Lenvatinib

Evidence Level: L5

Predicted Indications: 10

Lenvatinib
Lenvatinib: From Renal Cell Carcinoma, Thyroid Carcinoma and Hepatocellular Carcinoma to Liposarcoma

## Pharmacist Assessment Report

Lenvatinib: From Renal Cell Carcinoma, Thyroid Carcinoma and Hepatocellular Carcinoma to Liposarcoma

One-Sentence Summary

Lenvatinib is an oral multi-kinase inhibitor, originally used for advanced renal cell carcinoma (in combination with pembrolizumab or everolimus), radioiodine-refractory differentiated thyroid carcinoma and unresectable hepatocellular carcinoma. The TxGNN model predicts it may be effective for liposarcoma, with 1 clinical trial (a completed Phase 1b/2 single-arm study) and 4 publications (only one of them a clinical study) currently supporting this direction. Evidence is early-stage and comes from a single small, non-randomized study.

Quick Overview

Item	Content
Original Indication	Advanced renal cell carcinoma (in combination with pembrolizumab as first-line treatment, or with everolimus after one prior VEGF-targeted therapy)
Predicted New Indication	Liposarcoma
TxGNN Prediction Score	99.51%
Evidence Level	L2 (one completed Phase 1b/2 study; no randomized evidence)
EU Market Status	Cancelled only (no currently valid authorization in the compiled data)
Number of Authorizations	2 (both cancelled)
Recommended Decision	Hold (research question; see rationale below)

Why is This Prediction Reasonable?

Detailed mechanism-of-action data for lenvatinib was not available in the data compiled for this report. Based on the information that was compiled, lenvatinib inhibits VEGFR1-3, FGFR1-4, PDGFRα, KIT and RET. These pathways drive tumour angiogenesis and growth signalling, which is the basis of its use in renal, thyroid and liver cancers.

Liposarcoma is a soft tissue sarcoma. Anti-angiogenic therapy is mechanistically plausible there. Eribulin, a microtubule inhibitor, already has activity in liposarcoma, so combining it with lenvatinib is a logical approach. Preclinical work on eribulin combinations and a CDK4 biomarker study in dedifferentiated liposarcoma support a rationale for combination therapy.

The link is plausible but indirect. Liposarcoma is biologically different from the carcinomas for which lenvatinib is approved, and the supporting data are early-phase.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03526679	Phase 1/2	Completed	30	Single-arm study (LEADER) of lenvatinib plus eribulin in inoperable or metastatic adipocytic sarcoma and leiomyosarcoma; tests safety and efficacy, with no randomized comparator

Literature Evidence

PMID	Year	Type	Journal	Key Findings
36129471	2022	Phase 1b/2 single-arm trial	Clin Cancer Res	LEADER study of lenvatinib plus eribulin in advanced liposarcoma and leiomyosarcoma, where treatment options are limited
39103896	2024	Preclinical/biomarker study	Exp Hematol Oncol	CDK4 as a prognostic biomarker in soft tissue sarcoma; synergy of CDK4 inhibition in sequential treatment of dedifferentiated liposarcoma
29848686	2018	Preclinical review	Anticancer Res	Eribulin combined with mechanistically different anticancer agents showed broad-spectrum preclinical activity
34326745	2021	Case report	Case Rep Oncol	Marked tumour shrinkage in a dedifferentiated liposarcoma patient with lung metastasis on individualized combined treatment

EU Market Information

Authorization Number	Product Name	Dosage Form	Approved Indication
EMEA/H/C/004224	Kisplyx	Not specified	Advanced renal cell carcinoma (RCC): in combination with pembrolizumab, as first-line treatment; in combination with everolimus, following one prior VEGF-targeted therapy
EMEA/H/C/003727	Lenvima	Not specified	Monotherapy for progressive, locally advanced or metastatic differentiated thyroid carcinoma refractory to radioactive iodine; monotherapy for advanced or unresectable hepatocellular carcinoma with no prior systemic therapy

Both authorizations are listed as cancelled in the data compiled for this report.

Cytotoxicity

Item	Content
Cytotoxicity Classification	Targeted therapy (multi-kinase inhibitor)
Myelosuppression Risk	Please refer to the SmPC warnings and precautions
Emetogenicity Classification	Please refer to the SmPC warnings and precautions
Monitoring Items	Please refer to the SmPC warnings and precautions
Handling Protection	Please refer to the SmPC warnings and precautions

Safety Considerations

Drug Interactions: 260 interactions were identified. Examples include:
- Major: dolasetron, cisapride
- Moderate: clarithromycin, levofloxacin, famotidine, loperamide, granisetron, palonosetron, naltrexone, and several laxatives (bisacodyl, lactulose, magnesium citrate, polyethylene glycol, among others)
- Minor: metronidazole

Please refer to the SmPC for warnings and contraindications.

Conclusion and Next Steps

Decision: Hold (research question)

Rationale: Support for liposarcoma comes from one small, single-arm Phase 1b/2 study (n=30) that also included leiomyosarcoma, with no randomized evidence. Mechanistic reasoning is plausible but indirect. The EU authorizations are listed as cancelled in the compiled data, and safety label data is missing.

Other predictions were also reviewed. Renal carcinoma (rank 7) has the strongest evidence (L1, including the Phase 3 CLEAR trial), but this is already an approved indication and is not a new repurposing opportunity. Non-clear-cell and TFE3-rearranged RCC have early-phase data only. The remaining predictions (including ovarian myxoid liposarcoma, childhood kidney carcinoma, angiolipoma, familial spontaneous pneumothorax and endocrine-cerebro-osteodysplasia syndrome) rest on model scores alone and should be held.

To proceed, the following is needed:

Efficacy and safety results specific to the liposarcoma subgroup of the LEADER study, and ideally a randomized trial
Warnings and contraindications from the SmPC, and clarification of the EU authorization status (cancelled)
Detailed mechanism of action data
A safety monitoring plan, given the many major and moderate drug interactions
Disclaimer

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