Sorafenib
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Sorafenib: From Hepatocellular Carcinoma to Liposarcoma
One-Sentence Summary
Sorafenib is an oral multikinase inhibitor originally used to treat hepatocellular carcinoma, renal cell carcinoma and thyroid carcinoma. The TxGNN model predicts it may be effective for Liposarcoma, but support is thin: 1 clinical trial (a Phase 2 study in mixed soft tissue sarcomas) and 8 publications, of which only a few are clinical and none are liposarcoma-specific.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hepatocellular carcinoma (also liver cancer subtypes, renal cell carcinoma, thyroid carcinoma) |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.82% |
| Evidence Level | L2 |
| US Market Status | Cancelled only (all 6 listed authorizations are cancelled) |
| Number of NDAs | 6 (1 NDA and 5 ANDAs) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Sorafenib is a multikinase inhibitor. It blocks the RAF/MEK/ERK signalling pathway as well as VEGFR, PDGFR and KIT. The data compiled for this report did not include a formal mechanism-of-action entry, but these targets are well described for the drug.
Both the RAF/MEK/ERK pathway and angiogenesis signalling are implicated in soft tissue sarcoma growth. This is the basis for the prediction: sorafenib acts on tumour growth and blood supply pathways that sarcomas also use. Preclinical work in dedifferentiated liposarcoma cell lines and xenograft models is supportive but not specific to sorafenib’s activity.
The clinical picture is less encouraging. In Phase 2 studies of advanced soft tissue sarcomas, liposarcoma was only one histologic subgroup. Activity was modest and was seen mainly in vascular sarcomas, not liposarcoma. The TxGNN score is therefore best read as a hypothesis, not as confirmation of efficacy.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00217620 | Phase 2 | Completed | 51 | Sorafenib (BAY 43-9006) in advanced soft tissue sarcomas. Liposarcoma is included as a subtype, but results are not liposarcoma-specific and the study is single-arm, not a randomized comparison. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 21751200 | 2012 | Phase 2 trial | Cancer | SWOG-directed intergroup trial (S0505) of sorafenib in advanced soft tissue sarcomas; sorafenib targets RAF, VEGFR1-3, PDGFR-B, FLT3 and KIT. |
| 24554062 | 2014 | Phase 1 trial | Ann Surg Oncol | Neoadjuvant conformal radiotherapy plus sorafenib in locally advanced extremity soft tissue sarcoma. |
| 22987955 | 2012 | Review | Ann Oncol | Treatment of soft tissue sarcomas by histology; trabectedin is highlighted for liposarcoma, particularly myxoid liposarcoma. |
| 24712007 | 2014 | Review | Magy Onkol | Histology-driven medical treatment of soft tissue sarcomas. |
| 36003796 | 2022 | Review | Front Oncol | Patient-derived orthotopic xenograft models used to find combination therapies with palbociclib in sarcoma. |
| 18413802 | 2008 | Preclinical | Mol Cancer Ther | Sorafenib inhibits growth and MAPK signalling in malignant peripheral nerve sheath tumour cells; dedifferentiated liposarcoma cell lines were also tested. |
| 23416162 | 2013 | Preclinical xenograft | Am J Pathol | Dedifferentiated liposarcoma xenograft models showing PTEN down-regulation and response to PI3K pathway inhibition. |
| 25075796 | 2014 | Case report | Anti-Cancer Drugs | Response to trabectedin in synovial sarcoma; not about sorafenib. |
US Market Information
All six US authorizations listed are currently cancelled. Approved indication text was not available for any of them.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA021923 | Nexavar (Bayer HealthCare) | Film-coated tablet | Not available |
| ANDA207012 | Sorafenib Tosylate (Mylan) | Film-coated tablet | Not available |
| ANDA209567 | Sorafenib (Teva) | Film-coated tablet | Not available |
| ANDA216073 | Sorafenib (Dr. Reddy’s) | Film-coated tablet | Not available |
| ANDA217095 | Sorafenib (Torrent) | Film-coated tablet | Not available |
A sixth authorization, ANDA209050 (Golden State Medical Supply), is also cancelled.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (multikinase inhibitor), not a conventional cytotoxic |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions. The knowledge graph lists thrombocytopenia, neutropenia and agranulocytosis among contraindication-related conditions. |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Please refer to the package insert warnings and precautions. Reasonable items include CBC, liver function, blood pressure and electrolytes (phosphate), given the conditions listed below. |
| Handling Protection | Please refer to the package insert warnings and precautions |
Safety Considerations
- Drug-disease cautions (from a knowledge graph, not label text): The following conditions are flagged: hypertension, liver failure, thrombocytopenia, neutropenia, agranulocytosis, blood coagulation disease, acute coronary syndrome, coronary artery disease, myocardial infarction, myocardial ischemia, anemia, hemoglobinopathy, hypophosphatemia, pancreatitis, and anxiety, neurotic and dysthymic disorders.
- Drug Interactions: 100 interactions were found. Notable examples:
- Major: Dolasetron.
- Moderate: Clarithromycin, Dexamethasone, Levofloxacin, Famotidine, Loperamide, Palonosetron, Naltrexone, and several laxatives or bowel-preparation agents (bisacodyl, lactulose, lactitol, sodium sulfate, polyethylene glycol).
- Minor: Dapagliflozin, Metronidazole, Naloxegol.
- In combination trials, hand-foot skin reaction was a recognised toxicity that limited combination use.
Package insert warnings and contraindications were not available for this report; please consult the current label.
Conclusion and Next Steps
Decision: Hold
Rationale: The only direct evidence is a single-arm Phase 2 in mixed soft tissue sarcomas, and published results show modest activity concentrated in vascular sarcomas rather than liposarcoma. Other trials and studies are small, non-specific or preclinical. Established agents such as trabectedin have stronger histology-specific support. All US sorafenib authorizations are also currently cancelled.
To proceed, the following is needed:
- Liposarcoma-specific response data, for example subgroup analysis from the S0505 and NCT00217620 trials
- Package insert warnings and contraindications (a blocking safety gap)
- Detailed mechanism-of-action data from DrugBank
- Clarification of current US market and supply status
- Comparison with standard liposarcoma therapies, and a safety plan covering cardiovascular, hepatic and hematologic risks
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.