Everolimus
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Everolimus: From Renal Cell Carcinoma to Liposarcoma
One-Sentence Summary
Everolimus is an mTOR inhibitor, originally used for renal cell carcinoma, breast carcinoma, and tuberous sclerosis-related conditions. The TxGNN model predicts it may be effective for liposarcoma. Support so far is 1 clinical trial (a combination Phase 2 study) and 4 publications, only one of which reports clinical trial data.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Renal cell carcinoma, breast carcinoma, kidney angiomyolipoma, tuberous sclerosis (the registration records list no indication text, so these come from the knowledge-graph indication data) |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L2 (provisional: the only trial is a single-arm, non-randomised Phase 2 combination study that has not completed, so it does not strictly meet the L2 definition) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 5 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data are not available in the data compiled for this report. Everolimus is known to inhibit mTORC1, a central regulator of cell growth and proliferation. Its efficacy in renal cell carcinoma and other tumours has been established, and mechanistically it may be applicable to liposarcoma.
Dedifferentiated liposarcoma is typically driven by MDM2/CDK4 amplification, and it often shows activation of the PI3K/AKT/mTOR pathway. Blocking mTOR with everolimus while blocking CDK4/6 with ribociclib targets two complementary proliferation pathways. Preclinical models have shown synergistic growth inhibition from this combination.
The evidence is still early. The one directly relevant trial is a single-arm Phase 2 study of the combination. Its results are not established in the data compiled, and everolimus's own contribution cannot be separated from ribociclib's.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT03114527 | Phase 2 | Active, not recruiting | 48 | Ribociclib plus everolimus in advanced dedifferentiated liposarcoma and leiomyosarcoma after at least 1 prior systemic therapy; two-centre, two-arm study measuring anti-tumour activity; no randomised comparator; estimated completion December 2026 |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37967116 | 2024 | Phase 2 trial report | Clin Cancer Res | Report of the ribociclib plus everolimus study in advanced dedifferentiated liposarcoma and leiomyosarcoma; rationale is CDK4/6 and mTOR targeting with synergy in tumour models |
| 36003796 | 2022 | Review (preclinical) | Front Oncol | Patient-derived orthotopic xenograft sarcoma models used to identify combination therapies with the CDK inhibitor palbociclib (indirect evidence) |
| 41991999 | 2026 | Preclinical | Oncogene | XPO1 inhibitor KPT-330 (selinexor) impairs dedifferentiated liposarcoma cell viability (indirect evidence, not everolimus) |
| 29848686 | 2018 | Preclinical | Anticancer Res | Eribulin combinations with other anticancer agents across tumour models (indirect evidence, not everolimus) |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN13194P | Certican Tablets 0.25 mg | Tablet | Not listed in registration data |
| SIN13195P | Certican Tablets 0.75 mg | Tablet | Not listed in registration data |
| SIN13196P | Certican Tablets 0.5 mg | Tablet | Not listed in registration data |
| SIN13749P | Afinitor Tablet 10 mg | Tablet | Not listed in registration data |
| SIN13750P | Afinitor Tablet 5 mg | Tablet | Not listed in registration data |
All five registrations are valid single-ingredient oral tablets from Novartis.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (mTOR inhibitor), not a conventional cytotoxic agent |
| Myelosuppression Risk | Medium (anaemia, neutropenia, thrombocytopenia and leukopenia appear among the knowledge-graph contraindicated conditions) |
| Emetogenicity Classification | Low |
| Monitoring Items | CBC with differential, liver and renal function, fasting glucose and lipids |
| Handling Protection | Please refer to the package insert; follow local hazardous-drug handling practice |
Safety Considerations
- Contraindication-related conditions (from the knowledge graph, not label text): liver failure or liver disease, kidney disease, congestive heart failure, interstitial lung disease, diabetes mellitus, hyperglycaemia and diabetic ketoacidosis, hyperlipidaemia and hypertriglyceridaemia, thrombocytopenia, neutropenia, leukopenia and agranulocytosis, anaemia, haemolytic-uremic syndrome, stomatitis, pericardial effusion, and others. These flag conditions needing caution and must be checked against the official package insert.
- Drug Interactions: 100 interactions were recorded. Those shown include:
- Major: amphotericin B (including the lipid complex), aprepitant, dexamethasone, clarithromycin.
- Moderate: antidiabetic agents (metformin, acarbose, glimepiride, chlorpropamide, and the DPP-4, SGLT2 and GLP-1 classes), cimetidine, eliglustat, eluxadoline.
- Minor: zinc sulfate.
The package insert warnings and contraindications could not be retrieved, so please refer to the package insert for the authoritative safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The only directly relevant evidence is a single-arm Phase 2 combination trial that has not yet completed, so everolimus's own effect in liposarcoma cannot be established. The prediction score is very high, but the clinical evidence is early. The official label safety data have also not been reviewed.
To proceed, the following is needed:
- Final results of NCT03114527, including response and progression-free survival in the dedifferentiated liposarcoma cohort
- Data that separate everolimus's contribution from ribociclib's, ideally a randomised comparison
- The HSA package insert warnings and contraindications, to enable formal safety screening
- Detailed mechanism-of-action data
- A safety and drug-interaction management plan, particularly for CYP3A4-related interactions, cytopenias, and metabolic effects
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.