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Pemetrexed

Pemetrexed is a synthetic antifolate chemotherapy agent that functions as a folate analog metabolic inhibitor, targeting enzymes essential for DNA and RNA synthesis in rapidly dividing cancer cells.^[1] It is administered intravenously and is indicated for the treatment of unresectable malignant pleural mesothelioma in combination with cisplatin or with pembrolizumab and platinum chemotherapy, as well as for locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) either in combination with cisplatin, carboplatin, pembrolizumab plus platinum chemotherapy, or amivantamab plus carboplatin (for EGFR exon 20 insertion mutations), or as a single-agent maintenance therapy following initial treatment.^[2]^[3]^[4] Sold under brand names such as Alimta and Pemfexy, pemetrexed requires premedication with folic acid, vitamin B12, and corticosteroids to mitigate severe toxicities like myelosuppression and gastrointestinal effects.^[2] The mechanism of action of pemetrexed involves its transport into cells via the reduced folate carrier and subsequent intracellular conversion to polyglutamate forms, which potently inhibit multiple folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT).^[1] This multitargeted inhibition disrupts the synthesis of nucleotides required for cell replication, leading to cytotoxicity particularly in tumors with high proliferation rates, such as those in NSCLC and mesothelioma.^[5] Unlike earlier antifolates like methotrexate, pemetrexed's broad enzymatic inhibition and favorable polyglutamation contribute to its efficacy across various solid tumors, though it is not indicated for squamous NSCLC due to increased toxicity without clinical benefit.^[2] Developed through a collaboration between Princeton University researcher E.C. (Ted) Taylor and Eli Lilly and Company chemists led by Chuan (Joe) Shih, pemetrexed (initially coded as LY231514) emerged from 1980s research on antifolates like lometrexol, aiming to overcome resistance mechanisms in cancer therapies.^[5] It received its initial U.S. Food and Drug Administration (FDA) approval in February 2004 for malignant pleural mesothelioma based on phase III trial data showing improved survival when combined with cisplatin.^[6] Subsequent approvals expanded its use: in 2004 for second-line NSCLC treatment, in 2008 for first-line NSCLC with cisplatin, in 2009 for maintenance therapy, and further in 2017–2018 for combinations with pembrolizumab, in 2024 for combination with amivantamab in specific NSCLC subsets, and in September 2024 for first-line mesothelioma with pembrolizumab and platinum, reflecting ongoing clinical advancements in targeted chemotherapy regimens.^[6]^[3]^[4] As of 2022, generic formulations are available, broadening access while maintaining the drug's role as a cornerstone in non-squamous lung cancer management.^[2]

Medical uses

Indications

Pemetrexed is indicated in combination with cisplatin for the initial treatment of unresectable malignant pleural mesothelioma in adults.^[7] It is also indicated in combination with pembrolizumab and platinum chemotherapy (cisplatin or carboplatin) as first-line treatment for adult patients with unresectable advanced or metastatic malignant pleural mesothelioma.^[4] This approval stems from a phase III randomized trial demonstrating superior median overall survival of 12.1 months with pemetrexed plus cisplatin compared to 9.3 months with cisplatin alone, alongside improvements in time to progression and response rates.^[8] For non-small cell lung cancer (NSCLC), pemetrexed is indicated in combination with cisplatin or carboplatin as first-line therapy for locally advanced or metastatic nonsquamous NSCLC.^[7] It is also indicated in combination with pembrolizumab and platinum chemotherapy for the initial treatment of patients with metastatic nonsquamous NSCLC without EGFR or ALK genomic tumor aberrations.^[9] It is approved as single-agent maintenance therapy for locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed following four cycles of platinum-based chemotherapy.^[7] Supporting evidence includes the phase III JMEN trial, which showed switch maintenance with pemetrexed after non-pemetrexed platinum doublet induction improved median progression-free survival (4.3 months vs. 2.6 months) and overall survival (13.4 months vs. 10.6 months) compared to placebo.^[10] Similarly, the phase III PARAMOUNT trial demonstrated that continuation maintenance with pemetrexed after pemetrexed plus cisplatin induction extended median progression-free survival (4.1 months vs. 2.8 months) and overall survival (13.9 months vs. 11.0 months) versus placebo.^[11] Additionally, pemetrexed is indicated as monotherapy for the second-line treatment of recurrent or metastatic nonsquamous NSCLC after prior chemotherapy.^[7] Patient selection prioritizes nonsquamous histology, as subgroup analyses from trials like JMEN revealed no survival benefit in squamous NSCLC, leading to explicit limitations against its use in that subtype.^[7]

