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. The TxGNN model predicts it may be effective for pleural adenomatoid tumor, with 7 registered clinical trials and 20 publications currently supporting this direction. Most of this evidence comes from small Phase 2 studies, 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 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, pemetrexed is a multi-targeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT). This blocks purine and pyrimidine synthesis in rapidly dividing cells.
Peritoneal and pleural mesothelioma share the same mesothelial histology and folate-dependent proliferation. Pemetrexed plus cisplatin is the established first-line chemotherapy for pleural mesothelioma, supported by a pivotal Phase 3 trial, and is commonly extrapolated to the peritoneal form. Because peritoneal mesothelioma is rare, prospective disease-specific trials are scarce, and systemic therapy recommendations are mostly extrapolated from pleural disease.
Other TxGNN predictions in this list are not equally credible. Pleural mesothelioma and its epithelioid, sarcomatoid and biphasic subtypes are on-label or subtypes of an approved use, so they are not true repurposing. Iminoglycinuria and pleural adenomatoid tumour appear to be TxGNN model (deep learning) artefacts. This report focuses on peritoneal mesothelioma.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00061477 | Phase 2 | Completed | 48 | Front-line pemetrexed plus gemcitabine in pleural or peritoneal mesothelioma; includes the peritoneal population |
| NCT05001880 | Phase 2 | Recruiting | 66 | Randomised: carboplatin, pemetrexed and bevacizumab with or without atezolizumab in peritoneal mesothelioma |
| NCT06543069 | Phase 2 | Recruiting | 28 | Single-arm: sintilimab and bevacizumab with pemetrexed and cisplatin in unresectable peritoneal mesothelioma |
| NCT03875144 | Phase 2 | Suspended | 66 | PIPAC plus systemic cisplatin/pemetrexed versus systemic chemotherapy alone, first line |
| NCT06057935 | Phase 2 | Recruiting | 64 | ICARuS II: intraperitoneal versus 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; mixed population |
| NCT00402766 | Phase 1 | Completed | 19 | Cisplatin, pemetrexed and imatinib in metastatic mesothelioma; safety focus, mostly pleural |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31287877 | 2019 | Cohort | Jpn J Clin Oncol | Efficacy and safety of first-line pemetrexed plus cisplatin in advanced peritoneal mesothelioma |
| 28594258 | 2017 | Retrospective | Expert Rev Anticancer Ther | Retrospective evaluation of first-line pemetrexed and cisplatin in peritoneal mesothelioma |
| 21528659 | 2011 | Single-institution series | Tumori | Pemetrexed-cisplatin in chemotherapy-naive peritoneal mesothelioma; efficacy and safety |
| 41133016 | 2025 | Retrospective | Clin Med Insights Oncol | Compared first-line pemetrexed-platinum with gemcitabine-platinum in peritoneal mesothelioma |
| 38806763 | 2024 | Multi-centre study | Ann Surg Oncol | Treatment strategies and outcomes in peritoneal mesothelioma |
| 39413826 | 2024 | Review | J Natl Compr Canc Netw | Systemic options; pemetrexed-based chemotherapy or nivolumab plus ipilimumab, extrapolated from pleural trials |
| 30450291 | 2018 | Review | Transl Lung Cancer Res | Review of malignant peritoneal mesothelioma |
| 35407498 | 2022 | Review | J Clin Med | Cytoreduction plus HIPEC is the preferred initial treatment in selected patients; systemic therapy otherwise |
| 36765620 | 2023 | Review | Cancers | Diagnostic and therapeutic pathway; median overall survival of 34 to 92 months with CRS plus HIPEC |
| 33257382 | 2020 | Case report | BMJ Case Rep | Nivolumab in a patient with peritoneal mesothelioma after initial systemic chemotherapy |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 4600D | Pemetrexed Accord | Powder for I.V. infusion 100 mg (as disodium) | Indication text not listed in the data compiled for this report |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (antifolate class) |
| Emetogenicity Classification | Please refer to the Product Information (PI) |
| Monitoring Items | Full blood count with differential, renal function and liver function; renal function is particularly important because the drug is renally cleared |
| Handling Protection | Follow local cytotoxic drug handling requirements |
Safety Considerations
- Contraindication-related conditions (knowledge graph, not label text): kidney disease, impaired renal function, pyoureter, thrombocytopenia, neutropenia, agranulocytosis, anaemia and macrocytic anaemia.
- Drug interactions: 100 interactions were identified. The 20 listed in the compiled data are all rated Moderate. They include:
- Famotidine, ranitidine, cimetidine
- Metformin
- Amphotericin B (including lipid, cholesteryl sulfate and liposomal forms)
- Amoxicillin
- Aspirin
- Mesalazine, balsalazide, olsalazine
- Vancomycin, kanamycin, neomycin, polymyxin B, levofloxacin
- Sapropterin
Many of these are nephrotoxic or compete for renal tubular secretion, which may raise pemetrexed exposure.
Product label warnings and contraindications were not available. Please refer to the TGA-approved Product Information (PI) for full safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Pemetrexed has a strong mechanistic rationale and is already the standard backbone for pleural mesothelioma. Peritoneal-specific evidence consists of small Phase 2 trials, retrospective cohorts and reviews, with no completed Phase 3 trial, so the evidence level is L2. This is reasonable for specialist-led use with safeguards, not for routine adoption.
To proceed, the following is needed:
- The TGA Product Information for Pemetrexed Accord, including indication text, warnings and contraindications, since label data were unavailable.
- Mechanism of action data from DrugBank, which could not be retrieved.
- Results from the recruiting randomised peritoneal mesothelioma trials (NCT05001880, NCT03875144, NCT06057935).
- Multidisciplinary review of each patient, including the role of cytoreductive surgery with HIPEC and immunotherapy options.
- A monitoring plan for renal function and blood counts, with a medication review for nephrotoxic or interacting drugs.
- Standard vitamin supplementation and dosing per the PI, which should be confirmed from the label.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.