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PubMed2003

The emerging role of pemetrexed (Alimta) and gemcitabine in non-small cell lung cancer.

In recent years, several new cytotoxic agents have been investigated for the management of non-small cell lung cancer (NSCLC), including the antimetabolic gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and the new multitargeted antifolate pemetrexed (Alimta, Eli Lilly and Company), which are both among the most active agents in advanced NSCLC. Gemcitabine has become one of the key drugs in the management of NSCLC, alone or in association with platin compounds. Promising results have also been reported with pemetrexed used as a single-agent or in combination with cisplatin or gemcitabine. These results indicate that pemetrexed may also play a vital role in the treatment of NSCLC, malignant mesothelioma, and other solid tumors. Ongoing (and planned) trials are investigating the use of single-agent pemetrexed, or combinations with cisplatin, gemcitabine, and other cytotoxic agents in various malignancies.

Antimetabolites, Antineoplastic↗
PubMed2006

In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients.

The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization.

Administration, Intravesical↗
PubMed2002

Pemetrexed for diffuse malignant pleural mesothelioma.

The treatment of diffuse malignant pleural mesothelioma (MPM) is currently less than satisfactory. Survival statistics are best for the epithelial subtype and for tumors that can be completely removed by surgery. Radiotherapy provides no survival benefit and is used only to palliate symptoms or to prevent growth along needle tracks and incisions. The response to chemotherapeutic agents is poor, and to date there is no standard cytotoxic treatment. Antimetabolites may have some activity, and one trial of high-dose methotrexate has suggested a moderate response rate. There is also no evidence that any chemotherapy regimen given as a part of multimodality treatment, including radiotherapy and surgery, can improve survival. Recently, a renewed interest in MPM led to clinical trials with promising preliminary results for several agents alone or in combination, including gemcitabine, raltitrexed, vinorelbine, and pemetrexed. Pemetrexed, a folate-based inhibitor of thymidylate synthase and other enzymes, is currently under investigation in multiple malignancies. A phase I study of pemetrexed in combination with cisplatin showed a remarkable response rate of approximately 50% in patients with the epithelial subtype of MPM. This led to a large international study of the combination of pemetrexed plus cisplatin.

Antimetabolites, Antineoplastic↗
PubMed2002

Pemetrexed: translational research in breast cancer.

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel antifolate/antimetabolite with activity in breast cancer and has well-defined molecular targets, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. In a phase II trial in patients with T3-4, N0-2 breast cancer, expression of thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, p53, and c-erb-B2 (at the mRNA or protein level) is being examined before and 24 hours after the first dose of neoadjuvant pemetrexed and after three cycles of single-agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity. Full biomarker and clinical data are not yet available from this study; however, clinical responses to pemetrexed treatment have been observed in patients. Results of this trial should provide both an idea of the activity of neoadjuvant pemetrexed in breast cancer and information on biomarker association with clinical performance that can be used in the design of additional clinical studies to assess the predictive value of these markers.

Antimetabolites, Antineoplastic↗
PubMed2004

Physical compatibility of pemetrexed disodium with other drugs during simulated Y-site administration.

PURPOSE: The physical compatibility of pemetrexed disodium with selected other drugs during simulated Y-site injection was studied. METHODS: A 5 mL sample of pemetrexed disodium 20 mg/mL in 0.9% sodium chloride injection was combined with 5 mL of a solution of each of 79 other drugs. The other test drugs included antineoplastics, antiinfectives, and supportive care drugs used undiluted or diluted in 0.9% sodium chloride injection or 5% dextrose injection. Visual examinations were performed with the unaided eye in normal diffuse fluorescent light at intervals up to four hours after mixing. Combinations with no obvious incompatibility were examined further with a high-intensity monodirectional light source to enhance visualization of small particles and low-level turbidity. The combinations were also evaluated with a turbidimeter at one and four hours. All combinations without visual incompatibility were assessed with a particle sizer-counter. RESULTS: Of the 79 pemetrexed-secondary drug combinations, 55 were compatible for at least four hours. However,mixture with 24 drugs resulted in precipitation (including microprecipitation) and color change. CONCLUSION: Pemetrexed disodium was incompatible with 24 drugs during simulated Y-site administration and should not be administered with them.

Antineoplastic Agents↗
PubMed2003

Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines.

