Everolimus

證據等級: L5

預測適應症: 10 個

Everolimus: From Advanced Renal Cell Carcinoma to Liposarcoma

One-Sentence Summary

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor, established in oncology for its use in advanced renal cell carcinoma, hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumours. The TxGNN model predicts it may be effective for liposarcoma, with 1 Phase 2 clinical trial and 4 publications currently supporting this direction.

Quick Overview

Item	Content
Original Indication	Not available from NL registry data (CBG-MEB records empty in dataset)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.88%
Evidence Level	L2
NL Market Status	Not registered (per dataset — see note below)
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

⚠️ Dataset Note: This dataset records zero CBG-MEB authorisations for Everolimus. This likely reflects a data pipeline gap rather than the actual market situation. Everolimus (Afinitor®, Votubia®, Certican®) holds EMA centralised marketing authorisations and is expected to be commercially available in the Netherlands. Please verify the current status directly via the CBG-MEB medicines register before acting on this field.

Why is This Prediction Reasonable?

Detailed mechanism of action data was not included in this Evidence Pack (data gap DG002). Based on established pharmacological knowledge, Everolimus is a first-generation mTOR inhibitor (rapalog class) that acts by binding intracellularly to FKBP12, which then inhibits the mTORC1 complex. This blocks downstream translation of proteins controlling cell-cycle progression (notably S6K1 and 4E-BP1), arresting tumour cells in the G1 phase and suppressing angiogenesis via reduced HIF-1α/VEGF signalling. Its efficacy across multiple solid tumours — including renal cell carcinoma and breast cancer — has been clinically validated.

The biological rationale for liposarcoma is well-grounded. Dedifferentiated liposarcoma (DDL), the most clinically aggressive subtype, demonstrates frequent co-activation of the Akt/mTOR and MAPK pathways, as confirmed by immunohistochemical analysis of 99 DDL specimens (Ishii et al., 2016, PMID 26518767). In vitro studies in the same report showed antitumour activity with mTOR inhibitors in DDL cell lines, directly implicating mTORC1 as a druggable target. This mechanistic overlap with Everolimus’s established activity forms the core basis of the TxGNN prediction.

The current clinical strategy builds on this by pairing Everolimus with ribociclib — a CDK4/6 inhibitor — exploiting the fact that DDL is characterised by MDM2 and CDK4 amplification while leiomyosarcoma (LMS) is particularly mTOR-dependent. Multiple tumour models have demonstrated synergistic growth inhibition when CDK4/6 and mTOR pathways are co-targeted, which further strengthens the mechanistic plausibility of this repurposing prediction.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03114527	Phase 2	Active, Not Recruiting	48	Two-centre, 2-arm study evaluating ribociclib + everolimus in advanced DDL (Arm A) and leiomyosarcoma (Arm B) following ≥1 prior systemic therapy; ribociclib 300 mg/day 3 weeks on/1 week off + everolimus 2.5 mg; primary endpoint is anti-tumour activity; completion expected December 2025

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37967116	2024	Phase 2 Trial Report	Clinical Cancer Research	Published results of NCT03114527 (SAR-096); ribociclib + everolimus in advanced DDL and LMS; CDK4/6 + mTOR co-targeting rationale; synergistic growth inhibition confirmed in multiple tumour models
26518767	2016	Translational Study	Tumour Biology	Akt/mTOR and MAPK pathway activation confirmed immunohistochemically in 99 DDL specimens; in vitro antitumour effect of mTOR inhibitor demonstrated in DDL cell lines — key mechanistic support for mTOR targeting in liposarcoma
36003796	2022	Review	Frontiers in Oncology	Review of CDK inhibitor (palbociclib) combinations in sarcoma PDOX models; supports co-targeting of CDK and mTOR pathways as an effective strategy for liposarcoma and other soft-tissue sarcomas
29848686	2018	Preclinical Study	Anticancer Research	Broad-spectrum preclinical evaluation of eribulin in combination with mechanistically different anticancer agents across liposarcoma xenograft models; contextualises mTOR inhibitor combination rationale

Netherlands Market Information

No RVG numbers or CBG-MEB authorisations are recorded for Everolimus in the current dataset. This is likely a data pipeline issue. Clinicians and pharmacists should verify the current Dutch registration status directly:

CBG-MEB Medicines Register: https://www.geneesmiddeleninformatiebank.nl/
EMA EPAR (Afinitor — centrally authorised): https://www.ema.europa.eu/

The SmPC (Samenvatting van de Productkenmerken) for the relevant authorised product should be consulted for full prescribing information.

Cytotoxicity

Everolimus is an antineoplastic targeted therapy used in oncology. This section applies.

Item	Content
Cytotoxicity Classification	Targeted therapy — mTOR inhibitor (rapalog class); not a conventional cytotoxic
Myelosuppression Risk	Low to moderate — anaemia, thrombocytopenia and neutropenia are reported; less severe than conventional chemotherapy agents
Emetogenicity Classification	Low (oral mTOR inhibitors carry minimal to low emetogenic risk per MASCC/ASCO guidelines)
Monitoring Items	Full blood count (FBC/CBC), liver function tests (ALT, AST, bilirubin), renal function (creatinine, eGFR), fasting blood glucose, serum lipids (cholesterol/triglycerides), pulmonary function assessment (non-infectious pneumonitis is a class effect of mTOR inhibitors)
Handling Protection	Standard precautions for oral antineoplastic agents; follow local cytotoxic drug handling regulations (e.g., NIOSH guidelines or equivalent Dutch pharmacy standards)

Safety Considerations

Please refer to the SmPC (Samenvatting van de Productkenmerken) for complete safety information, including warnings, contraindications, and drug interactions.

Drug interaction data was not found in the current Evidence Pack query (DDI query status: not found). A dedicated DDI review should be performed before clinical use, particularly given Everolimus’s known CYP3A4/P-gp metabolism profile and narrow therapeutic index.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Everolimus has a mechanistically coherent and biologically well-supported basis for activity in liposarcoma — particularly dedifferentiated subtypes — through mTOR pathway dependence, with an active Phase 2 clinical trial (48 patients enrolled) and published trial data meeting L2 evidence threshold. However, the absence of CBG-MEB registry data, incomplete safety records, and an ongoing (not yet completed) Phase 2 trial require resolution before clinical adoption.

To proceed, the following is needed:

Regulatory verification: Confirm current NL market authorisation status via the CBG-MEB medicines register; dataset currently shows zero authorisations, which contradicts known EMA approval status
SmPC review: Retrieve and review the current EMA/CBG-MEB SmPC for Everolimus (Afinitor) to assess labelled warnings, contraindications, and special population restrictions (data gap DG001)
MOA data: Complete DrugBank API query for detailed mechanism of action (data gap DG002)
DDI assessment: Perform a full drug-drug interaction review — everolimus is a CYP3A4 and P-gp substrate with known clinically significant interactions
Trial completion data: Await and review final results from NCT03114527 (Phase 2; completion expected December 2025; currently active, not recruiting)
Histological subtype specification: Define eligible patient population by histological subtype (DDL vs LMS vs other), as efficacy signals in the trial are subtype-specific
Pharmacovigilance plan: Develop a monitoring protocol specifically addressing non-infectious pneumonitis, stomatitis, and metabolic toxicities (hyperglycaemia, hyperlipidaemia) characteristic of mTOR inhibitor therapy
Disclaimer

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