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AntifolatesIn useSyntheticNeeds review

Pemetrexed

Also known as Alimta, LY231514

A multitargeted folate analogue given by intravenous infusion. Its 2023 US label lists non-squamous non-small-cell lung cancer and malignant pleural mesothelioma.

From discovery to approval

  1. 1992 · First described

    A 1992 J Med Chem paper described a pyrrolo[2,3-d]pyrimidine dideazatetrahydrofolate analogue lacking a chiral centre at C-6, acting mainly at thymidylate synthase. Its chemical name matches pemetrexed's in the US label apart from tautomer notation; no source read states that it was the first description of pemetrexed.[2][3][1]

  2. 2004-02-04 · FDA regular · 12 years after first description

    Treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery (the letter's wording; the letter does not mention cisplatin). The letter contains no accelerated-approval wording; type "regular" is an inference from that.[4]

  3. 2004-09-20 · EMA regular · 12 years after first description

    In combination with cisplatin, treatment of chemotherapy-naive patients with unresectable malignant pleural mesothelioma (the EPAR wording for this indication; the 2004 EPAR scientific discussion also covers non-small cell lung cancer, as monotherapy after prior chemotherapy). The EMA documents contain no conditional or exceptional-circumstances wording; type "regular" is an inference from that.[5]

How it works

In laboratory studies it inhibits three folate-dependent enzymes involved in making thymidine and purine nucleotides: thymidylate synthase, dihydrofolate reductase and GARFT. Inside cells it is converted to retained polyglutamate forms.[1]

Where it came from and why

The 1992 abstract calls the compound a promising candidate for clinical evaluation. A 1998 review later described inhibition of several folate enzymes, which it said challenged the single-target approach to antifolate design.

Cancers

  • Malignant pleural mesothelioma

    In a phase III trial of 456 chemotherapy-naive patients, pemetrexed with cisplatin gave median survival of 12.1 months against 9.3 months for cisplatin alone (P = .020). The first FDA approval, in February 2004, was for this disease.[6]

  • Non-squamous non-small-cell lung cancer

    In a non-inferiority phase III trial of 1,725 patients, cisplatin with pemetrexed matched cisplatin with gemcitabine for overall survival (hazard ratio 0.94; 95% CI 0.84 to 1.05); the 2023 label lists non-squamous disease and says it is not indicated for squamous cell histology.[7]

Worth knowing

  • In the mesothelioma phase III trial, folic acid and vitamin B12 were added after 117 patients had enrolled, and the authors report that this significantly reduced toxicity without adversely affecting survival.[6]
  • In the 1,725-patient lung cancer trial, overall survival with cisplatin and pemetrexed was higher in adenocarcinoma (12.6 v 10.9 months) and large-cell carcinoma (10.4 v 6.7 months) but lower in squamous histology (9.4 v 10.8 months) than with cisplatin and gemcitabine; the authors call it the first prospective phase III study in NSCLC to show survival differences by histology.[7]
  • The 2023 US label recommends folic acid and vitamin B12 supplementation and dexamethasone premedication, and lists use in combination with pembrolizumab and platinum chemotherapy for metastatic non-squamous NSCLC; it gives 2004 as the year of initial US approval.[1]
  • The FDA's February 2004 letter approved pemetrexed for unresectable malignant pleural mesothelioma. Later indications are not listed in the approval records.[4]
  • The 2004 EMA scientific discussion records the CHMP's conclusion that the balance of benefit and risk was favourable for pemetrexed with cisplatin in chemotherapy-naive patients with unresectable malignant pleural mesothelioma and for monotherapy in locally advanced or metastatic non-small-cell lung cancer after prior chemotherapy. The EMA page gives 20 September 2004 as the date the authorisation was issued.[8]

On this site

References

  1. Eli Lilly and Company. Alimta (pemetrexed): prescribing information. DailyMed, set ID f5a860f3-37ec-429c-ae04-9c88d7c55c08, published 28 June 2023. Read 26 October 2026. Source
  2. Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, 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(23):4450-4. PubMedDOI
  3. Shih C, Habeck LL, Mendelsohn LG, Chen VJ, Schultz RM. Multiple folate enzyme inhibition: mechanism of a novel pyrrolopyrimidine-based antifolate LY231514 (MTA). Adv Enzyme Regul. 1998;38:135-52. PubMedDOI
  4. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Approval letter, NDA 21-462, Alimta (pemetrexed, LY231514), Eli Lilly and Company; electronic signature dated 4 February 2004 (scanned letter, read as page images). Source
  5. European Medicines Agency. Alimta (pemetrexed): European public assessment report page (authorised indication; marketing authorisation date printed as 20/09/2004; page last updated 18/08/2026). Read 25 October 2026. Source
  6. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636-44. PubMedDOI
  7. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-51. PubMedDOI
  8. European Medicines Agency (EMEA), CHMP. Alimta: EPAR scientific discussion, initial approval (2004). Study JMCH ('EMPHACIS'), malignant pleural mesothelioma. Source