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Pemetrexed in bladder, head and neck, and cervical cancers
Pemetrexed in Bladder, Head and Neck, and Cervical Cancers Luis Paz-Ares, Eva Ciruelos, Rocı´o Garcı´a-Carbonero, Daniel Castellano, Ana Lopez-Martı´n, and Herna´n Corte´s-Funes Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B12 appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies. Semin Oncol 29 (suppl 18):69-75. Copyright 2002, Elsevier Science (USA). All rights reserved.
F
OLATE-DEPENDENT pathways have been pursued as key targets in the development of anticancer agents over the last few decades.1 The antifolates interfere with the binding of natural folate cofactors to important biosynthetic enzymes such as thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide formyltransferase. Inhibition of these enzymes results in impeded synthesis of the nucleotide precursors of DNA and RNA. In 1948, Farber et al2 first showed that aminopterin, a four-amino analog of folic acid, could inhibit the proliferation of leukemic cells and produce remissions in patients with acute leukemia. Their findings ushered in the era of antimetabolite chemotherapy and generated great interest in the antifolates. Several compounds of this class, such as methotrexate and raltitrexed, are now extensively used in the treatment of leukemias, lymphomas, choriocarcinoma, and head and neck, gastrointestinal, breast, cervical, and bladder carcinomas. Pemetrexed (ALIMTA, LY231514; Eli Lilly and Company, Indianapolis, IN) is a novel pyrrolo(2,3-d) pyrimidine-based multitargeted antifolate analog.3-5 Given its favorable preclinical profile, this agent has entered clinical trials and has shown encouraging activity in a wide range of tumors, including non–small cell lung cancer (NSCLC), malignant mesothelioma, breast, colorectal, cervix, head and neck, and bladder carcinomas. Many studies using pemetrexed as a single Seminars in Oncology, Vol 29, No 6, Suppl 18 (December), 2002: pp 69-75
agent or in combination are currently ongoing or completed, including phase III trials in mesothelioma, NSCLC, and pancreatic cancer. This review will focus on available data and future prospects of pemetrexed in bladder, cervical, and head and neck cancers. PRECLINICAL FEATURES
The primary mechanism of action of pemetrexed consists of thymidylate synthase inhibition that results in a decrease in available thymidine necessary for DNA synthesis.5-7 In addition, pemetrexed potently inhibits dihydrofolate reductase, the primary target for methotrexate, and glycinamide ribonucleotide formyltransferase. Finally, it also inhibits, although to a lesser extent, aminoimidazole carboxamide formyltransferase, an enzyme that as glycinamide ribonucleotide formyltransferase is involved in the de novo purine biosynthesis. These targets are related to the cytotoxicity of pemetrexed because both thymidine and hypoxanthine are required to circumvent cellular death caused by pemetrexed.7 Pemetrexed is converted intracellularly to polyglutamated derivatives by folylpolyglutamate synthase. The polyglutamated forms of pemetrexed have much greater inhibitory activity against thymidylate synthase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide formyltransferase than the parent compound, whereas the inhibition of dihydrofolate reductase is not affected by polyglutamation. Glutamation increases cellular retention of the molecule, which translates into both a longer exposure time and increased intracellular concentrations of the drug.
From the Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain; and the Department of Medical Oncology, Clı´nico de Valencia University Hospital, Valencia, Spain. Drs Paz-Ares and Corte´s-Funes have received honoraria from Eli Lilly and Company. Address reprint requests to Luis Paz-Ares, MD, PhD, Servicio de Oncologı´a Me´dica, Hospital Universitario Doce de Octubre, Avenida de Co´rdoba Km 5,4, 28041 Madrid, Spain. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2906-1811$35.00/0 doi:10.1053/sonc.2002.37476 69
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Pemetrexed induces cell-cycle arrest in G1/S and cell death, which seems to be non–P53-mediated. Pemetrexed is cytotoxic against a number of cultured malignant cell lines including CCRFCEM leukemia, GC3/C1 colon carcinoma, and HCT-8 ileocecal carcinoma.5 In vitro activity has also been observed against human tumor colonyforming units obtained from patients with colon cancer, renal cancer, hepatoma, carcinoid tumor, and lung carcinoma.8 Consistent with its multitargeted mechanism of action, pemetrexed has significant activity in cell lines and xenografts resistant to methotrexate, 5-fluorouracil, and raltitrexed.5 CLINICAL DEVELOPMENT
The initial phase I program explored three treatment schedules of pemetrexed: daily ⫻ 5 every 3 weeks, weekly ⫻ 4 every 6 weeks, and once every 3 weeks.8-10 The predominant toxicity in all three trials was hematologic, particularly dose-limiting neutropenia. Other toxicities observed included asthenia, diarrhea, mucositis, cutaneous rash, and transient transaminase elevations. The once-every-3-weeks schedule was chosen for further investigation based on patient convenience considerations and the antitumor activity seen during the phase I trial, including partial responses (PRs) in two patients with pancreatic cancer and two with advanced colorectal cancer. Pemetrexed (500 to 600 mg/m2 every 3 weeks) has shown single-agent activity in multiple solid tumors including NSCLC, breast, colorectal, pancreatic, cervical, bladder, and head and neck cancers. Two trials in untreated NSCLC patients yielded a remarkable overall response rate (RR) of 16% and 23%, respectively.11,12 A third trial has been completed in previously treated NSCLC patients with a RR of 9%.13 Pemetrexed has also exhibited significant activity in colorectal cancer with a RR of 15% to 17% in untreated patients.14,15 Pemetrexed has been evaluated in advanced breast cancer in three trials as second- or third-line treatment and showed promising activity with an overall RR ranging from 19% to 28%.16-19A pooled toxicity analysis of 872 patients entered in phase II trials is presented in Table 1. As might be predicted given that pemetrexed is an antifolate, myelosuppression was the predominant side effect. Grade 3 to 4 neutropenia was observed in 50% of patients, although febrile neutropenia and neutropenic sepsis were uncommon. The in-
Table 1. Hematologic and Nonhematologic Toxicity in 872 Patients Treated in the Phase II Program of Pemetrexed (500 to 600 mg/m2 Every 3 Weeks)3 NCI-CTC Toxicity Grade (Highest Grade Per Patient, %)
ANC Hemoglobin Platelets Nausea Vomiting Stomatitis Diarrhea Alk Phos ALT AST Bilirubin Creatinine Cutaneous Fatigue Infection Pulmonary
1
2
3
4
10 31 22 28 15 20 15 32 39 47 ⬍1 11 19 16 7 2
17 37 8 22 20 12 8 9 21 20 9 3 27 19 6 4
23 14 8 7 3 3 3 3 12 8 6 ⬍1 5 6 3 2
27 3 7 ⬍1 2 ⬍1 2 0 ⬍1 ⬍1 2 0 2 ⬍1 2 2
Abbreviations: NCI-CTC, National Cancer Institute-Common Toxicity Criteria; ANC, absolute neutrophil count; Alk Phos, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase.