BACKGROUND: To assess antitumor activity and toxicity of pemetrexed in metastatic breast cancer (MBC) patients previously treated with anthracyclines. PATIENTS AND METHODS: Seventy-seven MBC patients from 12 European institutions were entered into the study. Seventy-two patients were considered evaluable for response and toxicity. Forty-two patients were classified as anthracycline-failure (relapse >30 days after completion of a prior anthracycline regimen) and 30 as anthracycline-refractory (progression within 30 days after anthracycline therapy). Pemetrexed 600 mg/m(2) was administered intravenously every 3 weeks until progressive disease or unacceptable toxicity. RESULTS: There were three complete and 12 partial responders [response rate 21% (95% confidence interval 12%)]. Response rates in the anthracycline-failure and anthracycline-refractory groups were 24% and 17%, respectively. A subset of 31 patients pretreated with anthracyclines and taxanes had a response rate of 26%. Median duration of response and median survival were 5.5 and 10.7 months, respectively (13 months in the failure group and 5.7 months for refractory). Grade 3/4 toxicities included neutropenia and thrombocytopenia in 56% and 19% of patients, respectively. Nine patients (12%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities included skin rash (10%), nausea (12%), fatigue (10%) and stomatitis (5%). CONCLUSION: Our trial demonstrates pemetrexed to be active in breast cancer, with manageable toxicity. Activity of pemetrexed did not appear to be adversely affected by prior taxane, 5-fluorouracil or endocrine treatments.

Adult↗
PubMed2005

Second-line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.

BACKGROUND: A phase III trial in patients with malignant pleural mesothelioma demonstrated a survival advantage for pemetrexed plus cisplatin compared with single-agent cisplatin. Because post-study chemotherapy (PSC) may have influenced the outcome of the trial, we examined its use and association with survival. PATIENTS AND METHODS: Eighty-four patients from the pemetrexed plus cisplatin arm and 105 patients from the single-agent cisplatin arm received PSC. Kaplan-Meier survival estimates were compared by treatment groups, and by PSC and non-PSC subgroups. RESULTS: The percentage of patients receiving PSC was imbalanced between the treatment arms. Fewer pemetrexed plus cisplatin treated patients received PSC (37.2% versus 47.3%). A multiple regression analysis performed in this trial showed that PSC had a statistically significant correlation with prolonged survival (P <0.01), adjusting for baseline prognostic factors and treatment intervention. The adjusted hazard ratio for PSC over non-PSC subgroups was 0.56 (confidence interval 0.44-0.72). CONCLUSIONS: PSC in malignant pleural mesothelioma was significantly associated with prolonged survival. It is not known whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. The pemetrexed plus cisplatin treatment group had a statistically significant survival advantage even though fewer patients from that arm of the trial received PSC. The potentially beneficial role of PSC should be assessed in prospective trials.

Adult↗
PubMed2006

Efficacy of a combination of pemetrexed and multiple redo-surgery in an 11-year-old girl with a recurrent multifocal abdominal mesothelioma.

We report the case of an 11-year-old girl with a recurrent progressive locally advanced abdominal mesothelioma. First, there was an incomplete surgical resection without any complementary chemotherapy, followed by a slow progression of the disease. Three years later, after two macroscopically complete surgical resections of peritoneal and ovarian tumors, she failed to respond to treatment with gemcitabin-carboplatin and gemcitabin-cisplatin, and developed splenic tumors and large multicystic hepatic tumors. She was then treated with pemetrexed. The schedule of chemotherapy was pemetrexed 400 mg intravenously plus cisplatin 60 mg once every 3 weeks associated with folic acid and vitamin B12. The tumor reduction was evaluated with positron emission tomography scan and tomodensitometry every three courses. Chemotherapy tolerance was good apart from a grade III neutropenia at the second course, a fever of unknown origin at the fifth course and a grade III thrombocytopenia at the sixth course. As tolerance and clinical responses were good, pemetrexed posology was increased up to 10%. After six courses, hepatic and splenic lesion tumors were initially diminished and then stablilized. Thus, a surgical resection was attempted: a first surgery followed by a second one 3 days later allowed completion of a difficult left hepatectomy, and resection of the hilum and splenic tumors. Fourteen months after the surgery, the girl remained in partial remission with stable disease. So far, pemetrexed associated with cisplatin revealed a good tolerance and promising results regarding its antitumoral efficacy in a progressive metastatic abdominal mesothelioma in childhood.

