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.     

Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors

Pemetrexed disodium (ALIMTA), "pemetrexed") is a novel, multi-targeted antifolate that has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck. Pemetrexed inhibits multiple folate-dependent enzymes involved in both purine and pyrimidine synthesis including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. As a single agent, pemetrexed exhibits a moderate toxicity profile at a dose of 500 mg/m(2) by 10-minute infusion once every 21 days with myelosuppression being the dose-limiting toxicity. Folic acid added to the diet in preclinical studies reduced toxicities while maintaining antitumor activity. Based on this observation and clinical toxicities, folic acid and vitamin B(12) dietary supplementation has been recently introduced into all ongoing trials. Studies combining pemetrexed with other active chemotherapeutic agents demonstrate that these combination therapies may become important treatment regimens in a variety of cancer types. Currently, pemetrexed phase III trials are ongoing in mesothelioma and non-small cell lung cancer with future trials planned to explore this unique multitargeted antifolate.     

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.     

培美曲塞在非小细胞肺癌治疗中的研究进展

培美曲塞（Pemetrexed，Alimta^R）是一种新型的多靶点抗叶酸药物．作为局部晚期或转移性非小细胞肺癌的二线治疗药物，目前已经有多个临床研究表明．培美曲塞单药或与其它药物联合在非小细胞肺癌的治疗中均获得显著疗效。该文对此作一回顾。     

Pharmacology and mechanism of action of pemetrexed

Pemetrexed is a novel multitargeted antifolate that inhibits > or = 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, and is approved in combination with cisplatin for the therapy of malignant mesothelioma. In a recent phase III trial, pemetrexed demonstrated equivalent efficacy to docetaxel, but with significantly less toxicity, in second-line treatment of non-small-cell lung cancer. The most common and serious toxicities of pemetrexed--myelosuppression and mucositis--have been significantly ameliorated by folic acid and vitamin B12 supplementation. More important, vitamin supplementation has not been shown to adversely affect efficacy in some tumor types. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. In this review, the biochemistry and mechanism of action of pemetrexed are discussed.     

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.     

The Importance of Balancing Toxicity and Efficacy in Chemotherapy

The goal of cancer treatment is not just prolonged life but improvement in disease-related symptoms without compromising the patient’s ability to carry out normal activities. Unfortunately, the toxicities associated with common chemotherapeutic treatments frequently cause adverse events that are equal to or worse than disease symptoms. Frequent or prolonged administration of chemotherapeutics and/or complicated measures to limit drug toxicity often disrupt the patient’s normal routine and negatively affect the patient’s quality of life. Targeted therapies aim to uncouple toxicity from efficacy; however, the efficacy of single-agent therapy has been disappointing, with the exception of imatinib. The novel cytotoxic agent pemetrexed has demonstrated the ability to prolong survival and improve disease-related symptoms and quality of life in malignant pleural mesothelioma without causing the toxicities seen with other cytotoxics of similar potency. Pemetrexed has demonstrated activity as a single agent and in combination with other agents. Because of its broad activity, good tolerability, and convenient administration schedule, pemetrexed has promise in treating patients with a variety of cancers.     

Updated Clinical Information on Multitargeted Antifolates in Lung Cancer

Pemetrexed, a third-generation antifolate already indicated in combination with cisplatin for the systemic treatment of malignant pleural mesothelioma and, as a single agent, for the second-line treatment of Non—Small-cell lung cancer was in 2008 granted approval for histologically based first-line treatment by both the EMEA and FDA. Thymidylate synthase, the main molecular target of pemetrexed, has higher mRNA and protein expression in squamous- and small-cell lung cancer compared with adenocarcinoma. This differential expression might well molecularly explain the differential clinical activity of pemetrexed in the various histotypes of lung cancer, including the marginal activity in small-cell lung cancer. These hypothesis-generating findings are currently validated in prospective studies     

A Review of Regimens Combining Pemetrexed With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in the Treatment of Advanced Nonsquamous Non–Small-Cell Lung Cancer

Pemetrexed is a standard first-line treatment for advanced nonsquamous non–small-cell lung cancer (NSCLC), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a standard first-line treatment for advanced nonsquamous NSCLC with activating EGFR mutations. Pemetrexed and EGFR TKIs have different mechanisms of action and minimally overlapping toxicity profiles; therefore, it is hypothesized that their combination might result in acceptable toxicity, provided that the synergistic antitumor activity observed in preclinical studies is achieved. This review summarizes clinical trials of pemetrexed in combination with an EGFR TKI for the treatment of advanced nonsquamous NSCLC in the first- and second-line settings, using intercalated, sequential, and concurrent treatment strategies. As would be expected, such strategies were most efficacious in patients with the activating EGFR mutations associated with response to an EGFR TKI. In the studies that compared a pemetrexed-EGFR TKI combination with pemetrexed alone or the EGFR TKI alone, the pemetrexed-EGFR TKI combination was more efficacious than the single-agent regimens. The pemetrexed-EGFR TKI combinations were generally associated with a higher incidence of grade 3/4 treatment-related adverse events than the single-agent regimens; however, such toxicities were clinically manageable. Future studies of pemetrexed-EGFR TKI combinations should focus on optimizing treatment strategies in patients with activating EGFR mutations.     

