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 inhibitor (rapalog) with established use in advanced renal cell carcinoma, based on descriptions found in the supporting literature. The TxGNN model predicts it may also be effective for Liposarcoma, with 1 clinical trial and 5 publications currently supporting this direction. No official Taiwan/Norway marketing authorization or label safety data are available for this candidate, which limits the strength of this conclusion.

Quick Overview

Item	Content
Original Indication	Advanced Renal Cell Carcinoma (post-antiangiogenic therapy) — inferred from literature context (PMID 33867192); no formal license/label data available
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.88%
Evidence Level	L2 (1 published Phase 2 trial, formal status still Active/Not Recruiting)
Norway Market Status	✗ Not marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed mechanism of action data was not provided directly in the DrugBank field for this candidate (data gap). However, the supporting literature in this evidence pack consistently and repeatedly describes everolimus as "an mTOR inhibitor" (e.g., PMID 33867192, PMID 27601542), consistent with its known classification as a rapalog. Everolimus was originally used in advanced renal cell carcinoma, a setting where the PI3K/Akt/mTOR signaling axis is a well-established driver of tumor growth.

Liposarcoma — specifically the dedifferentiated subtype (DDL) — shares this same pathway biology. PMID 26518767 directly demonstrates activation of the Akt-mTOR pathway in dedifferentiated liposarcoma specimens, providing a molecular rationale for mTOR-targeted intervention. Because DDL frequently also harbors CDK4 amplification, combining everolimus with a CDK4/6 inhibitor (ribociclib) — as tested in NCT03114527 and reported in PMID 37967116 — offers a mechanistically synergistic approach: CDK4/6 inhibition addresses the cell-cycle driver while mTOR inhibition addresses the downstream survival pathway. This provides a plausible, biology-driven basis for the TxGNN prediction rather than a purely statistical association.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03114527	Phase 2	Active, not recruiting	48	Two-arm study of ribociclib + everolimus in advanced dedifferentiated liposarcoma (Arm A) and leiomyosarcoma (Arm B) after ≥1 prior systemic therapy; evaluates anti-tumor activity of combined CDK4/6 and mTOR inhibition.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37967116	2024	Phase 2 clinical trial report	Clinical Cancer Research	Reports the ribociclib + everolimus (SAR-096) trial; CDK4/mTOR combination shows synergistic growth inhibition in DDL/LMS tumor models, supporting clinical rationale.
36003796	2022	Review	Frontiers in Oncology	PDOX mouse models identify effective combination regimens with CDK inhibitors (e.g., palbociclib) in sarcomas, supporting cell-cycle/mTOR pathway targeting strategy.
26518767	2016	Mechanistic/immunohistochemical study	Tumour Biology	Demonstrates activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcoma specimens; in vitro data show antitumor effect of an mTOR inhibitor.
29848686	2018	Preclinical	Anticancer Research	Evaluates eribulin in combination with mechanistically different anticancer agents in liposarcoma models; broad-spectrum combination antitumor activity context.
41991999	2026	Mechanistic study	Oncogene	Identifies XPO1 inhibitor (selinexor) disruption of the core transcriptional circuitry driving DDLPS; supports the concept of targeting dysregulated survival/transcriptional pathways in this tumor type.

Norway Market Information

Currently not marketed in Norway; no license/authorization records are available in the evidence pack.

Cytotoxicity

Everolimus is an oncology-use mTOR-targeted agent and is therefore included here.

Item	Content
Cytotoxicity Classification	Targeted therapy (mTOR inhibitor / rapalog) — not a conventional cytotoxic agent
Myelosuppression Risk	Not available in the evidence pack; please refer to the package insert
Emetogenicity Classification	Not available in the evidence pack; please refer to the package insert
Monitoring Items	Not available in the evidence pack; please refer to the package insert
Handling Protection	Not available in the evidence pack; please refer to the package insert

Safety Considerations

Please refer to the package insert for safety information. No key warnings, contraindications, or drug-drug interaction data were available in this evidence pack.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: There is a biologically plausible mechanistic link (Akt-mTOR pathway activation in DDL) and an actively reported Phase 2 combination trial (ribociclib + everolimus), which together support cautious further evaluation. However, the trial itself is not yet formally completed, and this candidate carries a Blocking data gap (TFDA/local label warnings and contraindications) that must be resolved before any safety-relevant decision can be finalized.

To proceed, the following is needed:

Resolve DG001 (Blocking): obtain official label/package insert warnings and contraindications
Resolve DG002 (High): confirm mechanism of action via DrugBank API query
Confirm formal completion and topline results of NCT03114527
Clarify the original approved indication(s) via an authoritative regulatory source, since taiwan_regulatory.licenses is currently empty and the "original indication" in this report was inferred from literature context only
Disclaimer

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