Everolimus
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
- Everolimus
- Everolimus: From Renal Cell Carcinoma to Unclassified (Non-Clear-Cell) Renal Cell Carcinoma
Everolimus: From Renal Cell Carcinoma to Unclassified (Non-Clear-Cell) Renal Cell Carcinoma
One-Sentence Summary
Everolimus is an oral mTOR inhibitor globally approved for advanced clear-cell renal cell carcinoma and several other oncology indications. Among 10 TxGNN-predicted new indications for this drug, Unclassified Renal Cell Carcinoma carries the strongest evidence base, supported by 1 identified clinical trial and 9 publications, including two completed randomized Phase 2 trials (ESPN, ASPEN) that directly tested everolimus in this population. This is the highest-priority candidate among the ten predictions reviewed; the others (e.g., liposarcoma, rhabdomyosarcoma subtypes, dermatofibrosarcoma protuberans) remain at earlier, weaker-evidence stages.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Advanced Renal Cell Carcinoma (clear-cell) — globally approved oncology use; India-specific registration record not available in this evidence pack |
| Predicted New Indication | Unclassified Renal Cell Carcinoma (non-clear-cell RCC) |
| TxGNN Prediction Score | 99.72% |
| Evidence Level | L2 |
| India Market Status | ✗ Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Currently, detailed mechanism-of-action data for Everolimus is not available in this evidence pack (flagged as data gap DG002). Based on established pharmacological knowledge, Everolimus is an orally administered mTOR (mechanistic target of rapamycin) inhibitor that blocks the PI3K/AKT/mTOR signalling pathway, and it is globally approved as a targeted oncology agent for advanced clear-cell renal cell carcinoma, among other indications.
The predicted new indication — unclassified (non-clear-cell) renal cell carcinoma — sits within the same organ and tumour lineage as everolimus’s original approved use. Non-clear-cell RCC is a heterogeneous group (papillary, chromophobe, and unclassified histologies) that frequently shows dysregulated PI3K/AKT/mTOR pathway activity, providing a direct mechanistic rationale for extending an mTOR inhibitor already validated in clear-cell disease.
This mechanistic link is not purely theoretical: everolimus has already been tested head-to-head against sunitinib in two randomized Phase 2 trials specifically enrolling non-clear-cell RCC patients (ESPN and ASPEN), plus multiple single-arm and combination studies. This gives the prediction a genuine clinical-trial track record rather than a purely computational hypothesis, which is why the internal scoring assigns this candidate the most advanced decision stage (S3) among all ten predictions for this drug.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04134390 | Phase 2 | Completed | 25 | Pilot study of Cabozantinib (not everolimus) in aged/fragile metastatic RCC patients; references CheckMate 025 data where the hazard ratio in patients >75 years favoured everolimus over nivolumab. Relevance is indirect — the tested drug in this trial is Cabozantinib, not Everolimus. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 26794930 | 2016 | RCT | Lancet Oncology | ASPEN trial: randomized Phase 2 comparison of everolimus vs. sunitinib as first-line therapy in metastatic non-clear-cell RCC |
| 26626617 | 2016 | RCT | European Urology | ESPN trial: randomized multicenter Phase 2 study of everolimus vs. sunitinib in metastatic non-clear-cell RCC |
| 32975815 | 2020 | Phase 2 (combo) | Cancer | Everolimus + bevacizumab as first-line therapy in advanced papillary/unclassified RCC — final results showed encouraging activity |
| 27601542 | 2016 | Phase 2 (combo) | J Clin Oncol | Everolimus + bevacizumab in advanced non-clear-cell RCC with correlative genomic analysis |
| 23180114 | 2013 | Phase 2 (single-arm) | Ann Oncol | Everolimus monotherapy (10 mg/day) until progression or unacceptable toxicity in non-clear-cell RCC |
| 33867192 | 2021 | Phase 1/2 (combo) | European Urology | Lenvatinib + everolimus, single-arm multicenter Phase 2 study in advanced non-clear-cell RCC |
| 24458473 | 2014 | Cohort/Retrospective | Ann Oncol | Outcomes with mTOR inhibitors (temsirolimus/everolimus) in sarcomatoid and non-clear-cell RCC |
| 33593885 | 2021 | Correlative/Biomarker | Clin Cancer Res | Angiokine biomarkers associated with outcomes in an everolimus-vs-sunitinib RCT in non-clear-cell RCC |
| 34765076 | 2021 | Correlative/Biomarker | Kidney Cancer Journal | Tissue-based biomarker analysis from the ASPEN trial (everolimus arm) in non-clear-cell RCC |
India Market Information
Everolimus currently has no marketing registration recorded in this evidence pack (0 licenses, market status: not marketed). India-specific product listings would need to be sourced separately (e.g., CDSCO registry lookup) before market-entry planning.
Cytotoxicity
Everolimus’s original and predicted indications are both oncology indications, and it is used as a targeted anticancer agent, so this section applies.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (mTOR inhibitor) — not a conventional cytotoxic chemotherapy agent |
| Myelosuppression Risk | Low–Moderate; formal toxicity/haematology data not included in this evidence pack — refer to package insert |
| Emetogenicity Classification | Low (typical of oral targeted agents) |
| Monitoring Items | CBC, fasting glucose and lipid panel, liver and renal function, pulmonary symptoms (risk of non-infectious pneumonitis) |
| Handling Protection | Standard oral oncology handling; not classified as requiring cytotoxic hazardous-drug handling precautions |
Safety Considerations
- Drug Interactions: DDI screening identified 383 total interacting drugs. Major-level interactions include Amphotericin B, Amphotericin B (lipid complex), Aprepitant, Clarithromycin, and Dexamethasone. Moderate-level interactions are common with antidiabetic agents (e.g., Metformin, Acarbose, Alogliptin, Canagliflozin, Dapagliflozin, Empagliflozin, Linagliptin, Dulaglutide, Albiglutide, Glimepiride, Chlorpropamide) and Cimetidine, Eliglustat, and Eluxadoline.
Detailed key warnings and contraindications are not available in this evidence pack (blocking data gap DG001) — please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Two completed randomized Phase 2 trials (ESPN, ASPEN) directly tested everolimus against sunitinib in non-clear-cell RCC, supported by several single-arm and combination-therapy studies, giving this prediction a genuine clinical track record and a clear PI3K/AKT/mTOR mechanistic rationale rooted in everolimus’s approved clear-cell RCC use.
To proceed, the following is needed:
- TFDA/CDSCO-equivalent package insert warnings and contraindications (blocking data gap DG001)
- Confirmed mechanism-of-action and original-indication documentation for India labeling purposes (DG002)
- India market registration status (currently 0 registrations) if commercial entry is intended
- Detailed efficacy/safety outcome data from the ESPN and ASPEN RCTs (primary endpoint results, not just trial identification)
- Review of the remaining 9 TxGNN-predicted indications for this drug (e.g., rhabdomyosarcoma, liposarcoma) — currently at earlier evidence stages and held pending further data
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.