Pemetrexed
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Pemetrexed: From Pleural Mesothelioma to Malignant Peritoneal Mesothelioma
One-Sentence Summary
Pemetrexed is a multitargeted antifolate chemotherapy agent whose antitumour efficacy against malignant pleural mesothelioma is internationally well established (platinum + pemetrexed is a recognised standard first-line regimen). The TxGNN model predicts it may also be effective for Malignant Peritoneal Mesothelioma, an anatomically related but distinct mesothelial malignancy, with 11 clinical trials and 20 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not on the Danish registry (drug currently not marketed); internationally established for malignant pleural mesothelioma (platinum + pemetrexed first-line regimen) |
| Predicted New Indication | Malignant Peritoneal Mesothelioma |
| TxGNN Prediction Score | 99.99% |
| Evidence Level | L2 |
| Denmark Market Status | Not Marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Formal DrugBank mechanism-of-action data could not be retrieved for this candidate (data gap, see below). However, the repurposing evidence itself documents the mechanism clearly: Pemetrexed is a multitargeted antifolate that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), blocking folate-dependent DNA synthesis. Mesothelioma cells, which proliferate rapidly, are highly dependent on this pathway, which is why pemetrexed plus platinum is already an internationally recognised (including FDA-approved) standard first-line treatment for malignant pleural mesothelioma.
Malignant peritoneal mesothelioma and malignant pleural mesothelioma are both malignancies of mesothelial-cell origin, differing essentially only in anatomical site (peritoneum vs. pleura). International treatment guidelines (e.g. NCCN) already list pemetrexed + platinum as a systemic therapy option for peritoneal mesothelioma, which supports the biological plausibility of the TxGNN prediction. That said, a dedicated Phase 3 randomised controlled trial for the peritoneal subtype is still lacking — current evidence is concentrated in Phase 1/2 trials and retrospective/case-series literature, placing this candidate at a moderate (not definitive) evidence strength.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT06057935 | Phase 2 | Recruiting | 64 | Multicenter RCT comparing normothermic intraperitoneal vs. intravenous chemotherapy after cytoreductive surgery + HIPEC for malignant peritoneal mesothelioma. |
| NCT06543069 | Phase 2 | Recruiting | 28 | Single-arm study of sintilimab + bevacizumab combined with pemetrexed/cisplatin for unresectable malignant peritoneal mesothelioma. |
| NCT04462809 | Phase 2 | Unknown | 40 | Talazoparib maintenance following first-line platinum-based chemotherapy in pleural or peritoneal mesothelioma. |
| NCT00061477 | Phase 2 | Completed | 48 | Pemetrexed + gemcitabine as front-line chemotherapy for pleural or peritoneal mesothelioma. |
| NCT01353482 | Phase 1/2 | Withdrawn | 0 | Vorinostat + pemetrexed-cisplatin as first-line therapy in malignant pleural mesothelioma (withdrawn prior to enrollment). |
| NCT05001880 | Phase 2 | Recruiting | 66 | Randomised trial of carboplatin/pemetrexed/bevacizumab with or without atezolizumab for peritoneal mesothelioma. |
| NCT00402766 | Phase 1 | Completed | 19 | Cisplatin + pemetrexed + imatinib mesylate in unresectable/metastatic malignant mesothelioma. |
| NCT03875144 | Phase 2 | Suspended | 66 | PIPAC combined with systemic chemotherapy (cisplatin/pemetrexed) vs. systemic chemotherapy alone as first-line treatment of malignant peritoneal mesothelioma. |
| NCT02535312 | Phase 1/2 | Active, not recruiting | 30 | TRC102 combined with pemetrexed/cisplatin in advanced solid tumours, including mesothelioma refractory to pemetrexed and platinum. |
| NCT02029690 | Phase 1 | Terminated | 85 | ADI-PEG 20 combined with pemetrexed and cisplatin in arginine-dependent tumours, including advanced peritoneal mesothelioma. |
