. A phase III trial comparing pemetrexed plus cisplatin with cisplatin alone showed for the first time a regimen that improves survival in this disease and led to FDA approval of pemetrexed in combination with cisplatin for mesothelioma. As a radiosensitizer, pemetrexed has been well-tolerated when given concurrent with chest radiation, and a phase I study is under way assessing its tolerability in combination with carboplatin in this setting. Pemetrexed is clearly a useful agent in the treatment of thoracic malignancies, and is worthy of further study in combination with other drugs having novel mechanisms of action.     

Audit of patients with mesothelioma treated with pemetrexed in a single institution in Western Australia

Malignant pleural mesothelioma (MPM) is a devastating malignancy that until recently has had no effective treatment. Pemetrexed in combination with cisplatin entered routine clinical practice following reports of efficacy in 2003. We performed a retrospective analysis of all patients with malignant mesothelioma at a single institution treated with pemetrexed in any combination or as monotherapy between 2004 and 2007. During this period, 62 patients received pemetrexed-based chemotherapy for MPM, most of whom were male (87%), treated in the palliative setting (84%) and received pemetrexed in combination with a platinum agent (95%). Pemetrexed was found to be well tolerated and produced clinical benefit and response rates similar to other published studies for its use in MPM in the phase IV or community practice settings. Patients with progressive disease as their best radiological response had very poor outcomes, while patients with stable disease had similar outcomes to those with responses. We confirmed that survival after commencement of pemetrexed-based chemotherapy remains under one year in this group of patients, somewhat less than the survival reported in phase III trials that currently inform clinical decision making. Further research is required to identify those patients who might benefit from pemetrexed based on molecular predictive markers.     

Current data with pemetrexed (Alimta) in non-small-cell lung cancer

Pemetrexed (Alimta ) is a novel multitargeted antifolate that inhibits 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors. In non-small-cell lung cancer (NSCLC), single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine. A pivotal phase III study in mesothelioma has been presented, indicating the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. Approval for pemetrexed in combination with cisplatin in advanced mesothelioma is expected within the next 12 months. This review discusses the activity of pemetrexed in NSCLC.     

Novel combinations using pemetrexed in malignant mesothelioma

Malignant mesothelioma is an uncommon malignancy that is locally invasive and rapidly fatal. The majority of patients with mesothelioma are not candidates for curative surgical resection. Chemotherapy has yielded only modest results in these patients. Pemetrexed is a multitargeted antifolate that is being evaluated in many tumor types. Recent single-agent data and data in combination with cisplatin have suggested that pemetrexed has therapeutic benefits in patients with malignant mesothelioma. This article summarizes the data regarding pemetrexed in the treatment of malignant mesothelioma and the potential novel combinations involving the drug that may be used in the future for the treatment of the disease.     

Multi-targeted-Enzyminhibition in der Tumortherapie

Pemetrexed is a newly developed therapeutic agent which inhibits several key enzymes in the folate metabolic pathway. In phase I trials, this novel multitargeted antifolate showed a broad antitumor activity as a single agent and in combination chemotherapy. Based on these findings, phase III studies have been conducted including patients with malignant pleural mesothelioma (MPM), non-small-cell lung cancer (NSCLC), and colorectal cancer. In a recent phase III trial in MPM, the combination of pemetrexed and cisplatin was significantly more efficacious than cisplatin alone. In addition, vitamin supplementation reduced treatment-associated toxicities with no apparent affect on activity. In patients with NSCLC, a phase III trial showed clinically equivalent efficacy of pemetrexed and docetaxel, but pemetrexed was associated with significantly fewer toxicities in second-line therapy. This review summarizes preclinical and clinical data to define the future role of pemetrexed in the treatment of tumor patients.     

Current Data with Pemetrexed in Non–Small-Cell Lung Cancer

Pemetrexed (Alimta®) is a novel multitargeted antifolate that inhibits 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has broad antitumor activity in phase II trials in a wide variety of solid tumors. In non–small-cell lung cancer (NSCLC), single-agent activity has been documented in the first- and second-line settings. Promising activity has also been demonstrated when pemetrexed is combined with cisplatin and gemcitabine. A pivotal phase III study in mesothelioma has been presented, indicating the superiority of pemetrexed in combination with cisplatin versus cisplatin alone in this disease. Approval for pemetrexed in combination with cisplatin in advanced mesothelioma is expected within the next 12 months. This review discusses the activity of pemetrexed in NSCLC.     