Administration and dosage

Pemetrexed is administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.^[9] The standard dose is 500 mg/m² body surface area for all approved indications, including malignant pleural mesothelioma and non-squamous non-small cell lung cancer (NSCLC).^[9] For malignant pleural mesothelioma, pemetrexed 500 mg/m² is given in combination with cisplatin 75 mg/m² intravenously on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity.^[9] Alternatively, for unresectable advanced or metastatic disease, pemetrexed 500 mg/m² may be combined with pembrolizumab 200 mg and platinum chemotherapy (cisplatin 75 mg/m² or carboplatin AUC 5-6 mg/mL/min) every 21 days for up to 6 cycles, followed by pembrolizumab 200 mg every 3 weeks as maintenance until disease progression, unacceptable toxicity, or up to 24 months.^[4] In first-line treatment of locally advanced or metastatic non-squamous NSCLC, the same pemetrexed dose is administered with cisplatin 75 mg/m² for up to six cycles in the absence of disease progression or unacceptable toxicity; alternatively, it may be combined with pembrolizumab and a platinum agent (cisplatin or carboplatin) for four cycles followed by maintenance therapy.^[9] For maintenance treatment of non-squamous NSCLC, pemetrexed 500 mg/m² is used as a single agent every 21 days after four cycles of platinum-based chemotherapy, continuing until progression or toxicity.^[9] In recurrent non-squamous NSCLC, single-agent pemetrexed 500 mg/m² is administered every 21 days until progression or toxicity.^[9] Dosage adjustments are required for renal impairment; pemetrexed is contraindicated in patients with creatinine clearance less than 45 mL/min (calculated using the Cockcroft-Gault equation), and no dose reduction is recommended for clearances between 45 mL/min and 79 mL/min.^[9] Premedication with corticosteroids, such as dexamethasone 4 mg orally twice daily for three consecutive days (beginning the day before each pemetrexed administration), is recommended to reduce the incidence and severity of cutaneous reactions.^[9] Standard antiemetics should be administered prior to pemetrexed infusion to manage potential nausea and vomiting.^[9]

Supplementation requirements

Pemetrexed inhibits multiple folate-dependent enzymes, resulting in depletion of intracellular folate pools and accumulation of toxic metabolites like homocysteine, which contribute to severe toxicities including myelosuppression and gastrointestinal disturbances.^[12] Supplementation with folic acid and vitamin B12 mitigates these effects by replenishing folate stores and supporting methylation pathways, thereby reducing the incidence and severity of life-threatening adverse events without interfering with pemetrexed's antitumor efficacy. This approach was incorporated into standard protocols following early clinical observations of excessive toxicity in unsupplemented patients.^[8] The recommended supplementation protocol requires patients to begin oral folic acid at 400 to 1000 mcg daily, ideally 7 days prior to the first pemetrexed dose (with at least 5 doses administered), and continue daily through the full course of therapy and for 21 days after the final dose.^[12] Concurrently, vitamin B12 is given as a 1000 mcg intramuscular injection within the week before the initial pemetrexed administration, with subsequent doses every 9 weeks; injections may coincide with treatment days.^[12] These measures are mandatory for all patients receiving pemetrexed to optimize tolerability.^[13] Clinical trials have shown that this regimen substantially lowers severe toxicity rates; for instance, in a phase II study of malignant pleural mesothelioma, grade 3/4 neutropenia decreased from 52% in unsupplemented patients to 23% with supplementation, representing a roughly 50% reduction, alongside similar improvements in leukopenia and overall myelosuppression. A phase III trial confirmed these benefits, with post-supplementation toxicity profiles showing 50-80% reductions in severe hematologic and gastrointestinal events compared to earlier unsupplemented cohorts, while maintaining response rates and survival outcomes.^[8] To verify adherence and detect early issues, baseline complete blood counts are required, followed by periodic monitoring throughout therapy.^[12]