cidence of grade 3 to 4 thrombocytopenia and anemia were 15% and 17%, respectively. The most common nonhematologic toxicity was hepatic enzyme elevation (grade 1 to 2, 60% to 70%; grade 3, 12%), particularly of transaminases, which usually returned to baseline values by the time the following cycle was to be administered. A diffuse maculopapular rash with a predominantly truncal distribution was frequent and preventable with steroid premedication. Other toxicities, usually mild to moderate, include emesis, fatigue, mucositis, and diarrhea. A relationship between the patient⬘s folic acid status and the incidence of toxicity with other antifolates has been previously noted.20 Worzalla et al21 reported an improved tolerance to pemetrexed when given along with folic acid to mice bearing xenografts, while the antitumor activity was preserved. Niyikiza et al22 assessed the relationship between homocysteine and other vitamin metabolites, systemic exposure to pemetrexed, and patient toxicities. They showed that high baseline homocysteine levels, a surrogate marker of folate
PEMETREXED IN BLADDER, SCCHN, & CERVICAL CANCERS
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Table 2. Response Data in Phase II Trials of Single-Agent Pemetrexed (Without Vitamin Supplementation) in Advanced Bladder Cancer, Squamous Cell Carcinoma of the Head and Neck, and Uterine Cervix Carcinoma Disease Type Bladder Cancer24 Pemetrexed dose Included patients Evaluable patients (efficacy) Complete response (%) Partial response (%) Response rate, CR⫹PR (%) Stable disease (%) Progressive disease (%) Not assessed (%)
2
500 to 600 mg/m 31 28 — 9 (32%) 9 (32%) (95% CI: 16%–52%) 10 (36%) 6 (21%) 3 (11%)
SCCHN27 2
500 mg/m 35 34 — 9 (26%) 9 (26%) (95% CI: 13%–44%) 15 (44%) 8 (24%) 2 (6%)
Cervix Carcinoma31 600 mg/m2 28 24 — 5 (21%) 5 (21%) (95% CI: 7%–42%) 17 (71%) NA NA
Abbreviations: SCCHN, squamous cell carcinoma of the head and neck; CI, confidence interval; CR, complete response; PR, partial response
status, were closely related to an increased risk of severe neutropenia, thrombocytopenia, mucositis, and diarrhea. A subsequent phase I study explored combining pemetrexed and high-dose intermittent oral folic acid.23 Preliminary results have indicated that folic acid ameliorates toxicity, permitting dose escalations of pemetrexed up to 925 mg/m2 in heavily pretreated patients. Comparative toxicity analysis of patients treated in several nonrandomized trials with (78 patients) or without (246 patients) vitamin supplementation showed that the addition of folic acid and vitamin B12 substantially reduced the incidence of adverse events such as grade 4 neutropenia (2.6% v 32%), grade 4 thrombocytopenia (0% v 8%), grade 3 to 4 mucositis (1.3% v 5%), grade 3 to 4 diarrhea (2.6% v 6%), and toxic death (0% v 5%).3 Based on these data, a patient requirement for daily oral folic acid and vitamin B12 has been implemented in all pemetrexed studies in recent years. PEMETREXED IN BLADDER CANCER
The safety and efficacy of pemetrexed in patients with advanced bladder cancer was explored in a recently concluded phase II study in a chemotherapy-naive population (Table 2).24 Thirtythree patients (31 men and two women; median age, 65 years) with metastatic/recurrent inoperable bladder carcinoma, measurable disease, and World Health Organization performance status ⱕ2 were included. Two patients were ineligible because one had received prior chemotherapy and the other had low creatinine clearance. Treatment consisted
of pemetrexed 600 mg/m2 (first six patients) or 500 mg/m2 (remaining patients) administered as a 10-minute intravenous infusion every 21 days. No vitamin supplementation was given. A total of 114 cycles of pemetrexed were administered to 31 eligible patients. The median number of cycles per patient was three (range, one to 12 cycles). The 25 patients who were treated with pemetrexed 500 mg/m2 received a median of four cycles (range, one to nine cycles) and a median dose intensity of 483 mg/m2 every 3 weeks. The six patients who received pemetrexed at 600 mg/m2 received a median of two cycles (range, one to 12 cycles) and a median dose intensity of 577 mg/m2 every 3 weeks. Toxicity in this trial was significant and predominantly hematologic, including grade 3/4 thrombocytopenia (6%), anemia (23%), neutropenia (71%), and febrile neutropenia (26%). Nonhematologic toxicity consisted of mild to moderate mucositis, diarrhea, and lethargy. Three early deaths were observed because of sepsis and renal failure (one patient) or mucositis (one patient), and atrial fibrillation and cardiac failure (one patient). We speculate that two factors might have contributed to the toxicity in our trial compared with other phase II studies in solid tumors. First, patients with bladder cancer often have some degree of renal impairment associated with their disease state. This might have led to a decreased pemetrexed clearance and a subsequent increase in the incidence of certain toxicities such as neutropenia.8 Secondly, the nutritional status, in particular the folate status of patients in this study, may
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have been worse than in other cohorts. Many patients with bladder cancer in Spain have a history of heavy alcohol consumption. Furthermore, the typical diet in Spain does not include the vitamin-enriched breakfast cereals consumed in the United States. Twenty-eight patients who received at least two cycles of therapy were evaluable for efficacy according to protocol. Nine patients (32%; 95% confidence interval [CI]): 16% to 52%) achieved a PR. Ten patients (36%) had disease stabilization, and six (21%) had progressive disease. Tumor response was not evaluated in three patients (11%). Response rate on an intent-to-treat basis was 29% (95% CI: 14% to 48%). Responses were seen at all disease sites including liver, and were more frequent among patients with better PS (0 v 1 to 2; P ⫽ .013) and nonvisceral metastases (P ⫽ .01), but were not related to the starting dose of pemetrexed (500 mg/m2 v 600 mg/m2; P ⫽ .01). The antitumor activity observed in this trial is encouraging, and identifies pemetrexed as the only new drug active against urothelial bladder cancer since the studies showing the activity of gemcitabine, paclitaxel, and docetaxel.25 Median duration of response (8.0 months; 95% CI: 7.4 to 10.5 months) and overall survival (9.4 months; 95% CI: 5.7 to 12.8 months) compare favorably with most single agents in this setting, and are similar to those noted with novel combination regimens such as carboplatin/paclitaxel.26 These results are particularly appealing considering that all patients in our series had metastatic or relapsing disease and 61% had visceral metastases. Based on this study, a new single-agent pemetrexed trial, delivering 500 mg/m2 with vitamin supplementation, has been initiated in pretreated patients in several centers in the United States. In addition, considering the combination regimen data in other patient populations, doublets and triplets of pemetrexed with platinum compounds, gemcitabine, and other active agents such as taxanes merit further investigation. PEMETREXED IN HEAD AND NECK CANCER