Abdominal Neoplasms↗
PubMed2004

Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent.

Pemetrexed (ALIMTA, LY231514, MTA) is a novel antimetabolite that inhibits at least three enzymes involved in the folate pathway. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has demonstrated clinical activity in non-small cell lung cancer as well as in a broad array of other solid tumors, including mesothelioma, breast, colorectal, bladder, cervical, gastric and pancreatic cancer. In non-small cell lung cancer, single-agent activity has been documented in the first- and second-line settings in Phase II and Phase III trials. Promising activity has also been demonstrated when pemetrexed is combined with platinum compounds (cisplatin, carboplatin, and oxaliplatin), vinorelbine, and gemcitabine. Low level dietary supplement of folic acid and vitamin B12 has significantly decreased the mucosal and bone marrow toxicity of pemetrexed without compromising its antitumor effect.

Antineoplastic Agents↗
PubMed2003

Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.

PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.

Adult↗
PubMed2003

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.

Adult↗
PubMed2001

Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis.

As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.

Adult↗
PubMed2005

Phase II study of pemetrexed in patients pretreated with an anthracycline, a taxane, and capecitabine for advanced breast cancer.

BACKGROUND: This phase II study evaluated the efficacy, safety, and health outcomes of pemetrexed treatment in heavily pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Women with metastatic breast cancer, Karnofsky performance status > or = 70, and previous treatment with > or = 3 regimens containing anthracyclines, taxanes, and capecitabine were eligible. Pemetrexed 500 mg/m2 intravenous infusion was administered on day 1 of a 21-day treatment cycle. RESULTS: Eighty patients were enrolled, and 60 received concurrent folic acid and vitamin B12 supplements per protocol amendment to minimize possible pemetrexed-related toxicity. The median numbers of cycles delivered were 3 for vitamin-supplemented patients and 2 for non-vitamin-supplemented patients. Regardless of vitamin supplementation, the overall response rate was 8% (95% CI, 3%-16.6%), stable disease was exhibited in 36% of patients, median time to disease progression was 2.9 months, and median survival was 8.2 months. Improvements in patient-reported symptoms ranged from 16.2% for pain intensity to 32.1% for nausea. Major grade 3/4 toxicities were hematologic, with grade 4 neutropenia in 10% of patients and grade 3 toxicities consisting primarily of neutropenia (29%) and leukopenia (21%). There were no clear trends of the effect of supplementation on toxicity. CONCLUSION: Pemetrexed has modest antitumor activity and is well tolerated in heavily pretreated patients with breast cancer. Further evaluation of this multitargeted antifolate in advanced breast cancer is warranted.

Adult↗
PubMed2004

The role of pemetrexed in the treatment of gastrointestinal malignancy.

Although advanced colorectal cancer (CRC) is a leading cause of morbidity and mortality in the United States and Europe, chemotherapeutic options have only recently expanded with concomitant improvements in survival. Through the 1980s and early 1990s, research focused mainly on the major fluoropyrimidine 5-fluorouracil, a thymidylate synthase (TS) inhibitor, and methods to enhance its activity through scheduling changes or by biochemical modulation. Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to TS. This agent has theoretical and preclinical advantages over fluoropyrimidines and more specific antifolates. Phase II studies have shown a broad spectrum of activity in solid tumors, including CRC and pancreatic cancer. Combinations of pemetrexed with gemcitabine, irinotecan, and oxaliplatin have also proven feasible. Further studies of higher and biweekly doses with the use of vitamin supplementation are under way. In pancreatic cancer, the phase II studies of pemetrexed and gemcitabine were sufficiently promising to warrant a completed phase III comparison. Based on a recent abstract presentation, it appears that this combination did not improve survival compared with gemcitabine alone. Nonetheless, pemetrexed has important promise for new and improved regimens in the therapy of gastrointestinal cancer.

Antimetabolites, Antineoplastic↗
PubMed2005

Phase I/II dose-escalation study of pemetrexed plus irinotecan in patients with advanced colorectal cancer.

