Regorafenib
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
Regorafenib: From Colorectal Cancer to Liposarcoma
One-Sentence Summary
Regorafenib (Stivarga) is an oral multikinase inhibitor originally approved for metastatic colorectal cancer, GIST, and hepatocellular carcinoma. TxGNN predicts high relevance for Liposarcoma (score 99.76%), but the two completed Phase 2 RCTs directly testing this indication (REGOSARC, SARC024) both showed no benefit specifically in liposarcoma, even though the drug worked in other sarcoma subtypes — this is a case where mechanistic plausibility is high but direct trial evidence is negative.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Metastatic Colorectal Cancer / GIST / Hepatocellular Carcinoma (per literature in this evidence pack; no EU marketing authorization on file — see Data Gaps) |
| Predicted New Indication | Liposarcoma |
| TxGNN Prediction Score | 99.76% |
| Evidence Level | L2 |
| EU Market Status | ✗ Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Per the drug monograph literature included in this pack (PMID 30069758, 24756792), regorafenib is an oral diphenylurea multi-kinase inhibitor targeting angiogenic receptors (VEGFR1-3, TIE2), stromal receptors (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, RAF). This broad antiangiogenic/multikinase profile is the basis for its approval in colorectal cancer and GIST, and mechanistically extends to soft tissue sarcomas, which are highly dependent on angiogenic signaling.
This mechanistic rationale is exactly why liposarcoma was investigated directly: the REGOSARC trial (NCT01900743, PMID 27751846) tested regorafenib against placebo across five sarcoma cohorts, including a dedicated liposarcoma cohort. The results showed clear efficacy in leiomyosarcoma and synovial sarcoma, but the liposarcoma cohort did not show benefit and was closed early on interim analysis (PMID 29902612). This finding was independently confirmed by the SARC024 trial’s liposarcoma-specific Phase 2 RCT (PMID 32701199), which explicitly concluded that results “do not support the routine use of regorafenib in this patient population.”
In other words: the TxGNN prediction is mechanistically sound (angiogenesis-driven tumor, multikinase inhibitor target match), and it correctly identified that regorafenib and liposarcoma are closely connected in the literature — but the connection reflects two negative Phase 2 RCTs, not a validated new indication. This is a useful example of why high TxGNN scores must be checked against actual trial outcomes rather than mechanism alone.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01900743 | Phase 2 | Completed | 219 | REGOSARC: international placebo-controlled RCT in anthracycline-refractory metastatic soft tissue sarcoma, five cohorts including a dedicated liposarcoma arm (Cohort A) |
| NCT02048371 | Phase 2 | Completed | 131 | SARC024: blanket protocol testing oral regorafenib across selected sarcoma subtypes, including a liposarcoma-specific cohort |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 27751846 | 2016 | RCT | Lancet Oncol | REGOSARC primary results: regorafenib improved PFS in non-adipocytic sarcoma after anthracycline failure |
| 32701199 | 2020 | RCT | The Oncologist | SARC024 liposarcoma cohort RCT: regorafenib showed no significant benefit vs placebo in treatment-refractory liposarcoma |
| 29902612 | 2018 | RCT (updated/crossover) | Eur J Cancer | Updated REGOSARC analysis: efficacy confirmed in leiomyosarcoma/synovial sarcoma, not in liposarcoma |
| 25884155 | 2015 | Protocol | BMC Cancer | REGOSARC trial protocol/rationale, based on angiogenesis’s role in sarcoma biology |
| 28295221 | 2017 | Secondary Analysis | Cancer | Q-TWiST analysis of REGOSARC showing quality-adjusted symptom-free time benefit (non-adipocytic cohorts) |
| 40975452 | 2025 | Review | Crit Rev Oncol Hematol | Review of maintenance strategies in advanced STS, referencing regorafenib trial data |
| 29931504 | 2018 | Review | Targeted Oncology | Overview of regorafenib’s role across sarcoma subtypes, including liposarcoma |
| 33290314 | 2021 | Retrospective (different drug: anlotinib) | Anti-Cancer Drugs | Retrospective study of anlotinib in WDLS/DDLS liposarcoma; cites regorafenib as comparator TKI class |
| 26266019 | 2015 | Case report (different drug: pazopanib) | Rare Tumors | Case report cited as rationale for adding sarcoma arms (including liposarcoma) to SARC024 |
EU Market Information
Regorafenib is currently not marketed in this evidence pack’s EU dataset (market status: Not marketed, 0 authorizations on file). No product/authorization records are available to summarize.
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Targeted therapy (oral multikinase/VEGFR-TKI; not a conventional cytotoxic agent) |
| Myelosuppression Risk | Low — regorafenib’s dose-limiting toxicities per the pack’s TKI-class literature are dermatologic and vascular rather than hematologic; no bone marrow suppression data in this pack |
| Emetogenicity Classification | Low — consistent with oral TKI class |
| Monitoring Items | Liver function tests (TKI-class hepatotoxicity risk, PMID 23981115), blood pressure (VEGF-inhibitor-induced hypertension, PMID 36583425), skin/hand-foot examination (hand-foot skin reaction meta-analysis specific to regorafenib, PMID 23700287), CBC as general baseline |
| Handling Protection | Oral formulation; standard oral anticancer agent handling precautions apply — no injectable/hazardous cytotoxic handling requirement identified in this pack |
Safety Considerations
Please refer to the SmPC for safety information. (Key warnings, contraindications, and DDI data are marked as Data Gaps in this evidence pack — see DG001, a Blocking gap for TFDA/EMA label warnings.)
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic case for regorafenib in liposarcoma is sound, but the two most relevant completed Phase 2 RCTs (REGOSARC, SARC024) both specifically found no benefit in the liposarcoma subgroup, even as they demonstrated benefit in other sarcoma subtypes. Combined with a Blocking data gap on official safety labeling (DG001), this indication does not meet the bar to proceed.
To proceed, the following is needed:
- Resolve DG001 (official EMA/TFDA label warnings and contraindications) before any safety evaluation can begin
- Resolve DG002 (formal DrugBank MOA record) — the MOA used in this report was reconstructed from literature abstracts within the pack, not an authoritative source
- If pursuing regorafenib repurposing further, redirect priority toward clear cell renal cell carcinoma / renal cell carcinoma (disease) (ranks 3 & 10), which carry the same L2 evidence level but are at decision stage S2 (“Research Question”) with a supportive single-arm Phase 2 trial (NCT00664326) and no contradicting negative RCT — a materially stronger evidence position than liposarcoma
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.