The results of a phase II trial of pemetrexed in advanced head and neck cancer have been reported (Table 2).27 In this study, 35 patients (31 male, four female; median age, 53 years) with local or metastatic relapse of squamous cell carcinoma
of the head and neck (SCCHN) were treated with single-agent pemetrexed at 500 mg/m2 without vitamin supplementation. Among 34 evaluable patients, nine achieved a PR (26%; 95% CI: 13% to 44%). Stable disease was observed in 15 patients (44%), and disease progression in eight (24%). The two remaining patients were not assessed for response. The encouraging 26% RR observed in this trial is among the highest for a single agent in this patient population.28 Likewise the duration of response (median, 3.8 months) and overall survival (median, 6.4 months) are in the range seen with standard single-agent or combination chemotherapy regimens for recurrent SCCHN. These figures are particularly remarkable because 88.6% of patients in the trial by Pivot et al27 presented with distant metastases, and chemotherapy has been suggested to be more effective in locoregional relapse than in metastatic disease.29,30 Toxicity in this trial exceeded that observed in other patient populations treated with pemetrexed. Twenty-four patients (67%) experienced grade 3 to 4 neutropenia, four (11%) febrile neutropenia, 12 (33%) grade 3 to 4 anemia, and six (17%) grade 3 to 4 mucositis. Limited pharmacokinetic sampling was performed in cycles one and three in this and other pemetrexed studies. Plasma concentrations from SCCHN patients overlapped with those from patients with other cancer types, as did clearance estimates. Therefore, because systemic exposure in patients with SCCHN did not differ from patients with other cancer types, the investigators concluded that the encountered differences in safety were not caused by differences in pharmacokinetics. Alternatively, they hypothesized that the typically poor nutritional status of this subset of patients contributed to the increased incidence of side effects, in accordance with the observations linking toxicity and folate status. The promising activity of pemetrexed in this trial supports further evaluation of this drug in SCCHN. Confirmatory trials of single-agent pemetrexed with concomitant vitamin supplementation in patients with recurrent disease are particularly desirable, as they will give a definitive idea of the therapeutic index of the compound in this setting. In addition, combination regimens of pemetrexed with other active agents in head and neck cancer, particularly platinum analogs, should be explored.
PEMETREXED IN BLADDER, SCCHN, & CERVICAL CANCERS
PEMETREXED IN CERVICAL CARCINOMA
Goedhals and van Wijk have reported preliminary results of pemetrexed in advanced carcinoma of the cervix (Table 2). Twenty-eight females with International Federation of Gynecology and Obstetrics stage III or IV squamous cell carcinoma of the cervix were treated with pemetrexed 600 mg/m2; 24 patients were evaluable for efficacy and toxicity at the time of the report. Partial responses were observed in five patients (21%; 95% CI: 7% to 42%) lasting from 4 to 14⫹ months. Seventeen patients (71%) showed stable disease, including six patients with unconfirmed PRs withdrawn from the study because of decreased creatinine clearance. Toxicity in this trial was also significant and included grade 3 to 4 neutropenia (81%), grade 3 to 4 leukopenia (62%), grade 3 to 4 anemia (35%), and toxic death (4%). Twelve patients (50%) developed renal function impairment with creatinine clearance values that prevented further drug administration. The clinical benefit of pemetrexed was challenged by the compound⬘s toxicity in women with advanced cervical cancer in this trial.32 A second phase of this study evaluating a reduced pemetrexed dose (500 mg/m2) given with oral folic acid has been recently concluded. Pemetrexed should continue to be explored both as a single agent and in combination against cervical cancer. 31
PEMETREXED IN COMBINATION THERAPY
Clinical trials of pemetrexed in combination with platinum compounds, gemcitabine, irinotecan, taxanes, anthracyclines, and 5-fluorouracil have been initiated. Initial results are available for some regimens, but many studies are still ongoing. Tho¨dtmann et al33 performed a phase I trial of the combination of pemetrexed and cisplatin in which neutropenia and delayed fatigue were the observed dose-limiting toxicities. They recommended the following dose and schedule for future trials: pemetrexed 500 mg/m2 followed after a 30-minute wash-out period by cisplatin 75 mg/m2, repeated every 3 weeks. Eleven out of 40 evaluable patients showed an objective remission including one complete response. Interestingly, five of 11 patients with malignant mesothelioma obtained a PR. Based on these data, a large phase III trial comparing cisplatin with pemetrexed/cisplatin has
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been performed in patients with malignant mesothelioma, and the results will soon be available.34 The same combination has yielded a RR of 39% and 43% in two separate trials in advanced NSCLC.35,36 The predominant toxicity of the combination of pemetrexed and carboplatin is short-lived myelosuppression.37 Responses were observed in eight of 25 patients evaluated during a phase I trial in mesothelioma patients. From this study, the recommended dose for phase II trials is 500 mg/m2 pemetrexed and area under the concentrationtime curve of 5 mg/mL䡠min carboplatin, every 3 weeks. In another trial, the doublet pemetrexed/ oxaliplatin has been investigated.38 A phase I study of sequences of gemcitabine and pemetrexed has been recently completed.39 The recommended dose and schedule for this combination is gemcitabine 1,250 mg/m2 on days 1 and 8, and pemetrexed 500 mg/m2 on day 8, 90 minutes after gemcitabine, every 3 weeks. The most common toxicity was neutropenia; other toxicities included emesis, fatigue, and transaminase elevation. Encouragingly, responses were observed in 13 out of 35 treated patients with a variety of solid tumors. CONCLUSION
Pemetrexed is a new multitargeted antifolate that exhibits significant antitumor activity against a wide range of solid tumors, including NSCLC, mesothelioma, breast, and colorectal cancers, as well as in cervical, SCCHN, and bladder carcinomas. Toxicity, particularly hematologic, is higher in patients with the latter tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B12 appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies such as the recently completed trial performed in patients with malignant mesothelioma.34 REFERENCES 1. Messmann RA, Allegra CJ: Antifolates, in Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy (3rd