BACKGROUND: Pemetrexed and irinotecan have demonstrated antitumor activity as single agents in lung, pancreatic, breast, and colorectal cancer (CRC). The distinct mechanisms of action and patterns of resistance displayed by pemetrexed and irinotecan make them attractive agents for combination therapy. PATIENTS AND METHODS: This phase I/II, nonrandomized, open-labeled, single-arm study was composed of 3 segments. The initial phase II portion of the study enrolled 23 patients with advanced CRC who had received 1 previous dose of 5-fluorouracil (5-FU)-based chemotherapy for advanced disease. Because of poorer than anticipated efficacy, a phase I dose-escalation study using vitamin supplementation (n = 12) was added to the original protocol. The phase II dose-escalation portion of the study enrolled 36 patients (64% with previous oxaliplatin-based therapy) who received pemetrexed 500 mg/m2 followed by irinotecan 300 mg/m2 on day 1, every 21 days. RESULTS: For the 35 evaluable patients in the phase II dose-escalation study, the objective response rate was 11.4% (95% confidence interval, 3.2%-26.7%); there was 1 patient with a complete response, 3 with partial responses, and 17 with stable disease. Three of four responders had received previous oxaliplatin-based combination therapy. Grade 3/4 hematologic toxicities included leukopenia (5.6%), anemia (2.8%), and thrombocytopenia (2.8%). Grade 3/4 nonhematologic toxicities included diarrhea (11.1%), increased aminotransferase levels (8.3%), nausea (8.3%), febrile neutropenia (5.6%), vomiting (5.6%), and reduced creatinine clearance (2.8%). CONCLUSION: Pemetrexed plus irinotecan appears to be at least as active as FOLFIRI (leucovorin/5-FU/irinotecan) for second-line therapy of CRC following 5-FU-based combination chemotherapy. Further studies are warranted.

Adult↗
PubMed2004

Second-line chemotherapy for non-small-cell lung cancer: recent data with pemetrexed.

Platinum-based chemotherapy offers a modest survival advantage over best supportive care (BSC) in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Based on 2 landmark studies that reported improved survival times and quality of life when comparing docetaxel with ifosfamide, vinorelbine, or BSC alone, docetaxel at 75 mg/m(2) given once every 3 weeks has been the standard of care as second-line chemotherapy since 2000. Docetaxel given at this dose and schedule resulted in significant hematologic toxicity, with many patients at risk for neutropenic fever. Pemetrexed is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A phase III study in 571 patients comparing pemetrexed with docetaxel demonstrated clinically equivalent therapeutic outcomes in second-line treatment of patients with recurrent NSCLC; however, patients on the pemetrexed arm had a more favorable hematologic toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Based on these data, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC.

Antineoplastic Agents↗
PubMed2002

A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed.

Pemetrexed is a novel antifolate effective in the treatment of mesothelioma. Studies were undertaken to characterize the transport of this antifolate in this tumor. We report the presence of a novel, concentrative high-affinity transport activity in three human mesothelioma cell lines, characterized in detail in the NCI-H28 line, with a pemetrexed influx K(t) of 30 nM and V(max) of 10 nmol/g protein/min. This route is highly specific for pemetrexed, with a substrate specificity pattern quite different from that of the reduced folate carrier and folate receptors. In particular, there is an apparent relatively low affinity for other antifolate inhibitors of dihydrofolate-reductase (MTX, aminopterin, PT523) and thymidylate synthase (ZD1694, ZD9331). Besides its impact on the transport of pemetrexed, this high-affinity route may represent another pathway by which physiological folates are transported into human cells.

Antineoplastic Agents↗
PubMed2004

The emerging role of pemetrexed for the treatment of malignant mesothelioma.

Malignant mesothelioma is a devastating disease with an onset 20 to 60 years after exposure to asbestos. Although most cytotoxic agents have been evaluated for the treatment of mesothelioma, few single agents have consistently yielded response rates above 20%. Antimetabolites are the most active drugs against mesothelioma, and of these, the antifolate group is the most widely studied and effective. Pemetrexed (Alimta), a new antifolate, may be more active because of its different mechanism of action. Several clinical trials have evaluated pemetrexed alone and in combination with a platinum agent for patients with malignant mesothelioma. A pivotal phase III trial has demonstrated that combination chemotherapy with pemetrexed and cisplatin improves survival, response rate, pulmonary function, and quality of life compared with single-agent cisplatin. Additional trials are evaluating pemetrexed in the neoadjuvant setting and in combination with other cytotoxic and targeted agents.

Antimetabolites, Antineoplastic↗