Skip to main content
SpringerLink
Log in

Pemetrexed

  • Adis Drug Profile
  • Published:
American Journal of Cancer

Abstract

▴ Pemetrexed inhibits several folate-dependent enzymes, thereby inhibiting both thymidine synthesis and purine nucleotide synthesis.

▴ The median survival time of patients with NSCLC treated with pemetrexed 500 mg/m2 monotherapy every 21 days versus docetaxel 75 mg/m2 every 21 days in a second-line setting was 8.3 and 7.9 months (hazard ratio = 0.99, 95% CI 0.82-1.20, with a preset 95% CI upper limit of <1.11) in a phase III randomized, nonblind, multicenter trial (n = 571). In a phase III randomized, single-blind, multicenter trial (n = 448) in chemotherapy-naive patients with malignant pleural mesothelioma (MPM), pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 every 21 days was better in terms of median survival time (12.1 vs 9.3 months; hazard ratio 0.77, p < 0.05) and tumor response rates (41.3% vs 16.7%, p < 0.001) than cisplatin 75 mg/m2 every 21 days.

▴ During the MPM trial, a protocol change required all patients to receive supplementation with oral folic acid daily and intravenous cyanocobalamin once every 9 weeks (i.e. supplementation) because of pemetrexed toxicity.

▴ Pemetrexed was generally well tolerated as monotherapy in patients with advanced NSCLC and as combination therapy in patients with MPM if supplemented. In patients with NSCLC, neutropenia, alopecia, and fatigue were the most common adverse events, whereas in patients with MPM they were neutropenia, leukopenia, nausea, and vomiting. Severe toxicities in pemetrexed recipients in the NSCLC trial were infrequent.

Table. Features and properties of pemetrexed (Alimta®)

Pemetrexed

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Notes

  1. Use of the registered name is for identification purposes only and does not imply endorsement.

References

  1. World Health Organization. Global cancer rates could increase by 50% to 15 milllion by 2020 [online]. Available from URL: http://www.who.int [Accessed 2003 Aug 21]

  2. American Cancer Society. Cancer facts and figures 2003 [online]. Available from URL: http://www.cancer.org [Accessed 2003 Jul 11]

  3. European Society for Medical Oncology. ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol 2001; 12: 1049–50

    Article  Google Scholar 

  4. Bunn Jr PA. Incorporation of pemetrexed (Alimta) into the treatment of non-small cell lung cancer (thoracic tumors). Semin Oncol 2002 Jun; 29(3 Suppl. 9): 17–22

    Article  CAS  Google Scholar 

  5. Carbone M, Kratzke RA, Testa JR. The pathogenesis of mesothelioma. Semin Oncol 2002 Feb; 29(1): 2–17

    Article  PubMed  CAS  Google Scholar 

  6. Spiro SG, Porter JC. Lung cancer—where are we today? Current advances in staging and nonsurgical treatment. Am J Respir Crit Care Med 2002; 166: 1166–96

    Article  PubMed  Google Scholar 

  7. Sugarbaker DJ, Norberte JJ. Multimodality management of malignant pleural mesothelioma. Chest 1998; 113(1 Suppl.): 61S–5S

    Article  PubMed  CAS  Google Scholar 

  8. Sterman DH, Kaiser LR, Albelda SM. Advances in the treatment of malignant pleural mesothelioma. Chest 1999 Aug; 116(2): 504–20

    Article  PubMed  CAS  Google Scholar 

  9. Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardiothorac Surg 2002 Aug; 22(2): 298–305

    Article  PubMed  Google Scholar 

  10. National Cancer Institute. Non-small cell lung cancer (PDQ): treatment [online]. Available from URL: http://www.cancer.gov [Accessed 2003 Apr 3]

  11. Tomek S, Emri S, Krejcy K, et al. Chemotherapy for malignant pleural mesothelioma: past results and recent developments. Br J Cancer 2003 Jan 27; 88(2): 167–74

    Article  PubMed  CAS  Google Scholar 

  12. Socinski MA, Morris DE, Masters GA, et al. Chemotherapeutic management of stage IV non-small cell lung cancer. Chest 2003; 123(1 Suppl.): 226S–43S

    Article  PubMed  Google Scholar 

  13. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000 May; 18(10): 2095–103

    PubMed  CAS  Google Scholar 

  14. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 2000; 18(12): 2354–62

    PubMed  CAS  Google Scholar 

  15. Shih C, Habeck LL, Mendelsohn LG, et al. Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul 1998; 38: 135–52

    Article  PubMed  CAS  Google Scholar 

  16. 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 1997 Mar 15; 57(6): 1116–23