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ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 139-184 2. Farber S, Diamond LK, Mercer RD, et al: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 238:787-793, 1948 3. Hanauske A-R, Chen V, Paoletti P, et al: Pemetrexed disodium: A novel antifolate clinically active against multiple solid tumors. Oncologist 6:363-373, 2001 4. Curtin NJ, Hughes AN: Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncology 2:298-306, 2001 5. Shih C, Thornton DE: Preclinical pharmacology studies and the clinical development of a novel multitargeted antifolate, MTA (LY231514), in Jackman AL (ed): Antifolate Drugs in Cancer Therapy. Totawa, NJ, Humana Press, 1999, pp 183-201 6. Shih C, Chen VJ, Gossett LS, et al: LY231514, a pyrrolo (2,3-d) pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116-1123, 1997 7. Shih C, Habeck LL, Mendelsohn LG, et al: Multiple folate enzyme inhibition: Molecular mechanisms of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul 38:135-152, 1998 8. Rinaldi DA, Kuhn JG, Burris HA, et al: A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 44:372-380, 1999 9. McDonald AC, Vasey PA, Adams L, et al: A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 4:605-610, 1998 10. Rinaldi DA, Burris HA, Dorr FA, et al: Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 13:2842-2850, 1995 11. Rusthoven J, Eisenhauer E, Butts C, et al: Multitargeted antifolate, LY231514, as first-line chemotherapy for patients with advanced non–small-cell lung cancer: A phase II study. J Clin Oncol 17:1194-1199, 1999 12. Clarke SJ, Abratt R, Goedhals L, et al: Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non–small-cell lung cancer. Ann Oncol 13:737-741, 2002 13. Postmus P, Bunn P: Pemetrexed as a single agent in the therapy of advanced lung cancer. Semin Oncol 29:17-22, 2002 (suppl 5) 14. Cripps C, Burnell M, Jolivet J, et al: Phase II study of first-line LY231514 (multitargeted antifolate) in patients with locally advanced or metastatic colorectal cancer: An NCIC clinical trials group study. Ann Oncol 10:1175-1179, 1999 15. John W, Picus J, Blanke C, et al: Multitargeted antifolate (pemetrexed disodium, LY231514) activity in patients with advanced colorectal cancer results from a phase II study. Cancer 88:1807-1813, 2000 16. Miles DW, Smith IE, Coleman RE, et al. A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. Eur J Cancer 37:1366-1371, 2001 17. Llombart A, Llombart-Cussac A, Theodoulou M, et al: A phase II trial of pemetrexed disodium (ALIMTA, LY231514,
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MTA) in metastatic breast cancer (MBC) patients who have failed anthracyclines (A) and taxanes (T) (salvage chemotherapy). Breast Cancer Res Treat 64:A526, 2000 (abstr) 18. Theodoulou M, Llombart A, Cruciani G, et al: Pemetrexed disodium (pemetrexed; LY231514, MTA) in locally advanced or metastatic breast cancer (MBC) patients (pts) with prior anthracycline or anthracenedione and taxane treatment: Phase II study. Proc Am Soc Clin Oncol 19:130a, 2000 (abstr 506) 19. Spielmann M, Martin M, Namer M, et al: Activity of pemetrexed (pemetrexed, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: An interim analysis. Clin Breast Cancer 2:47-51, 2001 20. Morgan SL, Baggott JE, Vaughn WH, et al: The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33:9-18, 1990 21. Worzalla JF, Shih C, Schultz RM: Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res 18:3235-3240, 1998 22. Niyikiza C, Baker SD, Seitz DE: Homocysteine and methylmalonic acid: Markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 1:545-552, 2002 23. Hammond L, Villalona-Calero M, Eckhardt SG, et al: A phase I and pharmacokinetic (PK) study of the multitargeted antifolate (MTA, LY231514) with folic acid (FA). Ann Oncol 9:129, 1998 (suppl 4) (abstr 620) 24. Paz-Ares L, Tabernero J, Moyano A, et al: Significant activity of the multi-targeted antifolate MTA (LY231514) in advanced transitional cell carcinoma (TCC) of the bladder: Results of a phase III trial. Ann Oncol 9:61, 1998 (suppl 4) (abstr 292) 25. Paz-Ares LG, Smith MR: Genitourinary malignancies. Cancer Chemother Biol Res Modif 19:573-595, 2001 26. Small EJ, Lew D, Redman BG, et al: Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: The importance of survival as a clinical trial end point. J Clin Oncol 18:2537-2544, 2000 27. Pivot X, Raymond E, Laguerre B, et al: Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 85:649-655, 2001 28. Schantz SP, Harrison LB, Forastiere AA: Tumors of the nasal cavity and paranasal sinuses, nasopharnyx, oral cavity, and oropharnyx, in De Vita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology (6th ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 797-860 29. Recondo G, Armand JP, Tellez-Bernal E, et al: Recurrent and/or metastatic head and neck squamous cell carcinoma: A clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy. Laryngoscope 101: 494-501, 1991 30. Schornagel JH, Verweij J, de Mulder PH, et al: Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: A European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group Study. J Clin Oncol 13:1649-1655, 1995 31. Goedhals L, van Wijk AL: MTA (LY231514) in ad-
PEMETREXED IN BLADDER, SCCHN, & CERVICAL CANCERS
vanced carcinoma of the cervix. Ann Oncol 9:70, 1998 (suppl 4) (abstr 339) 32. Eifel PJ, Berek JS, Thigpen JT: Cancer of the cervix, vagina, and vulva, in De Vita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology (6th ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1526-1572 33. Tho¨dtmann R, Depenbrock H, Dumez H, et al: Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 17: 3009-3016, 1999 34. Vogelzang NJ, Rusthoven J, Paoletti P, et al: Phase III single-blinded study of pemetrexed ⫹ cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural mesothelioma. Proc Am Soc Clin Oncol 21:2a, 2002 (abstr 5) 35. Manegold C, Gatzemeier U, von Pawel J, et al: Frontline treatment of advanced non–small-cell cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: A multicenter phase II trial. Ann Oncol 11:435-440, 2000
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36. Shepherd FA, Dancey J, Arnold A, et al: Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced non–small cell lung carcinoma: A study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 92:595-600, 2001 37. Hughes A, Calvert P, Azzabi A, et al: Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 20:3533-3544, 2002 38. Misset J-L, Gamelin E, Campone M, et al: Pemetrexed/ oxaliplatin (LOHP) combination: Results of a phase I study in metastatic solid tumors. Proc Am Soc Clin Oncol 21:107a, 2002 (abstr 427) 39. Adjei AA, Erlichman C, Sloan JA, et al: Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors. J Clin Oncol 18:1748-1757, 2000