Adverse effects

Common adverse effects

Pemetrexed therapy is associated with a range of common adverse effects, primarily affecting hematologic, gastrointestinal, and general systems, as observed in clinical trials involving patients with non-small cell lung cancer and malignant pleural mesothelioma. These effects are generally manageable with supportive care and are less severe when folic acid and vitamin B12 supplementation is administered prior to and during treatment. In pivotal trials, approximately 20-30% of patients experienced grade 3 or 4 events overall, though most adverse effects were mild to moderate.^[7] Hematologic effects are among the most frequent, including anemia (all grades: 15-33%; grade 3/4: 3-6%), neutropenia (all grades: 6-56%; grade 3/4: 3-23%), and thrombocytopenia (all grades: 8-23%; grade 3/4: 2-5%). These toxicities arise due to pemetrexed's interference with folate-dependent processes in rapidly dividing cells, but their incidence is notably reduced with vitamin supplementation.^[7] Gastrointestinal effects commonly include nausea (all grades: 12-82%; grade 3/4: 0.3-12%), vomiting (all grades: 6-57%; grade 3/4: 0-11%), diarrhea (all grades: 5-17%; grade 3/4: 0-4%), and mucositis or stomatitis (all grades: 5-23%; grade 3/4: 0.3-3%). These symptoms often respond to antiemetics and oral hygiene measures.^[7] Other common effects encompass fatigue (all grades: 18-48%; grade 3/4: 4.5-10%), rash or desquamation (all grades: 7-16%; grade 3/4: 0-1%), and elevations in liver enzymes such as ALT (all grades: 8-10%; grade 3/4: 0-2%) and AST (all grades: 7-8%; grade 3/4: 0-1%). Fatigue is often dose-related and improves with rest, while rash may be mitigated by dexamethasone premedication. Liver enzyme elevations are typically asymptomatic and transient.^[7] Management of these adverse effects involves monitoring complete blood counts and renal function, with dose delays or reductions recommended for grade 2 or higher toxicities to prevent escalation. Supportive interventions, such as growth factors for neutropenia or hydration for gastrointestinal symptoms, further aid in maintaining treatment continuity.^[7]

Serious adverse effects

Pemetrexed is associated with severe myelosuppression, manifesting as cytopenias that can lead to life-threatening complications such as infections and bleeding.^[2] Grade 3-4 neutropenia occurs in 15-23% of patients, anemia in 3-6%, and thrombocytopenia in 4-5%, with risks heightened in the absence of vitamin supplementation.^[2] Severe neutropenia with fever (febrile neutropenia) has an incidence of approximately 1-5% across clinical trials and may require hospitalization for neutropenic infections.^[14] Renal toxicity represents another critical risk, with acute kidney injury reported in 1-5% of patients, potentially progressing to fatal renal failure.^[2] Incidence rises to 2.1-2.2% when combined with cisplatin and is exacerbated by co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs), which reduce pemetrexed clearance by up to 20% through competition for renal tubular secretion.^[15]^[2] Pulmonary complications, though rare (<1%), include interstitial pneumonitis and radiation recall pneumonitis, with incidences of 1.1% in malignant pleural mesothelioma and 1.8% in non-small cell lung cancer patients.^[16] These can present as dyspnea, cough, and hypoxia, sometimes fatal, particularly in those with preexisting lung conditions or prior radiation.^[2] Other serious effects encompass severe cutaneous reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis (incidence <1%).^[2] To mitigate these risks, monitoring includes weekly complete blood counts during the first two cycles and prior to each subsequent dose, alongside creatinine clearance assessment before every cycle to ensure values exceed 45 mL/min.^[2] Interventions involve immediate dose interruption for grade 3-4 toxicities, permanent discontinuation for life-threatening events like confirmed pneumonitis or severe skin reactions, and use of granulocyte colony-stimulating factor (G-CSF) for febrile neutropenia.^[2] Renal function deterioration prompts withholding the drug, with NSAIDs avoided for at least 5 days before and 2 days after administration.^[15]