Emerging role of pemetrexed in ovarian cancer

The current treatment of choice of epithelial ovarian cancer involves aggressive tumor cytoreductive surgery followed by platinum- and taxane-based chemotherapy; however, despite the encouraging activity of these agents, most ovarian carcinomas relapse and many patients die from drug-resistant disease. After the failure of platinum- and taxane-based schedules, several cytotoxic agents have demonstrated activity in advanced ovarian cancer but none were able to induce significant and durable responses. Among the new cytotoxic agents, pemetrexed plays an emerging role in different tumors, demonstrating competitive activity and a promising safety profile. In ovarian cancer, pemetrexed has been investigated, with encouraging results, as a single agent and in association with platinum compounds; moreover, the drug has shown interesting activity both in platinum-sensitive and platinum-resistant ovarian cancer. According to these clinical results it appears reasonable to explore the combination of pemetrexed with other cytotoxic agents and also with targeted therapies in relapsed ovarian cancer patients.     

Pemetrexed disodium, a novel antifolate with multiple targets

Pemetrexed disodium is a potent new antifolate which inhibits many folate-dependent reactions that are essential for cell proliferation. Its primary target is thymidylate synthase but it also inhibits folate-dependent enzymes involved in purine synthesis. Cells that are resistant to antifolates are generally less resistant to pemetrexed, irrespective of the mechanism of resistance. Pemetrexed has shown good activity in preclinical models with human tumour cells and xenografts. In the majority of clinical trials of pemetrexed, the dose-limiting toxic effect is neutropenia; other side-effects are mostly gastrointestinal. Preclinical studies indicate that the toxic effects of pemetrexed can be reduced by dietary folate, resulting in an improved therapeutic index. Low folate status is also associated with higher levels of toxicity in patients. As a single agent pemetrexed has shown good activity against non-small-cell lung cancer, squamous-cell carcinoma of head and neck, colon cancer, and breast cancer, and it appears to be particularly active in combination with cisplatin against non-small-cell lung cancer and mesothelioma. Phase II and III studies are underway.     

Activity of pemetrexed (alimta), a new antifolate,against non-small cell lung cancer

Chemotherapy for non-small cell lung cancer (NSCLC) has developed within the past decade into an important part of treatment with palliative aims as well as part of curative combined-modality treatment. Furthermore, second-line treatment has become an accepted part of the palliative approach as well. Pemetrexed (alimta) is one of the recently introduced agents that have been evaluated for efficacy against NSCLC. In single-agent phase II studies in previously untreated NSCLC, pemetrexed resulted in a response rate of around 20%. In combination with cisplatin, response rates of 40% were achieved. As a second-line single agent in-patients with early progression after first-line treatment, the response rate is 9%. Toxicity is mainly hematologic and can be reduced by supportive measures. Overall, pemetrexed is an active agent that further improves the chemotherapeutic options of physicians involved in the treatment of NSCLC.     

Pemetrexed (Alimta): a new antifolate for non-small-cell lung cancer

Pemetrexed (Alimta) is a novel multitargeted antifolate that has activity against non-small-cell lung cancer (NSCLC). As a single agent, the response rate is 16%-23%. As second-line therapy, it has a 5% and 14% response rate with pemetrexed in NSCLC patients who have had prior cisplatin or nonplatinum chemotherapy, respectively. Pemetrexed combined with cisplatin has a response rate of 38.9%-44.8%, with a median survival of 8.9-10.9 months. Pemetrexed plus gemcitabine in NSCLC has a response rate of less than 25%. The major toxicity associated with pemetrexed is neutropenia, which may be reduced with vitamin B12 and folate nutritional supplement. Additional studies with pemetrexed in combination with other agents are needed for the treatment of NSCLC patients.     