F
OLATE-DEPENDENT pathways have been pursued as key targets in the development of anticancer agents over the last few decades.1 The antifolates interfere with the binding of natural folate cofactors to important biosynthetic enzymes such as thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide formyltransferase. Inhibition of these enzymes results in impeded synthesis of the nucleotide precursors of DNA and RNA. In 1948, Farber et al2 first showed that aminopterin, a four-amino analog of folic acid, could inhibit the proliferation of leukemic cells and produce remissions in patients with acute leukemia. Their findings ushered in the era of antimetabolite chemotherapy and generated great interest in the antifolates. Several compounds of this class, such as methotrexate and raltitrexed, are now extensively used in the treatment of leukemias, lymphomas, choriocarcinoma, and head and neck, gastrointestinal, breast, cervical, and bladder carcinomas. Pemetrexed (ALIMTA, LY231514; Eli Lilly and Company, Indianapolis, IN) is a novel pyrrolo(2,3-d) pyrimidine-based multitargeted antifolate analog.3-5 Given its favorable preclinical profile, this agent has entered clinical trials and has shown encouraging activity in a wide range of tumors, including non–small cell lung cancer (NSCLC), malignant mesothelioma, breast, colorectal, cervix, head and neck, and bladder carcinomas. Many studies using pemetrexed as a single Seminars in Oncology, Vol 29, No 6, Suppl 18 (December), 2002: pp 69-75
agent or in combination are currently ongoing or completed, including phase III trials in mesothelioma, NSCLC, and pancreatic cancer. This review will focus on available data and future prospects of pemetrexed in bladder, cervical, and head and neck cancers. PRECLINICAL FEATURES
The primary mechanism of action of pemetrexed consists of thymidylate synthase inhibition that results in a decrease in available thymidine necessary for DNA synthesis.5-7 In addition, pemetrexed potently inhibits dihydrofolate reductase, the primary target for methotrexate, and glycinamide ribonucleotide formyltransferase. Finally, it also inhibits, although to a lesser extent, aminoimidazole carboxamide formyltransferase, an enzyme that as glycinamide ribonucleotide formyltransferase is involved in the de novo purine biosynthesis. These targets are related to the cytotoxicity of pemetrexed because both thymidine and hypoxanthine are required to circumvent cellular death caused by pemetrexed.7 Pemetrexed is converted intracellularly to polyglutamated derivatives by folylpolyglutamate synthase. The polyglutamated forms of pemetrexed have much greater inhibitory activity against thymidylate synthase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide formyltransferase than the parent compound, whereas the inhibition of dihydrofolate reductase is not affected by polyglutamation. Glutamation increases cellular retention of the molecule, which translates into both a longer exposure time and increased intracellular concentrations of the drug.
From the Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain; and the Department of Medical Oncology, Clı´nico de Valencia University Hospital, Valencia, Spain. Drs Paz-Ares and Corte´s-Funes have received honoraria from Eli Lilly and Company. Address reprint requests to Luis Paz-Ares, MD, PhD, Servicio de Oncologı´a Me´dica, Hospital Universitario Doce de Octubre, Avenida de Co´rdoba Km 5,4, 28041 Madrid, Spain. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2906-1811$35.00/0 doi:10.1053/sonc.2002.37476 69
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Pemetrexed induces cell-cycle arrest in G1/S and cell death, which seems to be non–P53-mediated. Pemetrexed is cytotoxic against a number of cultured malignant cell lines including CCRFCEM leukemia, GC3/C1 colon carcinoma, and HCT-8 ileocecal carcinoma.5 In vitro activity has also been observed against human tumor colonyforming units obtained from patients with colon cancer, renal cancer, hepatoma, carcinoid tumor, and lung carcinoma.8 Consistent with its multitargeted mechanism of action, pemetrexed has significant activity in cell lines and xenografts resistant to methotrexate, 5-fluorouracil, and raltitrexed.5 CLINICAL DEVELOPMENT
The initial phase I program explored three treatment schedules of pemetrexed: daily ⫻ 5 every 3 weeks, weekly ⫻ 4 every 6 weeks, and once every 3 weeks.8-10 The predominant toxicity in all three trials was hematologic, particularly dose-limiting neutropenia. Other toxicities observed included asthenia, diarrhea, mucositis, cutaneous rash, and transient transaminase elevations. The once-every-3-weeks schedule was chosen for further investigation based on patient convenience considerations and the antitumor activity seen during the phase I trial, including partial responses (PRs) in two patients with pancreatic cancer and two with advanced colorectal cancer. Pemetrexed (500 to 600 mg/m2 every 3 weeks) has shown single-agent activity in multiple solid tumors including NSCLC, breast, colorectal, pancreatic, cervical, bladder, and head and neck cancers. Two trials in untreated NSCLC patients yielded a remarkable overall response rate (RR) of 16% and 23%, respectively.11,12 A third trial has been completed in previously treated NSCLC patients with a RR of 9%.13 Pemetrexed has also exhibited significant activity in colorectal cancer with a RR of 15% to 17% in untreated patients.14,15 Pemetrexed has been evaluated in advanced breast cancer in three trials as second- or third-line treatment and showed promising activity with an overall RR ranging from 19% to 28%.16-19A pooled toxicity analysis of 872 patients entered in phase II trials is presented in Table 1. As might be predicted given that pemetrexed is an antifolate, myelosuppression was the predominant side effect. Grade 3 to 4 neutropenia was observed in 50% of patients, although febrile neutropenia and neutropenic sepsis were uncommon. The in-
Table 1. Hematologic and Nonhematologic Toxicity in 872 Patients Treated in the Phase II Program of Pemetrexed (500 to 600 mg/m2 Every 3 Weeks)3 NCI-CTC Toxicity Grade (Highest Grade Per Patient, %)
ANC Hemoglobin Platelets Nausea Vomiting Stomatitis Diarrhea Alk Phos ALT AST Bilirubin Creatinine Cutaneous Fatigue Infection Pulmonary
1
2
3
4
10 31 22 28 15 20 15 32 39 47 ⬍1 11 19 16 7 2
17 37 8 22 20 12 8 9 21 20 9 3 27 19 6 4
23 14 8 7 3 3 3 3 12 8 6 ⬍1 5 6 3 2
27 3 7 ⬍1 2 ⬍1 2 0 ⬍1 ⬍1 2 0 2 ⬍1 2 2
Abbreviations: NCI-CTC, National Cancer Institute-Common Toxicity Criteria; ANC, absolute neutrophil count; Alk Phos, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase.
