Regorafenib

證據等級: L5

預測適應症: 8 個

Regorafenib: From Metastatic Colorectal Cancer to Liposarcoma

One-Sentence Summary

Regorafenib is an oral multi-kinase inhibitor originally developed for metastatic colorectal cancer, GIST, and hepatocellular carcinoma. The TxGNN model predicts it may be effective for Liposarcoma, with 2 clinical trials and 9 publications currently addressing this specific indication — however, the completed trials report negative efficacy results in liposarcoma specifically, which is an important caveat to the prediction.

Quick Overview

Item	Content
Original Indication	Metastatic colorectal cancer, GIST, hepatocellular carcinoma (drug not licensed in Norway; indication derived from literature, not from a market authorization record)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.76%
Evidence Level	L2
Norway Market Status	✗ Not marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Detailed DrugBank-sourced mechanism-of-action text is not available for this candidate. Based on the repurposing rationale supplied with this evidence pack, regorafenib is a multi-kinase inhibitor acting on VEGFR1–3, PDGFR-β, FGFR1, KIT, RET, and RAF, giving it combined anti-angiogenic and anti-proliferative activity. Liposarcoma, particularly the dedifferentiated subtype, is highly vascular-dependent, and activation of the RAS/RAF/MEK and VEGF signaling pathways is a recognized driver of its pathogenesis — providing a plausible mechanistic overlap with regorafenib's target profile, which is the basis for the TxGNN score.

However, this mechanistic plausibility is not confirmed by clinical outcomes. The two identified trials specifically evaluated liposarcoma as a pre-defined cohort within broader soft-tissue-sarcoma studies, and both report discordant, negative findings for liposarcoma: the REGOSARC trial found regorafenib effective in leiomyosarcoma, synovial sarcoma, and other non-adipocytic sarcomas, but explicitly not in liposarcoma; the SARC024 liposarcoma cohort (a dedicated randomized Phase 2 trial vs. placebo) concluded that results "do not support the routine use of regorafenib in this patient population." This means the high TxGNN score and the mechanistic rationale point in a different direction than the actual completed clinical evidence — a discrepancy that should be weighted heavily in any decision-making.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01900743	Phase 2	Completed	219	REGOSARC: randomized, placebo-controlled trial across 5 STS cohorts (including liposarcoma); reported efficacy in non-adipocytic sarcoma subtypes but not in liposarcoma
NCT02048371	Phase 2	Completed	131	SARC024: multi-cohort trial of oral regorafenib in selected sarcoma subtypes, including a dedicated liposarcoma arm

Literature Evidence

PMID	Year	Type	Journal	Key Findings
27751846	2016	RCT	Lancet Oncol	REGOSARC primary results: regorafenib improved PFS in doxorubicin-refractory STS
32701199	2020	RCT	The Oncologist	SARC024 liposarcoma cohort: results do not support routine use of regorafenib in refractory liposarcoma
29902612	2018	RCT	Eur J Cancer	REGOSARC updated/cross-over analysis: efficacy confirmed in non-adipocytic sarcoma, not in liposarcoma
25884155	2015	Trial Protocol	BMC Cancer	Study protocol for REGOSARC, rationale based on angiogenesis signaling in sarcoma biology
28295221	2017	RCT (secondary analysis)	Cancer	Q-TWiST analysis of REGOSARC quantifying quality-adjusted clinical benefit
29931504	2018	Review	Targeted Oncology	Review of regorafenib's growing role across STS subtypes including liposarcoma
40975452	2025	Review	Crit Rev Oncol Hematol	Review of maintenance therapy strategies in advanced STS after first-line chemotherapy
33290314	2021	Retrospective study (different drug, anlotinib)	Anti-Cancer Drugs	Indirect reference; notes regorafenib/pazopanib approved for non-adipocytic STS, anlotinib studied in liposarcoma
26266019	2015	Case report (different drug, pazopanib)	Rare Tumors	Indirect reference citing SARC024 rationale for adding sarcoma arms including liposarcoma

Norway Market Information

Regorafenib currently has no marketing authorization in Norway (0 licenses on record); no product/dosage-form data is available for this jurisdiction.

Cytotoxicity

Item	Content
Cytotoxicity Classification	Targeted therapy (oral multi-kinase inhibitor: VEGFR1-3, PDGFR-β, FGFR1, KIT, RET, RAF)
Myelosuppression Risk	Low — dose-limiting toxicities reported in the literature are predominantly non-hematologic (hand-foot skin reaction, hypertension, hepatotoxicity, proteinuria) rather than bone marrow suppression
Emetogenicity Classification	Low, consistent with oral TKI class
Monitoring Items	Liver function tests, blood pressure, urinalysis (proteinuria), skin/dermatologic exam (hand-foot skin reaction), CBC
Handling Protection	Oral targeted agent; standard oral-oncolytic handling precautions apply (avoid crushing/splitting, use gloves when handling); does not require IV-cytotoxic handling protocols, but institutional oral-chemotherapy policy should still be followed

Safety Considerations

Please refer to the package insert for safety information. TFDA/Norway-specific warnings, contraindications, and drug-interaction data were not retrievable at this data cutoff (flagged as a Blocking data gap — see Conclusion).

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Evidence level L2 is met on trial-count grounds (two completed Phase 2 RCTs with dedicated liposarcoma cohorts), and the mechanistic rationale (VEGF/PDGFR-driven angiogenesis in liposarcoma) is plausible. However, both trials report that regorafenib specifically failed to demonstrate efficacy in liposarcoma, in contrast to its activity in other soft-tissue sarcoma subtypes. This directional conflict between the TxGNN prediction and the actual clinical trial outcomes means "guardrails" should include an explicit efficacy caveat, not just a general safety caveat.

To proceed, the following is needed:

TFDA/Norway product-label warnings and contraindications (currently a Blocking data gap)
Confirmed drug-interaction profile (DDI query returned no data)
Formal DrugBank-sourced mechanism-of-action and toxicity data to replace the current rationale-derived summary
A structured re-assessment of whether "liposarcoma" as a monotherapy target should be downgraded to Hold, given that both completed trials in this exact indication were negative — combination-therapy or biomarker-selected subpopulation approaches would need separate justification before any development decision
Disclaimer

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