Everolimus

證據等級: L5

預測適應症: 10 個

Everolimus: From Renal Cell Carcinoma to Liposarcoma

One-Sentence Summary

Everolimus is an mTOR (mechanistic target of rapamycin) inhibitor globally approved for renal cell carcinoma, hormone receptor-positive breast cancer, pancreatic neuroendocrine tumors, and organ transplant rejection prevention. The TxGNN model predicts it may be effective for Liposarcoma (specifically dedifferentiated liposarcoma, DDL), with 1 Phase 2 clinical trial and 5 publications currently supporting this direction.

Quick Overview

Item	Content
Original Indication	No regulatory record for New Zealand (globally approved for renal cell carcinoma, breast cancer, neuroendocrine tumors, transplant rejection)
Predicted New Indication	Liposarcoma (Dedifferentiated Liposarcoma, DDL)
TxGNN Prediction Score	99.88%
Evidence Level	L2
New Zealand Market Status	Not Marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in the current Evidence Pack. Based on established pharmacology, Everolimus is a rapalog-class mTOR inhibitor that binds to FKBP-12, forming a complex that selectively inhibits mTORC1. This suppresses downstream signalling through S6K1 and 4E-BP1, leading to reduced cell proliferation, protein synthesis, angiogenesis, and tumour metabolism. Its efficacy in clear-cell renal cell carcinoma and other mTOR-driven malignancies is well established.

Dedifferentiated liposarcoma (DDLPS) is one of the two most common subtypes of soft-tissue sarcoma, characterised by CDK4 gene amplification and aggressive clinical behaviour. Immunohistochemical and in vitro analysis of 99 DDLPS specimens has directly demonstrated dual activation of both the AKT/mTOR and MAPK pathways in this tumour type (PMID 26518767), providing strong mechanistic justification for mTOR inhibitor use. This pathway activation is not merely incidental — it drives tumour proliferation and resistance to conventional chemotherapy.

The clinical hypothesis tested in NCT03114527 combines Ribociclib (a CDK4/6 inhibitor targeting the Rb-E2F axis) with Everolimus (mTOR inhibition) to achieve simultaneous dual-pathway blockade. Preclinical models across multiple tumour types have shown synergistic growth inhibition when these two mechanistically distinct targets are co-inhibited, making this combination rationally compelling for CDK4-amplified DDLPS.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03114527	Phase 2	Active, Not Recruiting	48	Two-arm trial: Ribociclib 300 mg/day (3 weeks on/1 week off) + Everolimus 2.5 mg daily in advanced DDL (Arm A) and LMS (Arm B) with ≥1 prior systemic therapy; Phase 2 results published 2024 (PMID 37967116)

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37967116	2024	Phase 2 Trial Results	Clinical Cancer Research	Phase II results of Ribociclib+Everolimus in advanced DDL and LMS; evaluated CDK4/6 and mTOR co-blockade; synergistic growth inhibition confirmed in multiple preclinical tumour models
26518767	2016	Translational/Mechanistic	Tumour Biology	AKT/mTOR and MAPK pathway activation demonstrated by immunohistochemistry in 99 DDLPS specimens; in vitro mTOR inhibitor antitumour effects evaluated, supporting mechanistic rationale
36003796	2022	Preclinical Review	Frontiers in Oncology	PDOX mouse model platform for sarcoma used to identify effective CDK inhibitor combinations; highlights intersection of CDK and mTOR pathway targeting in soft-tissue sarcomas
29848686	2018	Preclinical	Anticancer Research	Eribulin combined with mechanistically distinct agents (including mTOR inhibitors) evaluated in liposarcoma xenograft models; provides preclinical combination landscape context
41991999	2026	Preclinical/Translational	Oncogene	XPO1 inhibitor KPT-330 disrupts core transcriptional regulatory circuitry in DDLPS; contextualises the broader targeted therapy landscape and identifies translation-level vulnerabilities

New Zealand Market Information

Everolimus currently has no regulatory authorizations recorded in New Zealand. No product listings, dosage forms, or approved indications are available in the current regulatory record.

Cytotoxicity

Everolimus meets criteria for the antineoplastic section: it is globally approved and used for oncological indications (renal cell carcinoma, breast cancer, neuroendocrine tumours) and belongs to the targeted anticancer drug class.

Item	Content
Cytotoxicity Classification	Targeted therapy — mTOR inhibitor (rapalog class); not a conventional cytotoxic agent
Myelosuppression Risk	Low to Moderate — lymphopenia and thrombocytopenia are reported; anaemia and neutropenia less common than with conventional cytotoxics; haematological toxicity is manageable
Emetogenicity Classification	Low (oral administration; nausea generally mild)
Monitoring Items	CBC with differential, fasting blood glucose and HbA1c (hyperglycaemia risk), serum creatinine, liver function tests (AST/ALT), lipid panel (hyperlipidaemia), pulmonary function assessment (non-infectious pneumonitis is a class-specific toxicity), wound healing assessment if perioperative
Handling Protection	Standard oral targeted therapy handling precautions; cytotoxic waste disposal per institutional policy recommended

Safety Considerations

Key warnings, contraindications, and drug interaction data are not available in the current Evidence Pack for New Zealand.

Please refer to the package insert for safety information. Particular attention should be paid to non-infectious pneumonitis, immunosuppression-related infection risk, hyperglycaemia, and mucositis — known class effects of mTOR inhibitors that require proactive monitoring.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: A Phase 2 clinical trial (NCT03114527) directly evaluating Ribociclib + Everolimus in dedifferentiated liposarcoma has been completed and published (PMID 37967116, 2024), and independent mechanistic evidence confirms AKT/mTOR pathway activation in DDLPS tumour specimens (PMID 26518767). Together, these constitute Level 2 evidence with a clear biological rationale, justifying advancement to the next evaluation stage under defined guardrails.

To proceed, the following is needed:

Full review of NCT03114527 published results (PMID 37967116) to assess primary efficacy endpoints (PFS, ORR) and dose-limiting toxicities in the sarcoma-specific population
New Zealand or international package insert acquisition to complete the safety profile (warnings, contraindications, drug-drug interactions — currently blocking data gaps DG001/DG002)
Mechanism of action documentation (MOA data gap DG002) to support regulatory submission narrative
Molecular patient selection criteria: prospective identification of patients with confirmed CDK4 amplification and/or mTOR pathway hyperactivation is recommended to maximise benefit-risk
Dose optimisation confirmation: the trial used Ribociclib 300 mg (reduced from standard 600 mg) + Everolimus 2.5 mg — dose rationale and tolerability data should be reviewed before clinical application
Disclaimer

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