    PubMed  CAS  Google Scholar 

  17. 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 nonsmall cell lung carcinoma: a study of the National Cancer Institute of Canada Clinical Trials Group. Cancer 2001 Aug 1; 92(3): 595–600

    Article  PubMed  CAS  Google Scholar 

  18. Rusthoven JJ, 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 1999 Apr; 17(4): 1194–9

    PubMed  CAS  Google Scholar 

  19. Spielmann M, Martin M, Namer M, et al. Activity of MTA (multitargeted0 antifolate, LY231514) in metastatic breast cancer (MBC) patients previously treated with an anthracycline and a taxane [abstract no. 517]. Breast Cancer Res Treat 1999; 57: 123

    Google Scholar 

  20. Paz-Ares L, Tabemero 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 II trial [abstract no. 292]. Ann Oncol 1998; 9Suppl. 4: 61

    Google Scholar 

  21. Cripps MC, Burnell M, Jolivet J, et al. Phase II study of a multi-targeted antifolate (LY231514) (MTA) as first-line therapy in patients with locally advanced or metastatic colorectal cancer (MCC) [abstract no. 949]. Proc Am Soc Clin Oncol 1997 May; 16: 267a

    Google Scholar 

  22. Kindler HL, Dugan W, Hochster H, et al. Clinical outcome in patients (pts) with advanced pancreatic cancer treated with pemetrexed/gemcitabine [abstract no. 499]. Proc Am Soc Clin Oncol 2002 May; 21 (Pt 1): 125a

    Google Scholar 

  23. Celio L, Bajetta E, Ferrari L, et al. The multi-targeted antifolate premetrexed disodium (Alimta) with folic acid (FA) supplementation in advanced gastric cancer [abstract no. I4]. Ann Oncol 2001; 12Suppl. 4: 85

    Google Scholar 

  24. Chen VJ, Bewley JR, Smith PG, et al. An assessment of the antithymine and antipurine characteristics of MTA (LY231514) in CCRF-CEM cells. Adv Enzyme Regul 2000; 40: 143–54

    Article  PubMed  CAS  Google Scholar 

  25. Chen VJ, Bewley JR, Andis SL, et al. Preclinical cellular pharmacology of LY231514 (MTA): a comparison with methotrexate, LY309887 and raltitrexed for their effects on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Br J Cancer 1998; 78Suppl. 3: 27–34

    Article  PubMed  CAS  Google Scholar 

  26. Taylor EC, Kuhnt D, Shih C, et al. A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 1992; 35: 4450–4

    Article  PubMed  CAS  Google Scholar 

  27. Chen VJ, Bewley JR, Andis SL, et al. Cellular pharmacology of MTA: a correlation of MTA-induced cellular toxicity and in vitro enzyme inhibition with its effects on intracellular folate and nucleoside triphosphate pools in CCRF-CEM cells. Semin Oncol 1999 Apr; 26(2 Suppl. 6): 48–54

    PubMed  CAS  Google Scholar 

  28. Zhao R, Babani S, Gao F, et al. The mechanism of transport of the multitargeted antifolate (MTA) and its cross-resistance pattern in cells with markedly impaired transport of methotrexate. Clin Cancer Res 2000 Sep; 6(9): 3687–95

    PubMed  CAS  Google Scholar 

  29. Mendelsohn LG, Shih C, Chen VJ, et al. Enzyme inhibition, polyglutamation, and the effect of LY231514 (MTA) on purine biosynthesis. Semin Oncol 1999 Apr; 26(2 Suppl. 6): 42–7

    PubMed  CAS  Google Scholar 

  30. Schultz RM, Chen VJ, Bewley JR, et al. Biological activity of the multitargeted antifolate, MTA (LY231514), in human cell lines with different resistance mechanisms to antifolate drugs. Semin Oncol 1999 Apr; 26(2 Suppl. 6): 68–73

    PubMed  CAS  Google Scholar 

  31. Smith PG, Marshman E, Calvert AH, et al. Prevention of thymidine and hypoxan-thine rescue from MTA (LY231514) growth inhibition by dipyridamole in human lung cancer cell lines. Semin Oncol 1999 Apr; 26(2 Suppl. 6): 63–7

    PubMed  CAS  Google Scholar 

  32. Schultz RM, Patel VF, Worzalla JF, et al. Role of thymidylate synthase in the antitumor activity of the multitargeted antifolate, LY231514. Anticancer Res 1999; 19(1A): 437–44

    PubMed  CAS  Google Scholar 

  33. Rose MG, Farrell MP, Schmitz JC. Thymidylate synthase: a critical target for cancer chemotherapy. Clin Colorectal Cancer 2002 Feb; 1(4): 220–9