Contraindications and interactions

Contraindications

Pemetrexed is absolutely contraindicated in patients with a history of severe hypersensitivity reactions to the drug.^[2] Severe renal impairment, defined as creatinine clearance less than 45 mL/min, represents an absolute contraindication due to the drug's primary renal excretion pathway and lack of an established safe dose in this population, which increases the risk of severe toxicity.^[2] When administered in combination regimens with platinum agents such as cisplatin, absolute contraindications to the partner drug also apply, including severe hypersensitivity to cisplatin or conditions that preclude its use, such as preexisting severe renal impairment.^[17] Relative contraindications include low baseline hematologic parameters, specifically an absolute neutrophil count below 1,500 cells/mm³ or a platelet count below 100,000/mm³, as pemetrexed must not be initiated under these conditions to avoid exacerbating myelosuppression.^[2] Poor performance status, such as Eastern Cooperative Oncology Group (ECOG) score greater than 2, is a relative contraindication, as patients with ECOG performance status of 2 or higher were excluded from pivotal clinical trials evaluating pemetrexed's safety and efficacy.^[2] Pregnancy is a relative contraindication; pemetrexed can cause fetal harm when administered to pregnant women based on its mechanism of action and findings from animal reproduction studies showing embryotoxicity, fetotoxicity, and teratogenicity. Effective contraception is required for females of reproductive potential during treatment and for at least 6 months thereafter, and for males for 3 months after the last dose.^[7] Untreated central nervous system metastases constitute a relative contraindication, particularly if symptomatic or requiring recent intervention, due to exclusion criteria in clinical studies and potential for neurological complications, though pemetrexed has demonstrated activity against brain metastases in select cases.^[18] National Comprehensive Cancer Network (NCCN) guidelines reinforce these considerations, emphasizing renal function assessment and hematologic monitoring prior to pemetrexed initiation to mitigate risks in vulnerable patients.

Drug interactions

Pemetrexed is primarily excreted renally through glomerular filtration and active tubular secretion via organic anion transporters (OATs), making it susceptible to interactions with nephrotoxic agents that impair clearance.^[7] Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), particularly ibuprofen, inhibits OAT3-mediated secretion, increasing pemetrexed exposure by approximately 20% and elevating risks of nephrotoxicity, myelosuppression, and gastrointestinal toxicity, especially in patients with mild to moderate renal impairment (creatinine clearance 45-79 mL/min).^[7] To mitigate this, high-dose ibuprofen should be avoided for 2 days before, the day of, and 2 days after pemetrexed administration; other NSAIDs with short half-lives (e.g., diclofenac) require similar timing precautions, while long half-life agents (e.g., piroxicam) should be interrupted for at least 5 days prior.^[19] Probenecid and other drugs that inhibit tubular secretion can similarly delay pemetrexed elimination, necessitating avoidance or close monitoring of renal function and toxicity.^[19] Combination therapy with platinum agents like cisplatin or carboplatin enhances pemetrexed's antitumor efficacy in non-small cell lung cancer through synergistic pharmacodynamic effects but results in additive myelosuppression, including grade 3/4 neutropenia (up to 35%) and leukopenia, as well as increased renal toxicity.^[18]^[20] No significant pharmacokinetic interactions occur between pemetrexed and cisplatin, allowing standard coadministration per approved regimens, though routine monitoring of complete blood counts and creatinine clearance is essential, with dose reductions or delays recommended for grade 3/4 toxicities.^[7] Concurrent use of other antifolates, such as methotrexate, is generally avoided due to overlapping inhibition of folate-dependent enzymes, which can amplify myelosuppression and mucositis through competitive substrate effects on transport and metabolic pathways.^[18] Proton pump inhibitors (PPIs), particularly lansoprazole, exacerbate pemetrexed-induced hematologic toxicity by competitively inhibiting renal OAT3 (IC50 0.57 µM), with coadministration increasing the odds of severe events by over 10-fold in lung cancer patients; alternatives like pantoprazole or rabeprazole exhibit weaker inhibition and may be preferable if PPI use is unavoidable.^[21] Due to pemetrexed's immunosuppressive effects, live vaccines are contraindicated during treatment to prevent severe infections, with inactivated vaccines administered cautiously under medical supervision.^[18] Management of these interactions emphasizes timing adjustments, such as NSAID and PPI avoidance windows, and proactive monitoring of hematologic parameters, renal function, and electrolyte levels to guide dose modifications—typically reducing pemetrexed by 20-50% for persistent grade 2 toxicities or withholding for grade 3/4 events until resolution.^[7]^[18]