Pemetrexed as a possible cause of severe rhabdomyolysis in the treatment of lung cancer

According to many published clinical trials, both haematological and non-haematological toxicities resulting from pemetrexed were relatively mild and therefore this drug is considered to be well tolerated. We came across a 60 y/o woman patient with stage IV adenocarcinoma, suffered from unexpected life threatening complication, rhabdomyolysis. Severe lower leg weakness and respiratory failure occurred on the day 3 after pemetrexed administration. To the best of our knowledge, this is the first report that addresses severe and life-threatening rhabdomyolysis which occur during chemotherapy for the treatment of lung cancer. We believed pemetrexed is a safe drug but we should pay attention to possible complications related to pemetrexed-based treatment and to also treat the life-threatening disorder of rhabdomyolysis immediately to prevent further damage.     

Treatment rationale and study design for a phase III,double-blind,placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer

Background  

To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed.     

Costs of bevacizumab and pemetrexed for advanced non-squamous NSCLC in Italy and Germany

The new targeted agent bevacizumab in combination with cisplatin and gemcitabine, and a third-generation chemotherapy pemetrexed in combination with cisplatin, have been approved as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC). An indirect comparison between bevacizumab plus cisplatin and gemcitabine and pemetrexed plus cisplatin showed that bevacizumab (plus cisplatin and gemcitabine) achieved a favourable hazard ratio in terms of progression-free survival among patients with advanced NSCLC. This analysis aimed to compare the monthly cost of these treatments for advanced non-squamous NSCLC in Italy and Germany.The comparison used country specific cost data and adopted the payer perspective in Italy and Germany.The monthly cost of bevacizumab, including administration cost, as a single agent was €1,509 and €2,564 less than pemetrexed in Italy and Germany, respectively. The monthly treatment cost of bevacizumab plus cisplatin and gemcitabine was €1,001 and €446 less than pemetrexed plus gemcitabine in Italy and Germany, respectively.Results indicate that clinical benefits with bevacizumab plus cisplatin and gemcitabine therapy are achieved at a lower monthly cost than pemetrexed plus gemcitabine doublet therapy. Therefore, from a budget perspective, bevacizumab should be considered as a preferred targeted treatment of choice for advanced non-squamous NSCLC.     

培美曲赛单药与培美曲赛联合奥沙利铂用于IV期肺腺癌挽救性治疗的比较

背景与目的目前肺癌挽救性治疗尚无标准方案。本研究旨在比较培美曲赛单药与培美曲赛联合奥沙利铂挽救性治疗IV期肺腺癌患者的疗效及安全性,为联合化疗提供依据。方法 2009年1月-2011年2月共83例体能状态评分(performance status,PS)为0分-2分的IV期肺腺癌患者分别接受培美曲赛(单药组47例)和培美曲赛联合奥沙利铂(联合组36例)挽救性治疗,观察两组近期疗效和毒性反应并进行比较。结果 81例患者纳入最终分析。单药组与联合组中位无进展生存时间(progression-free survival,PFS)分别为3.6个月vs4.1个月(P=0.268),客观反应率(objective response rate,ORR)和疾病控制率(disease control rate,DCR)分别为6.5%vs20%(P=0.092)和56.5%vs65.7%(P=0.493)。单药组与联合组血液毒性及胃肠道反应发生率分别为33.9%vs47.2%(P=0.460)和21.2%vs25.0%(P=0.213)。结论培美曲赛联合奥沙利铂挽救性治疗PS评分较好的IV期肺腺癌患者耐受性良好,与培美曲赛单药相比显示出较高的缓解率,但未明显增加患者的PFS。     

Pemetrexed in heavily pretreated non-small-cell lung cancer patients: case report and review of the literature

To date, there is no standard treatment for patients with metastatic non-small-cell lung cancer after multiple previous lines of chemotherapy. Pemetrexed in combination with cisplatin or as a single agent demonstrated significant activity in patients with nonsquamous non-small-cell lung cancer with a good toxicity profile. In this article, we present a case of pulmonary adenocarcinoma treated with pemetrexed after five lines of treatment, including the cytotoxic agents cisplatin plus vinorelbine, docetaxel, gemcitabine and the tyrosine kinase inhibitor erlotinib. We also review the role of pemetrexed in this setting of patients.     

Pemetrexed-Induced Pneumonitis: A Case Report

Pemetrexed is a structurally novel antifolate agent approved in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma who have unresectable disease and for the therapy of previously treated patients with locally advanced or metastatic Non–Small-cell lung cancer (NSCLC) as a single agent or in association with cisplatin as a first-line treatment in patients with nonsquamous histology. Herein, we report a case of pemetrexed-induced pneumonitis. Because pemetrexed is being prescribed with increasing frequency for NSCLC and mesothelioma, we believe that physicians should be aware of this rare but serious complication.