cidence of grade 3 to 4 thrombocytopenia and anemia were 15% and 17%, respectively. The most common nonhematologic toxicity was hepatic enzyme elevation (grade 1 to 2, 60% to 70%; grade 3, 12%), particularly of transaminases, which usually returned to baseline values by the time the following cycle was to be administered. A diffuse maculopapular rash with a predominantly truncal distribution was frequent and preventable with steroid premedication. Other toxicities, usually mild to moderate, include emesis, fatigue, mucositis, and diarrhea. A relationship between the patient⬘s folic acid status and the incidence of toxicity with other antifolates has been previously noted.20 Worzalla et al21 reported an improved tolerance to pemetrexed when given along with folic acid to mice bearing xenografts, while the antitumor activity was preserved. Niyikiza et al22 assessed the relationship between homocysteine and other vitamin metabolites, systemic exposure to pemetrexed, and patient toxicities. They showed that high baseline homocysteine levels, a surrogate marker of folate
PEMETREXED IN BLADDER, SCCHN, & CERVICAL CANCERS
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Table 2. Response Data in Phase II Trials of Single-Agent Pemetrexed (Without Vitamin Supplementation) in Advanced Bladder Cancer, Squamous Cell Carcinoma of the Head and Neck, and Uterine Cervix Carcinoma Disease Type Bladder Cancer24 Pemetrexed dose Included patients Evaluable patients (efficacy) Complete response (%) Partial response (%) Response rate, CR⫹PR (%) Stable disease (%) Progressive disease (%) Not assessed (%)
2
500 to 600 mg/m 31 28 — 9 (32%) 9 (32%) (95% CI: 16%–52%) 10 (36%) 6 (21%) 3 (11%)
SCCHN27 2
500 mg/m 35 34 — 9 (26%) 9 (26%) (95% CI: 13%–44%) 15 (44%) 8 (24%) 2 (6%)
Cervix Carcinoma31 600 mg/m2 28 24 — 5 (21%) 5 (21%) (95% CI: 7%–42%) 17 (71%) NA NA
Abbreviations: SCCHN, squamous cell carcinoma of the head and neck; CI, confidence interval; CR, complete response; PR, partial response
status, were closely related to an increased risk of severe neutropenia, thrombocytopenia, mucositis, and diarrhea. A subsequent phase I study explored combining pemetrexed and high-dose intermittent oral folic acid.23 Preliminary results have indicated that folic acid ameliorates toxicity, permitting dose escalations of pemetrexed up to 925 mg/m2 in heavily pretreated patients. Comparative toxicity analysis of patients treated in several nonrandomized trials with (78 patients) or without (246 patients) vitamin supplementation showed that the addition of folic acid and vitamin B12 substantially reduced the incidence of adverse events such as grade 4 neutropenia (2.6% v 32%), grade 4 thrombocytopenia (0% v 8%), grade 3 to 4 mucositis (1.3% v 5%), grade 3 to 4 diarrhea (2.6% v 6%), and toxic death (0% v 5%).3 Based on these data, a patient requirement for daily oral folic acid and vitamin B12 has been implemented in all pemetrexed studies in recent years. PEMETREXED IN BLADDER CANCER
The safety and efficacy of pemetrexed in patients with advanced bladder cancer was explored in a recently concluded phase II study in a chemotherapy-naive population (Table 2).24 Thirtythree patients (31 men and two women; median age, 65 years) with metastatic/recurrent inoperable bladder carcinoma, measurable disease, and World Health Organization performance status ⱕ2 were included. Two patients were ineligible because one had received prior chemotherapy and the other had low creatinine clearance. Treatment consisted
of pemetrexed 600 mg/m2 (first six patients) or 500 mg/m2 (remaining patients) administered as a 10-minute intravenous infusion every 21 days. No vitamin supplementation was given. A total of 114 cycles of pemetrexed were administered to 31 eligible patients. The median number of cycles per patient was three (range, one to 12 cycles). The 25 patients who were treated with pemetrexed 500 mg/m2 received a median of four cycles (range, one to nine cycles) and a median dose intensity of 483 mg/m2 every 3 weeks. The six patients who received pemetrexed at 600 mg/m2 received a median of two cycles (range, one to 12 cycles) and a median dose intensity of 577 mg/m2 every 3 weeks. Toxicity in this trial was significant and predominantly hematologic, including grade 3/4 thrombocytopenia (6%), anemia (23%), neutropenia (71%), and febrile neutropenia (26%). Nonhematologic toxicity consisted of mild to moderate mucositis, diarrhea, and lethargy. Three early deaths were observed because of sepsis and renal failure (one patient) or mucositis (one patient), and atrial fibrillation and cardiac failure (one patient). We speculate that two factors might have contributed to the toxicity in our trial compared with other phase II studies in solid tumors. First, patients with bladder cancer often have some degree of renal impairment associated with their disease state. This might have led to a decreased pemetrexed clearance and a subsequent increase in the incidence of certain toxicities such as neutropenia.8 Secondly, the nutritional status, in particular the folate status of patients in this study, may
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have been worse than in other cohorts. Many patients with bladder cancer in Spain have a history of heavy alcohol consumption. Furthermore, the typical diet in Spain does not include the vitamin-enriched breakfast cereals consumed in the United States. Twenty-eight patients who received at least two cycles of therapy were evaluable for efficacy according to protocol. Nine patients (32%; 95% confidence interval [CI]): 16% to 52%) achieved a PR. Ten patients (36%) had disease stabilization, and six (21%) had progressive disease. Tumor response was not evaluated in three patients (11%). Response rate on an intent-to-treat basis was 29% (95% CI: 14% to 48%). Responses were seen at all disease sites including liver, and were more frequent among patients with better PS (0 v 1 to 2; P ⫽ .013) and nonvisceral metastases (P ⫽ .01), but were not related to the starting dose of pemetrexed (500 mg/m2 v 600 mg/m2; P ⫽ .01). The antitumor activity observed in this trial is encouraging, and identifies pemetrexed as the only new drug active against urothelial bladder cancer since the studies showing the activity of gemcitabine, paclitaxel, and docetaxel.25 Median duration of response (8.0 months; 95% CI: 7.4 to 10.5 months) and overall survival (9.4 months; 95% CI: 5.7 to 12.8 months) compare favorably with most single agents in this setting, and are similar to those noted with novel combination regimens such as carboplatin/paclitaxel.26 These results are particularly appealing considering that all patients in our series had metastatic or relapsing disease and 61% had visceral metastases. Based on this study, a new single-agent pemetrexed trial, delivering 500 mg/m2 with vitamin supplementation, has been initiated in pretreated patients in several centers in the United States. In addition, considering the combination regimen data in other patient populations, doublets and triplets of pemetrexed with platinum compounds, gemcitabine, and other active agents such as taxanes merit further investigation. PEMETREXED IN HEAD AND NECK CANCER