Pharmacology

Mechanism of action

Pemetrexed is a new-generation antifolate analog structurally similar to folic acid, designed to interfere with folate-dependent metabolic processes essential for DNA and RNA synthesis in rapidly dividing cells.^[22] As an antimetabolite, it mimics natural folates to gain entry into cells and subsequently disrupts nucleotide biosynthesis pathways.^[23] The primary mechanism of pemetrexed involves potent inhibition of multiple enzymes in folate metabolism. It primarily targets thymidylate synthase (TS), blocking the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), a critical step in DNA synthesis. This inhibition is depicted in the simplified reaction:

\text{dUMP} + \text{CH}_2\text{-THF} \rightarrow \text{dTMP} + \text{DHF}

where pemetrexed binds to TS, preventing the methylation of dUMP by 5,10-methylene-tetrahydrofolate (CH₂-THF) and leading to the accumulation of dUMP and depletion of dTMP.^[5] Additionally, pemetrexed inhibits dihydrofolate reductase (DHFR), which reduces the pool of tetrahydrofolate cofactors necessary for thymidylate and purine synthesis, and glycinamide ribonucleotide formyltransferase (GARFT), a key enzyme in the de novo purine biosynthesis pathway that requires 10-formyl-tetrahydrofolate for formylation reactions.^[23] These multitargeted actions collectively impair the production of thymidine and purine nucleotides, halting cell proliferation.^[22] Upon cellular uptake, pemetrexed undergoes intracellular activation through polyglutamation by the enzyme folylpolyglutamate synthetase (FPGS), forming polyglutamate derivatives (primarily pentaglutamates) that exhibit significantly higher affinity for TS, DHFR, and GARFT compared to the parent compound.^[5] These polyglutamated forms are retained within the cell for extended periods, prolonging enzyme inhibition and enhancing the drug's cytotoxic effects.^[23] This activation process is more efficient in tumor cells due to higher FPGS activity.^[5] Pemetrexed demonstrates selectivity for tumor cells through preferential uptake via the reduced folate carrier (RFC, SLC19A1), a transmembrane transporter overexpressed in many cancers, which facilitates entry of reduced folates and folate analogs.^[5] It also utilizes the proton-coupled folate transporter (PCFT) under acidic conditions common in tumor microenvironments.^[5] The drug exhibits S-phase specificity, as its inhibition of DNA synthesis enzymes predominantly affects cells actively replicating DNA during the S phase of the cell cycle, leading to S-phase arrest and apoptosis.^[24]

Pharmacokinetics

Pemetrexed is administered exclusively via intravenous infusion, resulting in complete bioavailability of 100% as there is no oral absorption phase.^[2] Following intravenous administration, pemetrexed exhibits linear pharmacokinetics, with area under the curve (AUC) and maximum plasma concentration (C_max) increasing proportionally to the dose across a wide range (0.2 to 838 mg/m²). The steady-state volume of distribution is 16.1 L, indicating moderate tissue distribution, while approximately 81% of the drug is bound to plasma proteins in vitro. Pemetrexed penetrates the cerebrospinal fluid (CSF) poorly, with CSF concentrations typically less than 5% of simultaneous plasma levels.^[2]^[18]^[25] Pemetrexed undergoes minimal systemic metabolism and is not appreciably metabolized by hepatic cytochrome P450 enzymes. Intracellularly, it is converted by folylpolyglutamate synthetase to polyglutamate metabolites, primarily in tumor cells, which enhances target affinity and results in an increased intracellular half-life compared to the parent compound, thereby prolonging its pharmacological action. The elimination half-life of the parent drug is 3.5 hours in patients with normal renal function (creatinine clearance ≥90 mL/min).^[2]^[18]^[26] Excretion of pemetrexed occurs primarily via the kidneys, with 70% to 90% of the administered dose recovered unchanged in urine within 24 hours through a combination of glomerular filtration and active tubular secretion mediated by the organic anion transporter 3 (OAT3). The total systemic clearance is 91.8 mL/min in patients with normal renal function. Renal impairment significantly reduces clearance, leading to increased AUC exposure (e.g., 65% higher at creatinine clearance of 45 mL/min compared to 100 mL/min), necessitating dose adjustments. Age, sex, and mild hepatic impairment do not meaningfully affect pharmacokinetics.^[2]^[18]

