Pemetrexed
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Pemetrexed: From Malignant Pleural Mesothelioma to Malignant Peritoneal Mesothelioma
One-Sentence Summary
Pemetrexed is a multi-targeted antifolate whose established first-line indication (in combination with cisplatin) is malignant pleural mesothelioma. The TxGNN model predicts it may also be effective for Malignant Peritoneal Mesothelioma, a prediction currently supported by 11 clinical trials and 20 publications.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Malignant Pleural Mesothelioma (established first-line indication, in combination with cisplatin) |
| Predicted New Indication | Malignant Peritoneal Mesothelioma |
| TxGNN Prediction Score | 99.99% |
| Evidence Level | L2 |
| New Zealand Market Status | Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Currently, detailed structured mechanism-of-action data is not available for this drug record. Based on the evidence collected, pemetrexed is a multi-targeted antifolate that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), blocking folate-dependent DNA synthesis in rapidly dividing tumour cells. This mechanism is well established in malignant pleural mesothelioma, where pemetrexed plus cisplatin is a globally accepted first-line regimen.
Malignant pleural mesothelioma and malignant peritoneal mesothelioma both arise from mesothelial cells and share the same underlying tumour biology — they differ mainly in the anatomic cavity of origin (pleura vs. peritoneum) rather than in cell-of-origin or driver biology. Because the antifolate mechanism targets a proliferation pathway common to mesothelial tumours regardless of location, extrapolation from pleural to peritoneal disease is mechanistically reasonable.
In practice, cisplatin plus pemetrexed is already used off-label as a standard systemic treatment option for peritoneal mesothelioma, and this is reflected in multiple ongoing prospective trials (e.g., ICARuS II, MESOTIP) evaluating its role alongside surgery/HIPEC. The absence of a completed disease-specific Phase 3 RCT — as opposed to the fully validated pleural indication — is the main gap separating this from a fully confirmed indication.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT06057935 | Phase 2 | Recruiting | 64 | ICARuS II: randomized trial of intraperitoneal vs. intravenous chemotherapy after cytoreductive surgery + HIPEC for malignant peritoneal mesothelioma |
| NCT05001880 | Phase 2 | Recruiting | 66 | Carboplatin/pemetrexed/bevacizumab ± atezolizumab as neoadjuvant/palliative therapy for peritoneal mesothelioma |
| NCT03875144 | Phase 2 | Suspended | 66 | MESOTIP: PIPAC + systemic cisplatin/pemetrexed vs. systemic chemotherapy alone as 1st-line treatment |
| NCT02535312 | Phase 1/2 | Active, not recruiting | 30 | TRC102 (methoxyamine) + cisplatin/pemetrexed in advanced solid tumours, including pemetrexed/platinum-refractory mesothelioma |
| NCT06543069 | Phase 2 | Recruiting | 28 | Sintilimab + bevacizumab + pemetrexed/cisplatin in unresectable peritoneal mesothelioma |
| NCT04462809 | Phase 2 | Unknown | 40 | Maintenance talazoparib following first-line platinum-based chemotherapy in pleural or peritoneal mesothelioma |
| NCT02029690 | Phase 1 | Terminated | 85 | ADI-PEG 20 + pemetrexed/cisplatin (TRAP study) in arginine-dependent tumours, including advanced peritoneal mesothelioma |
| NCT01353482 | Phase 1/2 | Withdrawn | 0 | Vorinostat + pemetrexed-cisplatin first-line therapy in mesothelioma (withdrawn before enrollment) |
| NCT00402766 | Phase 1 | Completed | 19 | Cisplatin + pemetrexed + imatinib mesylate in unresectable/metastatic mesothelioma; maximum tolerated dose determination |
| NCT03564691 | Phase 1 | Completed | 470 | MK-4830 ± pembrolizumab basket trial in advanced solid tumours (not mesothelioma-specific) |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26941986 | 2016 | Review | Journal of Gastrointestinal Oncology | Diagnosis and management overview of malignant peritoneal mesothelioma (MPeM), including treatment landscape |
| 35407498 | 2022 | Review | Journal of Clinical Medicine | Review of treatment approaches for MPeM, including CRS+HIPEC and systemic chemotherapy |
| 31417959 | 2019 | Cohort/Case series | Pleura and Peritoneum | Bidirectional chemotherapy enabling surgical resectability in initially unresectable MPeM |
| 28594258 | 2017 | Retrospective | Expert Review of Anticancer Therapy | First-line pemetrexed plus cisplatin efficacy in MPeM |
| 31287877 | 2019 | Retrospective | Japanese Journal of Clinical Oncology | Efficacy and safety of first-line pemetrexed plus cisplatin in advanced MPeM |
| 41133016 | 2025 | Retrospective | Clinical Medicine Insights: Oncology | Comparison of first-line pemetrexed-platinum vs. gemcitabine-platinum regimens in MPeM |
| 33743636 | 2021 | Retrospective | BMC Cancer | Second-line treatment efficacy and prognostic factors in advanced MPeM |
| 38806763 | 2024 | Multi-center cohort | Annals of Surgical Oncology | Treatment strategies and outcomes analysis across MPeM patients |
| 23291819 | 2013 | Case report | BMJ Case Reports | Response to rechallenge with cisplatin and pemetrexed in MPeM |
| 34723916 | 2022 | Case series | Journal of Immunotherapy | Chemoimmunotherapy in platinum-nonresponsive metastatic MPeM |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (multi-targeted antifolate/antimetabolite) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions |
| Handling Protection | Standard cytotoxic drug handling precautions apply |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Multiple Phase 2 trials (including RCTs) are actively investigating pemetrexed-based regimens specifically in malignant peritoneal mesothelioma, and one completed Phase 2 trial (NCT00061477) already included this population, supporting an L2 evidence level. However, no completed disease-specific Phase 3 RCT exists, and this is an off-label extrapolation from the approved pleural mesothelioma indication.
To proceed, the following is needed:
- TFDA/regulatory package insert warnings and contraindications (currently a blocking data gap)
- Confirmed mechanism of action (MOA) data from DrugBank
- Drug-drug interaction (DDI) data
- Route compatibility assessment (intravenous vs. intraperitoneal administration, given HIPEC/PIPAC use in this population)
- New Zealand market authorization status confirmation, given the drug is currently not marketed
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.