The results of a phase II trial of pemetrexed in advanced head and neck cancer have been reported (Table 2).27 In this study, 35 patients (31 male, four female; median age, 53 years) with local or metastatic relapse of squamous cell carcinoma
of the head and neck (SCCHN) were treated with single-agent pemetrexed at 500 mg/m2 without vitamin supplementation. Among 34 evaluable patients, nine achieved a PR (26%; 95% CI: 13% to 44%). Stable disease was observed in 15 patients (44%), and disease progression in eight (24%). The two remaining patients were not assessed for response. The encouraging 26% RR observed in this trial is among the highest for a single agent in this patient population.28 Likewise the duration of response (median, 3.8 months) and overall survival (median, 6.4 months) are in the range seen with standard single-agent or combination chemotherapy regimens for recurrent SCCHN. These figures are particularly remarkable because 88.6% of patients in the trial by Pivot et al27 presented with distant metastases, and chemotherapy has been suggested to be more effective in locoregional relapse than in metastatic disease.29,30 Toxicity in this trial exceeded that observed in other patient populations treated with pemetrexed. Twenty-four patients (67%) experienced grade 3 to 4 neutropenia, four (11%) febrile neutropenia, 12 (33%) grade 3 to 4 anemia, and six (17%) grade 3 to 4 mucositis. Limited pharmacokinetic sampling was performed in cycles one and three in this and other pemetrexed studies. Plasma concentrations from SCCHN patients overlapped with those from patients with other cancer types, as did clearance estimates. Therefore, because systemic exposure in patients with SCCHN did not differ from patients with other cancer types, the investigators concluded that the encountered differences in safety were not caused by differences in pharmacokinetics. Alternatively, they hypothesized that the typically poor nutritional status of this subset of patients contributed to the increased incidence of side effects, in accordance with the observations linking toxicity and folate status. The promising activity of pemetrexed in this trial supports further evaluation of this drug in SCCHN. Confirmatory trials of single-agent pemetrexed with concomitant vitamin supplementation in patients with recurrent disease are particularly desirable, as they will give a definitive idea of the therapeutic index of the compound in this setting. In addition, combination regimens of pemetrexed with other active agents in head and neck cancer, particularly platinum analogs, should be explored.
PEMETREXED IN BLADDER, SCCHN, & CERVICAL CANCERS
PEMETREXED IN CERVICAL CARCINOMA
Goedhals and van Wijk have reported preliminary results of pemetrexed in advanced carcinoma of the cervix (Table 2). Twenty-eight females with International Federation of Gynecology and Obstetrics stage III or IV squamous cell carcinoma of the cervix were treated with pemetrexed 600 mg/m2; 24 patients were evaluable for efficacy and toxicity at the time of the report. Partial responses were observed in five patients (21%; 95% CI: 7% to 42%) lasting from 4 to 14⫹ months. Seventeen patients (71%) showed stable disease, including six patients with unconfirmed PRs withdrawn from the study because of decreased creatinine clearance. Toxicity in this trial was also significant and included grade 3 to 4 neutropenia (81%), grade 3 to 4 leukopenia (62%), grade 3 to 4 anemia (35%), and toxic death (4%). Twelve patients (50%) developed renal function impairment with creatinine clearance values that prevented further drug administration. The clinical benefit of pemetrexed was challenged by the compound⬘s toxicity in women with advanced cervical cancer in this trial.32 A second phase of this study evaluating a reduced pemetrexed dose (500 mg/m2) given with oral folic acid has been recently concluded. Pemetrexed should continue to be explored both as a single agent and in combination against cervical cancer. 31
PEMETREXED IN COMBINATION THERAPY
Clinical trials of pemetrexed in combination with platinum compounds, gemcitabine, irinotecan, taxanes, anthracyclines, and 5-fluorouracil have been initiated. Initial results are available for some regimens, but many studies are still ongoing. Tho¨dtmann et al33 performed a phase I trial of the combination of pemetrexed and cisplatin in which neutropenia and delayed fatigue were the observed dose-limiting toxicities. They recommended the following dose and schedule for future trials: pemetrexed 500 mg/m2 followed after a 30-minute wash-out period by cisplatin 75 mg/m2, repeated every 3 weeks. Eleven out of 40 evaluable patients showed an objective remission including one complete response. Interestingly, five of 11 patients with malignant mesothelioma obtained a PR. Based on these data, a large phase III trial comparing cisplatin with pemetrexed/cisplatin has
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been performed in patients with malignant mesothelioma, and the results will soon be available.34 The same combination has yielded a RR of 39% and 43% in two separate trials in advanced NSCLC.35,36 The predominant toxicity of the combination of pemetrexed and carboplatin is short-lived myelosuppression.37 Responses were observed in eight of 25 patients evaluated during a phase I trial in mesothelioma patients. From this study, the recommended dose for phase II trials is 500 mg/m2 pemetrexed and area under the concentrationtime curve of 5 mg/mL䡠min carboplatin, every 3 weeks. In another trial, the doublet pemetrexed/ oxaliplatin has been investigated.38 A phase I study of sequences of gemcitabine and pemetrexed has been recently completed.39 The recommended dose and schedule for this combination is gemcitabine 1,250 mg/m2 on days 1 and 8, and pemetrexed 500 mg/m2 on day 8, 90 minutes after gemcitabine, every 3 weeks. The most common toxicity was neutropenia; other toxicities included emesis, fatigue, and transaminase elevation. Encouragingly, responses were observed in 13 out of 35 treated patients with a variety of solid tumors. CONCLUSION
Pemetrexed is a new multitargeted antifolate that exhibits significant antitumor activity against a wide range of solid tumors, including NSCLC, mesothelioma, breast, and colorectal cancers, as well as in cervical, SCCHN, and bladder carcinomas. Toxicity, particularly hematologic, is higher in patients with the latter tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B12 appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies such as the recently completed trial performed in patients with malignant mesothelioma.34 REFERENCES 1. Messmann RA, Allegra CJ: Antifolates, in Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy (3rd
