Regorafenib

Evidence Level: L5

Predicted Indications: 10

Regorafenib
Regorafenib: From Metastatic Colorectal Cancer, Hepatocellular Carcinoma and GIST to Liposarcoma

## Pharmacist Assessment Report

Regorafenib: From Metastatic Colorectal Cancer, Hepatocellular Carcinoma and GIST to Liposarcoma

One-Sentence Summary

Regorafenib is an oral multi-kinase inhibitor originally used for metastatic colorectal cancer, hepatocellular carcinoma and gastrointestinal stromal tumour (GIST). The TxGNN model predicts it may be effective for liposarcoma, but only 1 clinical trial and several publications address this directly, and the randomised data are largely negative for liposarcoma.

Quick Overview

Item	Content
Original Indication	Metastatic colorectal cancer, hepatocellular carcinoma, GIST (from the knowledge-graph indication list; the Singapore licence record contains no indication text)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.76%
Evidence Level	L2 (the data compiled for this report label it L1, but no Phase 3 RCT exists; by the strict definitions it is L2)
Singapore Market Status	✓ Marketed
Number of Registrations	1
Recommended Decision	Proceed with Guardrails (see the caveats in the conclusion)

Why is This Prediction Reasonable?

Regorafenib is a multi-kinase inhibitor that targets angiogenic kinases (VEGFR1-3, TIE2), stromal kinases (PDGFR, FGFR) and oncogenic kinases (KIT, RET, RAF). Detailed mechanism-of-action data were not available from the drug database, so this description comes from the published literature.

Its original indications are solid tumours that depend on angiogenesis and kinase signalling. Soft tissue sarcomas, including liposarcoma, share some of this biology, which is the basis for the model's prediction. Related multi-kinase inhibitors (sorafenib, sunitinib, pazopanib) have shown activity in some soft tissue sarcomas.

However, the efficacy signal in liposarcoma appears weaker than in other sarcoma subtypes. The REGOSARC trial showed benefit in non-adipocytic sarcomas but not in liposarcoma. The liposarcoma cohort of SARC024 likewise did not support routine use. The prediction is therefore mechanistically plausible but not clinically confirmed.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02048371	Phase 2	Completed	131	SARC024: blanket protocol of oral regorafenib in selected sarcoma subtypes, with liposarcoma as a defined cohort

Literature Evidence

PMID	Year	Type	Journal	Key Findings
32701199	2020	RCT	The Oncologist	SARC024 liposarcoma cohort (randomised, placebo-controlled Phase 2): results do not support routine use of regorafenib in this population
27751846	2016	RCT	Lancet Oncology	REGOSARC randomised placebo-controlled Phase 2 trial in anthracycline-pretreated advanced soft tissue sarcoma
29902612	2018	RCT	European Journal of Cancer	Updated REGOSARC analysis including cross-over: efficacy in non-adipocytic sarcoma, but not in liposarcoma
28295221	2017	Secondary analysis of RCT	Cancer	Quality-adjusted time without symptoms or toxicity analysis of REGOSARC
29931504	2018	Review	Targeted Oncology	Growing role of regorafenib across sarcoma subtypes
40975452	2025	Review	Critical Reviews in Oncology/Hematology	Maintenance therapy after first-line treatment for advanced soft tissue sarcoma
25884155	2015	Study protocol	BMC Cancer	REGOSARC trial protocol
33290314	2021	Retrospective study (different drug)	Anti-Cancer Drugs	Anlotinib in liposarcoma; indirect evidence only

Singapore Market Information

Authorization Number	Product Name	Dosage Form	Approved Indication
SIN14360P	Stivarga Tablet 40mg (Bayer AG, Leverkusen)	Film-coated tablet	Not listed in the available record

Cytotoxicity

Item	Content
Cytotoxicity Classification	Targeted therapy (multi-kinase inhibitor)
Myelosuppression Risk	Please refer to the package insert warnings and precautions
Emetogenicity Classification	Please refer to the package insert warnings and precautions
Monitoring Items	Literature on the drug class highlights hepatic toxicity, hand-foot skin reaction, hypertension and proteinuria; monitor liver function, blood pressure, urine protein and skin. Please also refer to the package insert.
Handling Protection	Please refer to the package insert warnings and precautions

Safety Considerations

Drug Interactions: 100 interactions were identified; the top 20 were reviewed. Major interactions include:
- Acetylsalicylic acid
- Deferasirox
- Ibritumomab tiuxetan
- Tositumomab (including I-131)
- Abciximab
- Alteplase
- Antithrombin III human
- Apixaban
Moderate interactions include dexamethasone, clarithromycin, naltrexone, rosuvastatin, cobicistat, fenfluramine, dexfenfluramine and sibutramine. Several of the major interactions involve anticoagulants, antiplatelets or thrombolytics, so bleeding risk should be reviewed in any co-prescription.

Package insert warnings and contraindications were not available. Please refer to the package insert for the full safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Regorafenib is marketed in Singapore and has randomised Phase 2 data in sarcoma. However, the liposarcoma-specific results (SARC024 and REGOSARC) did not show benefit and do not support routine use. The recommendation therefore applies only to a cautious, research-oriented approach. Given the negative randomised signal, a Hold for routine clinical use would also be defensible.

To proceed, the following is needed:

Review of the Singapore package insert, including warnings, contraindications and approved indications, since the available record has none
Detailed mechanism-of-action data
Subtype-specific analysis (well-differentiated, dedifferentiated, myxoid and other liposarcoma) to identify any responsive subgroup
Evaluation of combination approaches, as the SARC024 authors suggest
A bleeding and hepatic safety monitoring plan, with a review of the major anticoagulant and antiplatelet interactions
Disclaimer

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