Chemistry and development

Chemical structure and properties

Pemetrexed, chemically known as N-[4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid, is a synthetic antifolate analog of folic acid.^[27]^[28] Its molecular formula is C₂₀H₂₁N₅O₆, with a molecular weight of 427.41 g/mol for the diacid form.^[27]^[28] In clinical use, it is administered as the disodium heptahydrate salt (C₂₀H₁₉N₅Na₂O₆ · 7H₂O), which has a molecular weight of 597.48 g/mol and enhances water solubility for intravenous formulation.^[29] The molecular structure features a central pyrrolo[2,3-d]pyrimidine core, which mimics the pteridine ring of folic acid, connected via an ethyl linker to a p-benzoyl-L-glutamic acid side chain.^[27] This configuration is essential for its antifolate properties, enabling inhibition of folate-dependent enzymes involved in nucleotide synthesis.^[30] The L-glutamic acid moiety allows for intracellular polyglutamation, enhancing retention and potency, though detailed activation occurs via enzymatic processes.^[27] Pemetrexed disodium heptahydrate appears as a white to off-white, crystalline, hygroscopic powder.^[28] It exhibits high solubility in water (approximately 30 mg/mL at room temperature), as well as in alkaline solutions like sodium hydroxide, but the diacid form is poorly soluble in neutral water.^[31]^[28] The compound is stable at neutral pH and under standard storage conditions (up to 30°C and 65% relative humidity for 36 months), with degradation primarily under acidic, basic, or oxidative stress; it shows photostability per ICH guidelines.^[28]^[32] Synthesis of pemetrexed involves a multi-step process to construct the pyrrolopyrimidine ring system, starting from substituted pyrimidine and pyrrole precursors, followed by coupling with the benzoylglutamic acid moiety.^[30] The original method, developed by E. C. Taylor and colleagues, was patented and assigned to Eli Lilly and Company (US Patent 5,344,932, 1994), enabling scalable production for clinical development. Subsequent processes optimize purification to minimize impurities and ensure enantiomeric purity of the active L-form.^[28]

History

Pemetrexed, initially designated as LY231514, was developed by Eli Lilly and Company during the 1990s as a novel multitargeted antifolate (MTA) aimed at inhibiting multiple enzymes in folate metabolism pathways, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, to address limitations and resistance seen with earlier antifolates like methotrexate.^[33] This design sought to enhance antitumor activity across various solid tumors by broadly disrupting DNA and RNA synthesis. Preclinical studies confirmed its potent cytotoxicity in cell lines resistant to classical antifolates, paving the way for clinical evaluation.^[5] A landmark phase III trial, published in 2003, evaluated pemetrexed in combination with cisplatin against cisplatin alone in 448 patients with malignant pleural mesothelioma, demonstrating a median survival of 12.1 months versus 9.3 months, which supported its initial regulatory approval. The U.S. Food and Drug Administration (FDA) approved pemetrexed on February 4, 2004, for use with cisplatin in unresectable malignant pleural mesothelioma, marking the first chemotherapy regimen approved for this rare cancer. This approval was based on the trial's evidence of improved response rates (41% versus 17%) and progression-free survival, though it required mandatory folic acid and vitamin B12 supplementation to reduce severe toxicities like myelosuppression.^[34]^[35] Further clinical development expanded pemetrexed's indications in non-small cell lung cancer (NSCLC). In 2004 for second-line NSCLC treatment, in 2008 for first-line NSCLC with cisplatin.^[6]^[36] Building on this, the JMEN phase III trial, reported in 2009, assessed pemetrexed as switch-maintenance therapy in 663 patients with advanced nonsquamous NSCLC who had not progressed after four cycles of platinum-based doublet chemotherapy, revealing a significant overall survival benefit (13.4 months versus 10.6 months with placebo). This led to FDA approval for maintenance use on July 2, 2009.^[6]^[37] In recent years, the first generic version of pemetrexed was approved by the FDA in February 2020, with additional formulations approved in 2022 and beyond, which aimed to improve access following the expiration of Eli Lilly's patents. Pediatric investigations have explored its potential, with phase I trials establishing safe dosing in children with refractory solid tumors and phase II studies evaluating efficacy in recurrent osteosarcoma and other malignancies, but no approvals have been granted for pediatric indications due to limited response rates observed. Early adoption of pemetrexed faced challenges from its high initial cost—exceeding $3,000 per dose in the mid-2000s—and the need for supplementation to manage adverse effects, which complicated administration and contributed to slower integration into standard care protocols despite proven efficacy. More recently, in September 2024, the FDA approved pemetrexed in combination with amivantamab and carboplatin for first-line treatment of EGFR exon 20 insertion-mutated NSCLC, and with pembrolizumab and platinum chemotherapy for unresectable advanced or metastatic malignant pleural mesothelioma.^[38]^[39]^[40]^[41]^[42]^[43]^[4]