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ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 139-184 2. Farber S, Diamond LK, Mercer RD, et al: Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 238:787-793, 1948 3. Hanauske A-R, Chen V, Paoletti P, et al: Pemetrexed disodium: A novel antifolate clinically active against multiple solid tumors. Oncologist 6:363-373, 2001 4. Curtin NJ, Hughes AN: Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncology 2:298-306, 2001 5. Shih C, Thornton DE: Preclinical pharmacology studies and the clinical development of a novel multitargeted antifolate, MTA (LY231514), in Jackman AL (ed): Antifolate Drugs in Cancer Therapy. Totawa, NJ, Humana Press, 1999, pp 183-201 6. Shih C, Chen VJ, Gossett LS, et al: LY231514, a pyrrolo (2,3-d) pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes. Cancer Res 57:1116-1123, 1997 7. Shih C, Habeck LL, Mendelsohn LG, et al: Multiple folate enzyme inhibition: Molecular mechanisms of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul 38:135-152, 1998 8. Rinaldi DA, Kuhn JG, Burris HA, et al: A phase I evaluation of multitargeted antifolate (MTA, LY231514), administered every 21 days, utilizing the modified continual reassessment method for dose escalation. Cancer Chemother Pharmacol 44:372-380, 1999 9. McDonald AC, Vasey PA, Adams L, et al: A phase I and pharmacokinetic study of LY231514, the multitargeted antifolate. Clin Cancer Res 4:605-610, 1998 10. Rinaldi DA, Burris HA, Dorr FA, et al: Initial phase I evaluation of the novel thymidylate synthase inhibitor, LY231514, using the modified continual reassessment method for dose escalation. J Clin Oncol 13:2842-2850, 1995 11. Rusthoven J, Eisenhauer E, Butts C, et al: Multitargeted antifolate, LY231514, as first-line chemotherapy for patients with advanced non–small-cell lung cancer: A phase II study. J Clin Oncol 17:1194-1199, 1999 12. Clarke SJ, Abratt R, Goedhals L, et al: Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non–small-cell lung cancer. Ann Oncol 13:737-741, 2002 13. Postmus P, Bunn P: Pemetrexed as a single agent in the therapy of advanced lung cancer. Semin Oncol 29:17-22, 2002 (suppl 5) 14. Cripps C, Burnell M, Jolivet J, et al: Phase II study of first-line LY231514 (multitargeted antifolate) in patients with locally advanced or metastatic colorectal cancer: An NCIC clinical trials group study. Ann Oncol 10:1175-1179, 1999 15. John W, Picus J, Blanke C, et al: Multitargeted antifolate (pemetrexed disodium, LY231514) activity in patients with advanced colorectal cancer results from a phase II study. Cancer 88:1807-1813, 2000 16. Miles DW, Smith IE, Coleman RE, et al. A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. Eur J Cancer 37:1366-1371, 2001 17. Llombart A, Llombart-Cussac A, Theodoulou M, et al: A phase II trial of pemetrexed disodium (ALIMTA, LY231514,
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MTA) in metastatic breast cancer (MBC) patients who have failed anthracyclines (A) and taxanes (T) (salvage chemotherapy). Breast Cancer Res Treat 64:A526, 2000 (abstr) 18. Theodoulou M, Llombart A, Cruciani G, et al: Pemetrexed disodium (pemetrexed; LY231514, MTA) in locally advanced or metastatic breast cancer (MBC) patients (pts) with prior anthracycline or anthracenedione and taxane treatment: Phase II study. Proc Am Soc Clin Oncol 19:130a, 2000 (abstr 506) 19. Spielmann M, Martin M, Namer M, et al: Activity of pemetrexed (pemetrexed, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: An interim analysis. Clin Breast Cancer 2:47-51, 2001 20. Morgan SL, Baggott JE, Vaughn WH, et al: The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33:9-18, 1990 21. Worzalla JF, Shih C, Schultz RM: Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res 18:3235-3240, 1998 22. Niyikiza C, Baker SD, Seitz DE: Homocysteine and methylmalonic acid: Markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 1:545-552, 2002 23. Hammond L, Villalona-Calero M, Eckhardt SG, et al: A phase I and pharmacokinetic (PK) study of the multitargeted antifolate (MTA, LY231514) with folic acid (FA). Ann Oncol 9:129, 1998 (suppl 4) (abstr 620) 24. Paz-Ares L, Tabernero J, Moyano A, et al: Significant activity of the multi-targeted antifolate MTA (LY231514) in advanced transitional cell carcinoma (TCC) of the bladder: Results of a phase III trial. Ann Oncol 9:61, 1998 (suppl 4) (abstr 292) 25. Paz-Ares LG, Smith MR: Genitourinary malignancies. Cancer Chemother Biol Res Modif 19:573-595, 2001 26. Small EJ, Lew D, Redman BG, et al: Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: The importance of survival as a clinical trial end point. J Clin Oncol 18:2537-2544, 2000 27. Pivot X, Raymond E, Laguerre B, et al: Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer 85:649-655, 2001 28. Schantz SP, Harrison LB, Forastiere AA: Tumors of the nasal cavity and paranasal sinuses, nasopharnyx, oral cavity, and oropharnyx, in De Vita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology (6th ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 797-860 29. Recondo G, Armand JP, Tellez-Bernal E, et al: Recurrent and/or metastatic head and neck squamous cell carcinoma: A clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy. Laryngoscope 101: 494-501, 1991 30. Schornagel JH, Verweij J, de Mulder PH, et al: Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: A European Organization for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group Study. J Clin Oncol 13:1649-1655, 1995 31. Goedhals L, van Wijk AL: MTA (LY231514) in ad-
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vanced carcinoma of the cervix. Ann Oncol 9:70, 1998 (suppl 4) (abstr 339) 32. Eifel PJ, Berek JS, Thigpen JT: Cancer of the cervix, vagina, and vulva, in De Vita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology (6th ed). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1526-1572 33. Tho¨dtmann R, Depenbrock H, Dumez H, et al: Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 17: 3009-3016, 1999 34. Vogelzang NJ, Rusthoven J, Paoletti P, et al: Phase III single-blinded study of pemetrexed ⫹ cisplatin vs. cisplatin alone in chemonaive patients with malignant pleural mesothelioma. Proc Am Soc Clin Oncol 21:2a, 2002 (abstr 5) 35. Manegold C, Gatzemeier U, von Pawel J, et al: Frontline treatment of advanced non–small-cell cancer with MTA (LY231514, pemetrexed disodium, ALIMTA) and cisplatin: A multicenter phase II trial. Ann Oncol 11:435-440, 2000
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36. Shepherd FA, Dancey J, Arnold A, et al: Phase II study of pemetrexed disodium, a multitargeted antifolate, and cisplatin as first-line therapy in patients with advanced non–small cell lung carcinoma: A study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 92:595-600, 2001 37. Hughes A, Calvert P, Azzabi A, et al: Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 20:3533-3544, 2002 38. Misset J-L, Gamelin E, Campone M, et al: Pemetrexed/ oxaliplatin (LOHP) combination: Results of a phase I study in metastatic solid tumors. Proc Am Soc Clin Oncol 21:107a, 2002 (abstr 427) 39. Adjei AA, Erlichman C, Sloan JA, et al: Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors. J Clin Oncol 18:1748-1757, 2000