Pemetrexed

證據等級: L5

預測適應症: 10 個

Pemetrexed: From Pleural Mesothelioma to Malignant Peritoneal Mesothelioma

One-Sentence Summary

Pemetrexed is an antifolate chemotherapy already established (in combination with cisplatin) as a treatment for pleural mesothelioma. The TxGNN model predicts it may also be effective for Malignant Peritoneal Mesothelioma, with 11 clinical trials and 20 publications currently identified in the evidence pack for this indication.

Note: This evidence pack contains no Australian regulatory (TFDA/TGA) license data for pemetrexed — the drug is currently not marketed in Australia under this dataset, and mechanism-of-action data is also a confirmed gap (see Data Gaps below). The “original indication” above is drawn from the trial/literature context within this evidence pack (see Clinical Trial Evidence for pleural mesothelioma, ranked #3), not from an ARTG-approved product label.

Quick Overview

Item	Content
Original Indication	Pleural mesothelioma (with cisplatin) — per trial-context evidence in this pack; no ARTG label text available
Predicted New Indication	Malignant Peritoneal Mesothelioma
TxGNN Prediction Score	99.99%
Evidence Level	L2
Australia Market Status	Not marketed
Number of ARTG Entries	0
Recommended Decision	Research Question

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data for pemetrexed is not available in this evidence pack (flagged as a High-severity data gap, DG002). Based on well-established pharmacology, pemetrexed is a multitargeted antifolate that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) — enzymes required for folate-dependent DNA synthesis in rapidly dividing cells.

Malignant peritoneal mesothelioma and pleural mesothelioma are both tumours of mesothelial cell origin, sharing overlapping molecular biology (including BAP1 alterations and mesothelin expression). Pemetrexed plus cisplatin is already an established regimen for pleural mesothelioma, and the mechanism of antifolate-driven cytotoxicity is not organ-site specific — it targets the same underlying proliferative biology regardless of whether the mesothelioma arises in the pleura or peritoneum.

This mechanistic overlap is reflected in the trial evidence itself: several trials for peritoneal mesothelioma directly reuse pemetrexed/cisplatin-based regimens developed for the pleural disease (e.g. NCT00061477, NCT05001880), and case-level literature (PMID 23291819, 28594258) reports clinical responses when pemetrexed-cisplatin is applied specifically to peritoneal disease. However, no completed Phase 3 RCT exists specifically for the peritoneal site, which is why the evidence level here is L2 rather than L1.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrolment	Key Findings
NCT06057935	Phase 2	Recruiting	64	ICARuS II: compares intraperitoneal vs intravenous chemotherapy after cytoreductive surgery + HIPEC in malignant peritoneal mesothelioma
NCT03875144	Phase 2	Suspended	66	MESOTIP: PIPAC + systemic chemotherapy (cisplatin+pemetrexed) vs systemic chemotherapy alone as 1st-line treatment
NCT06543069	Phase 2	Recruiting	28	Sintilimab + bevacizumab + pemetrexed + cisplatin in unresectable malignant peritoneal mesothelioma
NCT04462809	Phase 2	Unknown	40	Talazoparib maintenance following 1st-line platinum-based chemotherapy in pleural/peritoneal mesothelioma
NCT00061477	Phase 2	Completed	48	ALIMTA (pemetrexed) + gemcitabine as front-line chemotherapy, explicitly including a peritoneal mesothelioma cohort
NCT00402766	Phase 1	Completed	19	Cisplatin + pemetrexed + imatinib mesylate in unresectable/metastatic malignant mesothelioma
NCT02029690	Phase 1	Terminated	85	ADI-PEG 20 + pemetrexed + cisplatin (TRAP study), including a peritoneal mesothelioma dose-escalation cohort
NCT05001880	Phase 2	Recruiting	66	Carboplatin + pemetrexed + bevacizumab ± atezolizumab in peritoneal mesothelioma
NCT01353482	Phase 1/2	Withdrawn	0	Vorinostat + pemetrexed-cisplatin, covering both pleural and peritoneal mesothelioma (withdrawn before enrolment)
NCT02535312	Phase 1/2	Active, not recruiting	30	TRC102 + cisplatin/pemetrexed in solid tumours/mesothelioma refractory to pemetrexed-platinum