Pemetrexed (Alimta): improving outcomes in malignant pleural mesothelioma

During the past four decades, chemotherapy has failed to demonstrate a consistent clinical benefit for patients with unresectable or recurrent malignant pleural mesothelioma (MPM). Consequently, there has been no standard chemotherapy nor US Food and Drug Administration (FDA)-approved drug for patients with this disease. The introduction of pemetrexed (Alimta, Eli Lilly), a multitargeted antifolate agent, has improved the outlook for patients with mesothelioma by demonstrating a positive impact on quality of life and by prolonging survival. Pemetrexed is the first FDA-approved drug for the treatment of MPM. The combination of cisplatin plus pemetrexed is now the standard of care for the treatment of the disease. Furthermore, supplementation with vitamin B12 and folate has vastly improved the toxicity profile of pemetrexed. This article summarizes historical chemotherapy trials in MPM; discusses key features of clinical trial design for MPM; summarizes the results of a landmark Phase III trial of pemetrexed and cisplatin in MPM; discusses the relative contributions of pemetrexed and cisplatin to the regimen; explains the importance of vitamin supplementation of pemetrexed; and provides direction for future clinical trials in this disease.     

Systemic Treatments for Mesothelioma: Standard and Novel

OPINION STATEMENT: Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes--epithelial, sarcomatoid, and biphasic--that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.     

Pemetrexed: a novel antifolate agent enters clinical practice

Pemetrexed (Alimta, Eli Lilly) is a multitargeted antifolate that inhibits at least three enzymes in the nucleic acid synthetic pathways. The US Food and Drug Administration recently approved pemetrexed, in combination with cisplatin, for the first-line treatment of advanced malignant pleural mesothelioma. Moreover, pemetrexed was recently shown to be as efficacious as docetaxel (Taxotere, Aventis) in the second-line treatment of non-small cell lung cancer, and its toxicity profile was preferable. The main toxicity seen with pemetrexed is myelosuppression, which is considerably reduced by coadministration of folic acid and vitamin B12. Multiple Phase II clinical trials have demonstrated that pemetrexed has promising single-agent activity in many other solid tumors, including head and neck, breast and colorectal cancers. Combination regimens consisting of pemetrexed and other chemotherapeutics or novel molecular-targeted agents are currently under investigation. Future studies will better define and likely expand the role of pemetrexed for the treatment of cancer.     

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.     

Chemotherapy and targeted therapies for unresectable malignant mesothelioma

The global burden of mesothelioma is expected to increase in the coming decades. As a result the development of more effective therapies with an emphasis on personalized treatments based on validated prognostic and predictive biomarkers is an essential requirement. Progress has been made in the last decade with the development of newer generation anti-folates leading to the current standard of care of pemetrexed and cisplatin in patients with unresectable disease. However, the median overall survival of patients with this combination treatment is only 12 months. There is no consensus regarding second line therapy for patients who have progressed or not responded to pemetrexed based therapies although gemcitabine in combination with a platinum compound or single agent vinorelbine is a reasonable option. The development of effective targeted agents that are active in mesothelioma has to date been disappointing. Strategies involving the addition of bevacizumab to pemetrexed and cisplatin in the frontline setting, the histone deacetylase inhibitor vorinostat as second line therapy and studies evaluating the utility of maintenance therapy in mesothelioma are all ongoing and appear promising. In addition clinical trials investigating immunotherapy and gene therapy in combination with chemotherapy could potentially improve the prognosis of patients with mesothelioma.     

Clinical activity of pemetrexed: a multitargeted antifolate anticancer agent

Pemetrexed is a new generation antifolate anticancer agent that inhibits several folate-dependent enzymes required for production of DNA and RNA intermediates. Early studies showed significant hematologic and nonhematologic toxicities with this agent. However it was found that many of these toxicities related to functional folate status and could be markedly reduced through routine supplementation with folic acid and vitamin B(12), without adversely affecting efficacy. Phase III studies with pemetrexed have established a clinical role for this drug as a single agent in the second-line treatment of non-small cell lung cancer and in combination with cisplatin for the frontline treatment of unresectable malignant pleural mesothelioma. Clinical trials of pemetrexed alone or in combination with other chemotherapeutic agents have shown considerable activity in many tumor types including colorectal, pancreatic and breast cancer, and urothelial tumors.     

Pemetrexed (Alimta®): improving outcomes in malignant pleural mesothelioma

During the past four decades, chemotherapy has failed to demonstrate a consistent clinical benefit for patients with unresectable or recurrent malignant pleural mesothelioma (MPM). Consequently, there has been no standard chemotherapy nor US Food and Drug Administration (FDA)-approved drug for patients with this disease. The introduction of pemetrexed (Alimta^®, Eli Lilly), a multitargeted antifolate agent, has improved the outlook for patients with mesothelioma by demonstrating a positive impact on quality of life and by prolonging survival. Pemetrexed is the first FDA-approved drug for the treatment of MPM. The combination of cisplatin plus pemetrexed is now the standard of care for the treatment of the disease. Furthermore, supplementation with vitamin B12 and folate has vastly improved the toxicity profile of pemetrexed. This article summarizes historical chemotherapy trials in MPM; discusses key features of clinical trial design for MPM; summarizes the results of a landmark Phase III trial of pemetrexed and cisplatin in MPM; discusses the relative contributions of pemetrexed and cisplatin to the regimen; explains the importance of vitamin supplementation of pemetrexed; and provides direction for future clinical trials in this disease.     

FDA drug approval summaries: pemetrexed (Alimta)

The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting.On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.