    Article  PubMed  CAS  Google Scholar 

  34. Mendelsohn LG, Shih C, Schultz RM, et al. Biochemistry and pharmacology of glycinamide ribonucleotide formyltransferase inhibitors: LY309887 and lometrexol. Invest New Drugs 1996; 14(3): 287–94

    Article  PubMed  CAS  Google Scholar 

  35. Britten CD, Izbicka E, Hilsenbeck S, et al. Activity of the multitargeted antifolate LY231514 in the human tumor cloning assay. Cancer Chemother Pharmacol 1999; 44(2): 105–10

    Article  PubMed  CAS  Google Scholar 

  36. van der Wilt CL, Backus HHJ, Smid K, et al. Modulation of both endogenous folates and thymidine enhance the therapeutic efficacy of thymidylate synthase inhibitors. Cancer Res 2001 May 1; 61(9): 3675–81

    PubMed  Google Scholar 

  37. Worzalla JF, Shih C, Schultz RM. Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res 1998; 18(5A): 3235–40

    PubMed  CAS  Google Scholar 

  38. Backus HHJ, Pinedo HM, Wouters D, et al. Folate depletion increases sensitivity of solid tumor cell lines to 5-fluorouracil and antifolates. Int J Cancer 2000; 87(6): 771–8

    Article  PubMed  CAS  Google Scholar 

  39. Backus HHJ, Wouters D, van der Wilt CL, et al. Thymidylate synthase inhibition induces p53 dependent and independent cell death. Adv Exp Med Biol 2000; 486: 303–6

    Article  PubMed  CAS  Google Scholar 

  40. Lu X, Errington J, Curtin NJ, et al. The impact of p53 status on cellular sensitivity to antifolate drugs. Clin Cancer Res 2001 Jul; 7(7): 2114–23

    PubMed  CAS  Google Scholar 

  41. Tonkinson JL, Marder P, Andis SL, et al. Cell cycle effects of antifolate antimetabolites: implications for cytotoxicity and cytostasis. Cancer Chemother Pharmacol 1997; 39(6): 521–31

    Article  PubMed  CAS  Google Scholar 

  42. 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 2000 Apr; 18(8): 1748–57

    PubMed  CAS  Google Scholar 

  43. Dempsey JA, Schultz RM. Interaction between the multitargeted antifolate (MTA, LY231514) and doxorubicin in ZR-75-1 human breast carcinoma cells [abstract no. 3894]. 90th Annu Meet Am Assoc Cancer Res 1999; 40: 590

    Google Scholar 

  44. Tonkinson JL, Worzalla JF, Teng CH, et al. Cell cycle modulation by a multitarged antifolate, LY231514, increases the cytotoxicity and antitumor activity of gemcitabine in HT29 colon carcinoma. Cancer Res 1999 Aug; 59: 3671–6

    PubMed  CAS  Google Scholar 

  45. Teicher BA, Chen V, Shih C, et al. Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts. Clin Cancer Res 2000 Mar; 6(3): 1016–23

    PubMed  CAS  Google Scholar 

  46. Bischof M, Weber KJ, Blatter J, et al. Interaction of pemetrexed disodium (Alimta, multitargeted antifolate) and irradiation in vitro. Int J Radiat Oncol Biol Phys 2002 Apr; 52(5): 1381–8

    Article  PubMed  CAS  Google Scholar 

  47. Mauritz R, Peters GJ, Priest DG, et al. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem Pharmacol 2002 Jan 15; 63(2): 105–15

    Article  PubMed  CAS  Google Scholar 

  48. Rhee MS, Ryan TJ, Galivan J. Glutamyl hydrolase and the multitargeted antifolate LY231514. Cancer Chemother Pharmacol 1999; 44(5): 427–32

    Article  PubMed  CAS  Google Scholar 

  49. 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 2002 Aug 15; 20(16): 3533–44

    Article  PubMed  CAS  Google Scholar 

  50. Thödtmann R, Depenbrock H, Dumez H, et al. Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. J Clin Oncol 1999 Oct; 17(10): 3009–16

    PubMed  Google Scholar 

  51. 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 1999; 44(5): 372–80

    Article  PubMed  CAS  Google Scholar 

  52. Sweeney C, Baker S, Murry D, et al. Pharmacokinetic (PK) and pharmacodynamic analysis of aspirin administered with multi-targeted antifolate (ALIMTA) [abstract no. 104]. Eur J Cancer 2001 Oct; 37Suppl. 6: 31

    Article  Google Scholar 

  53. Takimoto CH, Forero L, Baker SD, et al. Phase I and pharmacokinetic study of LY231514 (pemetrexed disodium, MTA) in renal dysfunction patients [abstract no. 41PD]. Ann Oncol 2002 Oct; 13Suppl. 5: 12

