Pemetrexed
| Evidence Level: L5 | Predicted Indications: 3 |
Table of Contents
Pemetrexed: Pleural adenomatoid tumor
One-Sentence Summary
Pemetrexed is an antifolate chemotherapy originally used for non-small cell lung cancer and malignant pleural mesothelioma. with 7 clinical trials and 20 publications currently supporting this direction. Most of the evidence is early-phase trials, retrospective series and reviews.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Pleural adenomatoid tumor |
| TxGNN Prediction Score | 0.9999 |
| Evidence Level | L5 |
| Canada Market Status | Marketed (marketed DINs: 13 of 14; dormant: 1) |
| Number of DINs | 14 (marketed: 13) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the source record. Based on the analysis compiled for this report, pemetrexed is a multitargeted antifolate. It inhibits thymidylate synthase, dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). This blocks folate-dependent nucleotide synthesis in rapidly dividing cells.
Peritoneal and pleural mesothelioma share the same histology and much of the same biology. Pemetrexed plus platinum is the established standard for pleural mesothelioma, so extending it to the peritoneal site is mechanistically plausible. Peritoneal disease is rare, so few trials are specific to it. Current systemic therapy recommendations are largely extrapolated from pleural mesothelioma studies, and pemetrexed-platinum is among the recommended first-line options.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00061477 | Phase 2 | Completed | 48 | Pemetrexed plus gemcitabine as front-line therapy in pleural or peritoneal mesothelioma. It directly includes the peritoneal population. |
| NCT05001880 | Phase 2 | Recruiting | 66 | Carboplatin, pemetrexed and bevacizumab with or without atezolizumab in peritoneal mesothelioma. No results yet. |
| NCT03875144 | Phase 2 | Suspended | 66 | Pressurized intraperitoneal aerosol chemotherapy (PIPAC) plus cisplatin-pemetrexed versus systemic chemotherapy alone as first-line treatment. |
| NCT06543069 | Phase 2 | Recruiting | 28 | Single-arm trial of sintilimab and bevacizumab with pemetrexed and cisplatin in unresectable disease. |
| NCT06057935 | Phase 2 | Recruiting | 64 | ICARuS II compares intraperitoneal and intravenous chemotherapy after cytoreductive surgery and HIPEC. Pemetrexed’s role is indirect. |
| NCT02535312 | Phase 1/2 | Active, not recruiting | 30 | TRC102 with cisplatin and pemetrexed in advanced solid tumours and mesothelioma. It is mainly a safety study. |
| NCT00402766 | Phase 1 | Completed | 19 | Cisplatin, pemetrexed and imatinib in malignant mesothelioma. A small safety study. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 39413826 | 2024 | Review | J Natl Compr Canc Netw | Systemic therapy recommendations for peritoneal mesothelioma are mostly extrapolated from pleural trials. First-line options include nivolumab plus ipilimumab or pemetrexed-platinum. |
| 31287877 | 2019 | Retrospective study | Jpn J Clin Oncol | Efficacy and safety of pemetrexed plus cisplatin as first-line therapy in advanced peritoneal mesothelioma. |
| 28594258 | 2017 | Retrospective study | Expert Rev Anticancer Ther | Retrospective evaluation of first-line pemetrexed-cisplatin. Outcomes varied widely, in part because of borderline malignant variants. |
| 21528659 | 2011 | Single-institution study | Tumori | Pemetrexed-cisplatin in chemotherapy-naïve patients, evaluated for efficacy and safety. |
| 41133016 | 2025 | Retrospective study | Clin Med Insights Oncol | Compares first-line pemetrexed-platinum with gemcitabine-platinum regimens. Pemetrexed-platinum is at the forefront of first-line systemic treatment. |
| 38806763 | 2024 | Multi-centre cohort | Ann Surg Oncol | Treatment strategies and outcomes in a rare, heterogeneous peritoneal mesothelioma population. |
| 36765620 | 2023 | Review | Cancers | Diagnostic and therapeutic pathway. Median overall survival ranges from 34 to 92 months in patients suitable for cytoreductive surgery with HIPEC. |
| 35407498 | 2022 | Review | J Clin Med | Surgical cytoreduction with HIPEC is the preferred initial treatment in selected patients. |
| 30450291 | 2018 | Review | Transl Lung Cancer Res | Overview of this very rare malignancy, which has a poor prognosis. |
| 26941986 | 2016 | Review | J Gastrointest Oncol | Diagnosis and management of peritoneal mesothelioma. |
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02463083 | PEMETREXED FOR INJECTION, USP | Not listed | Not listed |
| 02517647 | PEMETREXED DISODIUM FOR INJECTION | Not listed | Not listed |
| 02528754 | PEMETREXED DISODIUM FOR INJECTION | Not listed | Not listed |
| 02463091 | PEMETREXED FOR INJECTION, USP | Not listed | Not listed |
| 02515423 | PEMETREXED FOR INJECTION | Not listed | Not listed |
Fourteen valid single-ingredient licences are on record in total. The five above are shown as the main authorizations.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (antifolate / antimetabolite) |
| Myelosuppression Risk | High. The knowledge-graph contraindications include thrombocytopenia, neutropenia, agranulocytosis and anaemia. |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count with differential, renal function (the knowledge-graph contraindications include impaired renal function and kidney disease), liver function |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Drug Interactions: 100 interactions were found, and the 20 reviewed are all rated Moderate. They include:
- H2 blockers: famotidine, ranitidine, cimetidine.
- Metformin.
- Nephrotoxic agents: amphotericin B (including lipid, liposomal and cholesteryl sulfate forms), vancomycin, kanamycin, neomycin, polymyxin B.
- Salicylates and aminosalicylates: acetylsalicylic acid, mesalazine, balsalazide, olsalazine.
- Others: amoxicillin, levofloxacin, sapropterin.
Many of these interacting drugs are renally cleared or nephrotoxic. Renal function should be considered when they are co-administered.
Label warnings and contraindications from the Health Canada package insert were not available for this report. Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Pemetrexed-platinum is the established standard for pleural mesothelioma. It is a recommended first-line option for peritoneal mesothelioma, supported by a completed Phase 2 trial that included peritoneal patients, several ongoing Phase 2 trials and multiple retrospective series. No dedicated Phase 3 trial exists for the peritoneal site, so the evidence is moderate (L2).
To proceed, the following is needed:
- The Health Canada package insert warnings and contraindications, which were not available for this report
- Detailed mechanism of action data from DrugBank
- Approved indication text and dosage forms for the Canadian licences
- Results from the ongoing randomised Phase 2 trials in peritoneal mesothelioma (NCT05001880, NCT03875144, NCT06057935)
- A monitoring plan for myelosuppression and renal function, including review of nephrotoxic co-medications
Other predictions in the ranked list:
- Established indications: pleural mesothelioma, including its epithelioid, sarcomatoid and biphasic subtypes, is already labelled. Those results confirm the drug’s activity rather than representing true repurposing.
- Research question: pericardial mesothelioma has only case reports and one pooled review.
- Hold: pleural adenomatoid tumour, well-differentiated papillary mesothelioma, lymphohistiocytoid mesothelioma and iminoglycinuria. These are benign or indolent conditions, or have no mechanistic or clinical support.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.