Regorafenib

證據等級: L5

預測適應症: 8 個

Regorafenib: From Colorectal Cancer/GIST/Hepatocellular Carcinoma to Liposarcoma

One-Sentence Summary

Regorafenib is an oral multi-kinase inhibitor originally approved for metastatic colorectal cancer, gastrointestinal stromal tumour (GIST), and hepatocellular carcinoma. The TxGNN model ranks Liposarcoma as its top predicted new indication (score 99.76%), but the 2 dedicated clinical trials and 9 publications currently available actually report that regorafenib failed to show efficacy specifically in liposarcoma, even though it worked in other soft tissue sarcoma subtypes.

Quick Overview

Item	Content
Original Indication	Metastatic colorectal cancer, GIST, hepatocellular carcinoma (established global approvals cited in literature; no Finland-specific label text available)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.76%
Evidence Level	L2
Finland Market Status	✗ Not Marketed
Number of Authorizations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Regorafenib is an oral multi-kinase inhibitor targeting VEGFR1-3, TIE2, PDGFR-β, FGFR, KIT, RET, and RAF-1/BRAF. This anti-angiogenic and anti-stromal mechanism is biologically plausible for soft tissue sarcomas, which are typically highly vascularized tumours, and overlaps with pazopanib, a multi-kinase inhibitor already approved for non-adipocytic soft tissue sarcoma.

However, the mechanistic plausibility does not hold up in the liposarcoma-specific data. The REGOSARC trial (NCT01900743) enrolled a dedicated liposarcoma cohort and its published results (PMID 29902612) state explicitly that regorafenib demonstrated efficacy in leiomyosarcoma, synovial sarcoma, and other non-adipocytic sarcomas but not in liposarcoma. The SARC024 liposarcoma cohort (NCT02048371, reported in PMID 32701199) independently confirmed this: results "do not support the routine use of regorafenib in this patient population." In other words, two separate Phase 2 trials specifically designed to test this hypothesis returned negative results for liposarcoma, even though the drug's general kinase-inhibition rationale looks sound on paper.

This is a case where the TxGNN network-based score (99.76%, rank 3120) and the raw evidence-level metric (L2, based on trial count/phase) do not capture treatment failure — both qualifying trials were completed and well-designed, but their outcome was negative for this specific tumour subtype.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01900743	Phase 2	Completed	219	REGOSARC trial; randomized, placebo-controlled study across 5 sarcoma cohorts including a dedicated Liposarcoma cohort (Cohort A), in patients previously treated with anthracycline-based chemotherapy
NCT02048371	Phase 2	Completed	131	SARC024 basket study of oral regorafenib across selected sarcoma subtypes, including a liposarcoma-specific cohort

Literature Evidence

PMID	Year	Type	Journal	Key Findings
27751846	2016	RCT	Lancet Oncology	REGOSARC primary results: regorafenib efficacy/safety assessed across STS subtypes in patients previously treated with anthracycline
32701199	2020	RCT	The Oncologist	SARC024 liposarcoma cohort: results confirm prior data and do not support routine use of regorafenib in treatment-refractory liposarcoma
29902612	2018	RCT	European Journal of Cancer	Updated REGOSARC analysis with cross-over data: efficacy shown in leiomyosarcoma/synovial/other non-adipocytic sarcoma but not liposarcoma
28295221	2017	RCT (post-hoc)	Cancer	Q-TWiST analysis of REGOSARC trial (NCT01900743): quality-adjusted PFS benefit in doxorubicin-pretreated advanced non-adipocytic sarcoma
25884155	2015	Trial Protocol	BMC Cancer	REGOSARC study protocol; rationale based on angiogenesis signaling in sarcoma biology
29931504	2018	Review	Targeted Oncology	Overview of regorafenib's evolving role across STS subtypes including liposarcoma
40975452	2025	Review	Critical Reviews in Oncology/Hematology	Review of maintenance therapy strategies after first-line treatment for advanced STS
33290314	2021	RCT (different drug, anlotinib — indirect)	Anti-Cancer Drugs	Retrospective study of anlotinib in WDLS/DDLS; notes regorafenib/pazopanib as approved TKIs in non-adipocytic STS only
26266019	2015	Cohort (different drug, pazopanib — indirect)	Rare Tumors	Case report providing rationale for adding a Ewing sarcoma arm to SARC024

Finland Market Information

Regorafenib currently has no marketing authorization on record in Finland (0 authorizations; market status: not marketed).

Cytotoxicity

Item	Content
Cytotoxicity Classification	Targeted therapy (multi-target tyrosine kinase inhibitor: VEGFR1-3, TIE2, PDGFR-β, FGFR, KIT, RET, RAF-1/BRAF)
Myelosuppression Risk	Low — literature on regorafenib and related TKIs highlights hand-foot skin reaction, hypertension, hepatotoxicity, and proteinuria as the dominant toxicities rather than bone marrow suppression
Emetogenicity Classification	Low (typical of small-molecule multi-kinase inhibitors)
Monitoring Items	Blood pressure, liver function tests, renal function/proteinuria, CBC, skin examination for hand-foot skin reaction
Handling Protection	Standard oral oncolytic handling precautions apply; not a conventional cytotoxic agent requiring cytotoxic-drug reconstitution/handling protocols

Safety Considerations

Please refer to the package insert for safety information. (TFDA/Fimea package insert warnings and contraindications are flagged as a Blocking data gap and are not yet available for this candidate.)

Conclusion and Next Steps

Decision: Hold

Rationale: Although TxGNN ranks liposarcoma as the top predicted indication with a high score, the two dedicated Phase 2 trials that directly tested this hypothesis (REGOSARC and SARC024) both reported that regorafenib failed to demonstrate efficacy specifically in liposarcoma, even while showing benefit in other non-adipocytic soft tissue sarcoma subtypes. Evidence quantity (L2) is not evidence of benefit here — the qualifying data are negative.

To proceed, the following is needed:

TFDA/Fimea package insert warnings and contraindications (currently a Blocking data gap, DG001)
Confirmed DrugBank mechanism of action record (currently a data gap, DG002)
If this indication is to be reconsidered, a mechanistic explanation for why liposarcoma specifically does not respond, and whether a biomarker-selected subpopulation might still benefit
Given the negative liposarcoma signal, evaluate whether clear cell renal carcinoma (rank 3, L2, "Proceed with Guardrails," with a positive single-arm Phase 2 trial in RCC) is a more promising candidate from this same evidence pack
Disclaimer

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