    Google Scholar 

  54. Woodland JM, Barnett CJ, Dorman DE, et al. Metabolism and disposition of the antifolate LY231514 in mice and dogs. Drug Metab Dispos 1997 Jun; 25(6): 693–700

    PubMed  CAS  Google Scholar 

  55. Smit EF, Mattson K, von Pawel J, et al. ALIMTA (pemetrexed disodium) as second-line treatment of non-small-cell lung cancer: a phase II study. Ann Oncol 2003; 14: 455–60

    Article  PubMed  CAS  Google Scholar 

  56. Shepherd FA, Pereira JR, Von Pawel J, et al. A phase III study of pemetrexed vs. docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) who were previously treated with chemotherapy, [abstract no. PL-5] Lung Cancer 2003; 41Suppl. 2: S4. Plus oral presentation at the 10th World Lung Cancer Conference of the International Association for the Study of Lung Cancer; 2003 Aug 10-14; Vancouver

    Article  Google Scholar 

  57. Data on file, Eli Lilly and Company, 2003

  58. Gralla R, Hollen P, Liepa A, et al. Health-related quality of life of patients with malignant pleural mesothelioma treated with pemetrexed disodium [abstract no. 1039]. Eur J Cancer 2001 Oct; 37Suppl. 6: S282

    Article  Google Scholar 

  59. Scagliotti G, Shin D, Kindler H, et al. Lung function (LF) and respiratory symptoms (RS) before and after treatment with pemetrexed (Alimta) in patients with malignant pleural mesothelioma [abstract]. Am J Respir Crit Care Med 2002 Apr; 165 (8 Pt 2): A32

    Google Scholar 

  60. Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 2003 Apr; 21(8): 1556–61

    Article  PubMed  CAS  Google Scholar 

  61. Liepa A, Rusthoven JJ, Denham C, et al. Clinical benefit algorithm for malignant pleural mesothelioma: results from randomized trial of pemetrexed plus cisplatin vs. cisplatin [abstract no. 475PD]. Ann Oncol 2002 Oct; 13Suppl. 5: 129–130

    Google Scholar 

  62. Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant pleural mesothelioma: results of the randomized pemetrexed + cisplatin vs. cisplatin trial using the LCSS-meso instrument [abstract no. 2496]. Proc Am Soc Clin Oncol 2003; 22: 621. Plus oral presentation at the 39th Annual Meeting of the American Society of Clinical Oncology; 2003 May 31-Jun 3; Chicago

    Google Scholar 

  63. Symanowski JT, Rusthoven J, Nguyen B, et al. Multiple regression analysis of prognostic variables for survival from the phase III study of pemetrexed + cisplatin vs. cisplatin in malignant pleural mesotheliomia [abstract no. 2602]. Proc Am Soc Clin Oncol 2003; 22: 647

    Google Scholar 

  64. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003 Jul 15; 21(14): 2636–44

    Article  PubMed  CAS  Google Scholar 

  65. Hollen PJ, Gralla RJ, Liepa AM, et al. Validation of a quality of life instrument for patients with pleural mesothelioma: lung cancer symptom scale (LCSS) [abstract no. 1579]. Proc Am Soc Clin Oncol 2001; 20 (Pt 1): 396a

    Google Scholar 

  66. Niyikiza C, Baker SD, Seitz DE, et al. Homocysteine and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy. Mol Cancer Ther 2002 May; 1(7): 545–52

    PubMed  CAS  Google Scholar 

  67. Niyikiza C, Hanauske AR, Rusthoven JJ, et al. Pemetrexed safety and dosing strategy. Semin Oncol 2002 Dec; 29(6 Suppl. 18): 24–9

    PubMed  Google Scholar 

  68. Data on file, Eli Lilly and Company, 2003

  69. Eli Lilly and Company, US Food & Drug Administration. Lilly given OK to make Alimta (pemetrexed) available on expanded access basis [online]. Available from URL: http://newsroom.lilly.com [Accessed 2002 Dec 31]

Download references

Author information

Authors and Affiliations

  1. Adis International Inc., 770 Township Line Road, Suite 300, Yardley, PA, 19067, USA

    Tracy Swainston Harrison & Lesley J. Scott

Authors
  1. Tracy Swainston Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lesley J. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tracy Swainston Harrison.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harrison, T.S., Scott, L.J. Pemetrexed. Am J Cancer 2, 359–370 (2003). https://doi.org/10.2165/00024669-200302050-00009

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00024669-200302050-00009

Keywords

Search

Navigation