Literature Evidence

PMID	Year	Type	Journal	Key Findings
35407498	2022	Review (treatment-focused)	J Clin Med	Overview of treatment approaches for malignant peritoneal mesothelioma, including systemic chemotherapy role
31417959	2019	Cohort	Pleura and Peritoneum	Bidirectional chemotherapy improved resectability in initially unresectable peritoneal mesothelioma
28594258	2017	Retrospective study	Expert Rev Anticancer Ther	First-line pemetrexed + cisplatin evaluated specifically in malignant peritoneal mesothelioma
31287877	2019	Retrospective study	Jpn J Clin Oncol	Efficacy and safety of pemetrexed + cisplatin as first-line therapy in advanced peritoneal mesothelioma
38806763	2024	Multi-centre cohort	Ann Surg Oncol	Treatment strategies and outcomes across a multi-centre peritoneal mesothelioma population
34723916	2022	Case series	J Immunother	Chemoimmunotherapy in platinum-nonresponsive metastatic peritoneal mesothelioma
33257382	2020	Case report	BMJ Case Rep	Nivolumab used after prior pemetrexed-based chemotherapy in peritoneal mesothelioma
23291819	2013	Case report	BMJ Case Rep	Response to rechallenge with cisplatin + pemetrexed in peritoneal mesothelioma
26941986	2016	Review	J Gastrointest Oncol	Diagnosis and management overview of peritoneal mesothelioma, including systemic therapy options
30450291	2018	Review	Transl Lung Cancer Res	General review of peritoneal mesothelioma biology and treatment

Australia Market Information

Pemetrexed is currently not marketed in Australia under the data available in this evidence pack — there are no ARTG entries recorded (total_licenses = 0). No product-level Australian regulatory information (brand names, dosage forms, or approved indication text) is available to report.

Cytotoxicity

Pemetrexed is an antineoplastic agent (multitargeted antifolate class), so this section applies.

Item	Content
Cytotoxicity Classification	Conventional cytotoxic (antifolate class)
Myelosuppression Risk	Please refer to the Product Information (PI) warnings and precautions
Emetogenicity Classification	Please refer to the Product Information (PI) warnings and precautions
Monitoring Items	Full blood count (with differential), renal function, and hepatic function are standard monitoring parameters for antifolate cytotoxic therapy
Handling Protection	Standard cytotoxic drug handling and protection protocols apply

Safety Considerations

Please refer to the TGA-approved Product Information (PI) for safety information. No key warnings, contraindications, or drug-drug interaction data are available for pemetrexed in this evidence pack (DDI query status: not found).

Conclusion and Next Steps

Decision: Research Question

Rationale: The mechanistic rationale for extending pemetrexed to malignant peritoneal mesothelioma is strong given its established role in pleural mesothelioma, and several Phase 1/2 trials and retrospective studies support activity in the peritoneal setting. However, no completed Phase 3 RCT exists for this specific site, and most supporting trials are early-phase, small, or use pemetrexed as part of multi-drug combinations rather than as the sole variable under study.

To proceed, the following is needed:

TFDA/TGA-approved Product Information (warnings, contraindications, DDI) — currently a Blocking data gap
Detailed mechanism of action documentation from DrugBank — currently a High-severity data gap
A dedicated prospective (ideally randomised) trial in peritoneal mesothelioma to confirm efficacy independent of pleural-disease extrapolation
Confirmation of intended route of administration and dosing compatibility for the peritoneal setting (e.g. IP vs IV, as tested in NCT06057935)
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.