Note: one additional Phase 1 trial (NCT03564691, a broad advanced-solid-tumour study with only tangential relevance) was excluded from this table to keep the list to the 10 most relevant trials.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35407498 | 2022 | Review | Journal of Clinical Medicine | Overview of treatment approaches for malignant peritoneal mesothelioma, including the role of systemic chemotherapy. |
| 31417959 | 2019 | Cohort/Case report | Pleura and Peritoneum | Bidirectional chemotherapy enabling surgical resectability in initially unresectable peritoneal mesothelioma. |
| 28594258 | 2017 | Retrospective study | Expert Review of Anticancer Therapy | Evaluates efficacy of first-line systemic pemetrexed + cisplatin chemotherapy in peritoneal mesothelioma. |
| 31287877 | 2019 | Retrospective study | Japanese Journal of Clinical Oncology | Efficacy and safety of pemetrexed + cisplatin as first-line chemotherapy in advanced peritoneal mesothelioma. |
| 23291819 | 2013 | Case report | BMJ Case Reports | Response to rechallenge with cisplatin and pemetrexed in peritoneal mesothelioma. |
| 41710652 | 2026 | Retrospective study | Frontiers in Oncology | Single-center analysis of chemotherapy with/without bevacizumab after CRS+HIPEC in peritoneal mesothelioma. |
| 34723916 | 2022 | Case report | Journal of Immunotherapy | Chemoimmunotherapy in platinum-nonresponsive metastatic peritoneal mesothelioma (2 patients). |
| 26941986 | 2016 | Review | Journal of Gastrointestinal Oncology | Diagnosis and management overview of malignant peritoneal mesothelioma. |
| 30450291 | 2018 | Review | Translational Lung Cancer Research | Review of peritoneal mesothelioma pathology, prognosis, and treatment options. |
| 38806763 | 2024 | Retrospective multi-center study | Annals of Surgical Oncology | Treatment strategies and outcomes across a multi-center peritoneal mesothelioma cohort. |
Denmark Market Information
Pemetrexed currently holds no marketing authorisation on record in Denmark (market status: Not Marketed; 0 licenses identified). No national (Laegemiddelstyrelsen) or centralised (EMA) authorisation data is available in this evidence pack to summarise in a product table.
Cytotoxicity
Pemetrexed is a conventional cytotoxic antineoplastic agent (multitargeted antifolate/antimetabolite class), so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic chemotherapy (multitargeted antifolate/antimetabolite) |
| Myelosuppression Risk | Please refer to the Summary of Product Characteristics (SmPC) warnings and precautions |
| Emetogenicity Classification | Please refer to the Summary of Product Characteristics (SmPC) warnings and precautions |
| Monitoring Items | Please refer to the Summary of Product Characteristics (SmPC) warnings and precautions |
| Handling Protection | As a cytotoxic chemotherapy agent, standard cytotoxic drug handling and protective measures apply |
Safety Considerations
Please refer to the approved Summary of Product Characteristics (SmPC) for safety information. No drug-drug interaction data could be retrieved (DDI query status: not found).
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: The TxGNN score is very high (99.99%) and the mechanistic rationale is strong — malignant peritoneal mesothelioma shares the same mesothelial cell origin and antifolate-sensitive proliferative biology as malignant pleural mesothelioma, for which pemetrexed + platinum is already an internationally accepted standard. This is reinforced by 11 clinical trials and consistent literature, but evidence remains at Phase 1/2 and retrospective/case-series level (no peritoneal-specific completed Phase 3 RCT), placing this at evidence level L2 / decision stage S2 rather than a full Go.
To proceed, the following is needed:
- Danish-specific SmPC/label safety data (key warnings, contraindications) — currently a Blocking data gap preventing initial safety screening (S1)
- Confirmed DrugBank mechanism-of-action record (currently a data gap; mechanism was reconstructed from trial/literature rationale only)
- Clarification of the regulatory pathway, since Pemetrexed has no current Danish marketing authorisation (0 licenses)
- A peritoneal mesothelioma-specific Phase 3 RCT to raise the evidence level beyond L2
- A formal drug-drug interaction (DDI) review, as none could currently be retrieved
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.