Society and culture

Brand names and availability

Pemetrexed is marketed under the primary brand name Alimta by Eli Lilly and Company in the United States and internationally.^[44] In the United States, following the expiration of Alimta's key vitamin regimen patent in May 2022, the FDA has approved multiple generic versions, including Pemfexy (Eagle Pharmaceuticals), Pemrydi RTU (ready-to-use formulation approved in 2023), Axtle, and Pemetrexed Injection from manufacturers such as Teva, Viatris (formerly Mylan), Apotex, and others, leading to several Abbreviated New Drug Applications (ANDAs).^[45]^[39]^[46] In the European Union, generic pemetrexed became available starting in 2015 after the compound patent expired in major countries, with approvals for products such as Pemetrexed Sandoz, Pemetrexed medac, Pemetrexed Baxter, Pemetrexed Fresenius Kabi, and Pemetrexed Pfizer by the European Medicines Agency (EMA).^[47]^[48] The drug is formulated as a lyophilized powder for intravenous injection in single-use vials containing 100 mg or 500 mg of pemetrexed (as pemetrexed disodium), which must be reconstituted prior to administration; a ready-to-use liquid formulation (Pemrydi RTU) is also available in the US.^[49] Pemetrexed received FDA approval in the United States in 2004 for initial indications and is authorized by the EMA across the EU since 2004.^[6]^[50] Its availability remains limited in low-income countries primarily due to high costs associated with importation and distribution.

Economics

In the United States, as of 2025, the wholesale acquisition cost for a branded 500 mg vial of pemetrexed, such as Alimta, is approximately $3,957–$5,000, while generic versions available since patent expiry in 2022 have reduced prices to around $1,000–$2,500 per vial, depending on the manufacturer and pharmacy.^[51]^[52]^[53] A typical treatment course for non-small cell lung cancer (NSCLC) involves 4–6 cycles of pemetrexed, often administered at 500 mg/m² every 21 days, resulting in total drug costs of $20,000–$50,000 when used alone or in combination with platinum agents like cisplatin or carboplatin, excluding administration and supportive care expenses.^[54]30589-X/fulltext) Pemetrexed is covered under Medicare Part B for approved indications such as nonsquamous NSCLC and malignant pleural mesothelioma when administered in outpatient settings, with beneficiaries typically paying 20% coinsurance after the deductible.^[55] Private insurers, including Aetna and UnitedHealthcare, generally reimburse pemetrexed for FDA-approved uses following prior authorization, though coverage varies by plan; uninsured patients face high out-of-pocket costs exceeding $3,000 per dose.^[56]^[57] Globally, pemetrexed imposes a significant economic burden in low- and middle-income countries (LMICs), where cancer treatment affordability is limited and out-of-pocket expenses can exceed 50% of household income; the introduction of generics has improved access by reducing prices up to 70% in regions like Southeast Asia and Eastern Europe, though availability remains inconsistent without widespread WHO prequalification.^[58]3199-3/pdf)^[59] Economic analyses indicate that pemetrexed maintenance therapy for advanced nonsquamous NSCLC is cost-effective in certain models, with incremental cost-effectiveness ratios (ICERs) ranging from $50,000–$78,000 per quality-adjusted life-year (QALY) gained compared to best supportive care, particularly when factoring in survival benefits from clinical trials like PARAMOUNT.^[60]30589-X/fulltext)

Research

Ongoing clinical trials

As of November 2025, more than 50 active clinical trials involving pemetrexed are registered on ClinicalTrials.gov, primarily evaluating its role in combination regimens with immunotherapies for non-small cell lung cancer (NSCLC) and applications in rare tumors.^[61] Ongoing studies are exploring pemetrexed in combination with immunotherapy in NSCLC settings post-PD-1 inhibition. In bladder cancer, phase II trials continue to investigate pemetrexed-platinum combinations, building on prior efficacy data. Pediatric applications remain under investigation, with phase I and II trials demonstrating pemetrexed's activity in osteosarcoma and relapsed or refractory leukemia, including acute lymphoblastic leukemia (ALL), reporting manageable toxicity profiles with evidence of antitumor activity.^[62] Biomarker research is prominent, including studies on thymidylate synthase (TS) expression as a predictor of response. A prospective phase II trial further confirmed that low TS expression correlates with better progression-free survival in pemetrexed-treated advanced nonsquamous NSCLC.^[63] Preliminary outcomes from these phase II/III trials in refractory settings report objective response rates of 20-30%, particularly in immunotherapy combinations for NSCLC and rare tumors, highlighting pemetrexed's potential in overcoming resistance.^[64]

Investigational uses

Pemetrexed has shown preliminary activity in several solid tumors beyond its established indications, including bladder, breast, and pancreatic cancers. In advanced urothelial bladder cancer, phase II trials have reported objective response rates of approximately 28% to 30% with single-agent pemetrexed as second-line therapy, suggesting potential utility in platinum-refractory settings.^[65]^[66] For triple-negative breast cancer, phase II studies combining pemetrexed with agents like sorafenib or gemcitabine have demonstrated modest response rates and disease control in recurrent or metastatic cases, with one trial noting a clinical benefit rate of around 13%.^[67]^[68] In pancreatic cancer, however, efficacy appears limited, with phase II evaluations of pemetrexed alone or in combination yielding low response rates of about 5.7% and median survival times of 6 to 8 months, indicating minimal impact in gemcitabine-refractory disease.^[69]^[70] In hematologic malignancies, pemetrexed is under investigation for pediatric acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma subtypes. Phase I studies in relapsed or refractory leukemia, including ALL, have explored pemetrexed's tolerability in children and adolescents, reporting manageable toxicity profiles with evidence of antitumor activity, though specific response data in pediatric ALL remain preliminary.^[62] For non-Hodgkin lymphoma, particularly primary central nervous system lymphoma (PCNSL), phase II trials have shown objective response rates of 55% to 65% with pemetrexed-based regimens in relapsed/refractory cases, attributed to its central nervous system penetration and multitargeted antifolate mechanism.^[71]^[72] Investigational combinations aim to enhance pemetrexed's efficacy through synergy with targeted therapies. In non-small cell lung cancer (NSCLC), pairing pemetrexed with EGFR inhibitors like osimertinib in platinum-based regimens has prolonged progression-free survival in EGFR-mutant patients post-progression, with one analysis indicating a significant benefit in delaying disease advancement.^[73] For mesothelioma, additions of anti-angiogenic agents such as bevacizumab to pemetrexed-platinum backbones have improved outcomes in select populations, though broader applications with other anti-angiogenics like vandetanib show preclinical synergy without widespread clinical adoption.^[74]^[75] Resistance to pemetrexed poses key challenges, often involving thymidylate synthase (TS) overexpression, which reduces drug efficacy by countering its primary inhibitory action on folate metabolism.^[76] Biomarkers like folate receptor alpha (FR-α) expression may predict response, with higher levels correlating to improved uptake and outcomes in NSCLC and other tumors, guiding patient selection in ongoing studies.^[77]^[78] Preclinical efforts focus on nanoparticle formulations to overcome delivery limitations and enhance targeting. Pemetrexed-loaded folic acid-conjugated nanoparticles have demonstrated superior antitumor effects in colorectal and lung cancer models by improving cellular uptake and reducing systemic toxicity compared to free drug.^[79] Similarly, supramolecular nanoparticles incorporating pemetrexed have inhibited tumor growth in murine models through targeted mitochondrial disruption, highlighting potential for translation to resistant solid tumors.^[80]

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