Vismodegib

證據等級: L5

預測適應症: 10 個

Vismodegib: From No Registered Indication (Not Marketed) to Skin Cancer (Basal Cell Carcinoma)

One-Sentence Summary

Vismodegib (DrugBank DB08828) is currently not marketed in this jurisdiction and has no registered original indication on file. Among the 10 TxGNN-predicted indications in this evidence pack, the only one with substantive supporting data is Skin Cancer (Basal Cell Carcinoma), backed by 23 clinical trials and 20 publications, and it corresponds to vismodegib's globally established use as the first-in-class oral Hedgehog-pathway inhibitor. The model's single highest-scoring candidate (medulloblastoma with extensive nodularity, 99.93%) shares the same mechanism but currently has zero retrievable trials or literature, so it is flagged separately below as an unvalidated research question rather than the primary subject of this report.

Quick Overview

Item	Content
Original Indication	Not available — no marketing authorizations on file (untuk market: 未上市)
Predicted New Indication	Skin Cancer (Basal Cell Carcinoma)
TxGNN Prediction Score	99.82%
Evidence Level	L2
Finland Market Status	未上市 (Not Marketed)
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, the formal DrugBank-sourced mechanism-of-action field is flagged as a data gap (DG002, High severity, pending DrugBank API query). Based on the literature evidence retrieved in this pack, however, vismodegib (GDC-0449) is well characterized as the first-in-class, orally bioavailable small-molecule antagonist of the Hedgehog (Hh) signaling pathway. It binds Smoothened (SMO), a seven-transmembrane receptor, blocking downstream activation of GLI transcription factors and suppressing pathway-driven proliferation (PMID 22679179, 22653209, 24756807).

The mechanistic fit to skin cancer is direct rather than inferred: basal cell carcinoma is primarily driven by aberrant Hedgehog signaling, and genomic profiling shows roughly 85% of BCCs carry activating mutations in this pathway (PTCH1 ~73%, SMO ~20%, SUFU ~8%; PMID 26950094). Vismodegib was in fact the first Hedgehog-pathway inhibitor approved (FDA, 2012) specifically for locally advanced and metastatic BCC, and it remains referenced across current European and US treatment guidelines (PMID 37604067, 31288208, 29331385). In this evidence pack, "skin cancer" is therefore best understood not as a novel repurposing hypothesis but as a re-confirmation of vismodegib's canonical, mechanistically validated indication in a market where the product is not yet registered.

Separately, the model's top-ranked candidate overall, medulloblastoma with extensive nodularity (TxGNN score 99.93%), reflects the same SMO/Hedgehog mechanism (SHH-activated molecular subgroup of medulloblastoma) and is biologically plausible, but no clinical trials or literature were retrieved for it in this data pull — it is scored L5/S0 ("Research Question") and requires a dedicated literature search on vismodegib in pediatric/recurrent SHH-medulloblastoma before it can be evaluated further.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01367665	Phase 2	Completed	1232	STEVIE study — large single-arm, open-label safety/efficacy trial of vismodegib 150 mg/day in locally advanced/metastatic BCC; primary supportive safety dataset behind approval
NCT00607724	Phase 1	Completed	68	First-in-human study of GDC-0449 (vismodegib) in refractory advanced/metastatic solid tumors; established dose and safety basis
NCT01815840	Phase 2	Completed	229	Randomized, double-blind comparison of two vismodegib dosing regimens (intermittent vs. induction+intermittent) in multiple BCC
NCT01835626	Phase 2	Completed	24	Vismodegib combined with radiation therapy in locally advanced head/neck BCC
NCT03035188	Phase 2	Completed	40	Neoadjuvant vismodegib in large/recurrent resectable BCC, aimed at scar/tissue-sparing surgery
NCT01631331	Early Phase 1	Completed	15	Pilot study of vismodegib as pre-surgical adjuvant in sporadic BCC
NCT01543581	Phase 2	Completed	3	Placebo-controlled, double-blind trial of vismodegib prior to Mohs micrographic surgery
NCT06357988	Phase 2	Active, not recruiting	35	NCI-MATCH subprotocol T — vismodegib in non-BCC tumors with SMO/PTCH1 mutations (basket trial, mechanism-extension use)
NCT05651828	Early Phase 1	Recruiting	34	Adaptive/personalized intermittent dosing schedules vs. fixed regimens in advanced BCC
NCT05463757	N/A (registry)	Recruiting	80	Netherlands prospective registration study comparing vismodegib and sonidegib in advanced/multiple BCC

Literature Evidence

PMID	Year	Type	Journal	Key Findings
37604067	2023	Review/Guideline	European Journal of Cancer	Updated European consensus guideline (EADO/ESTRO) on BCC diagnosis and treatment, including Hedgehog inhibitor use
34000246	2021	RCT/Cohort	Lancet Oncology	Phase 2 trial of cemiplimab after Hedgehog-inhibitor (incl. vismodegib) failure in locally advanced BCC
31288208	2019	Review/Guideline	European Journal of Cancer	European consensus-based interdisciplinary BCC treatment guidelines
29331385	2018	Review/Guideline	J Am Acad Dermatol	AAD guidelines of care for BCC management
32759706	2020	Review	Int J Mol Sci	Comprehensive review of BCC biology and molecular features
26950094	2016	Cohort/Genomic	Nature Genetics	Genomic profiling of 293 BCCs: 85% carry Hedgehog pathway mutations (PTCH1/SMO/SUFU)
27436804	2016	Review	Actas Dermo-Sifiliográficas	Review of resistance mechanisms to nonsurgical BCC treatments including vismodegib
24756807	2014	Review	Recent Results Cancer Res	MOA review: vismodegib binds SMO, inhibits aberrant Hh pathway activation; notes relevance beyond BCC (medulloblastoma, GI, brain, lung, breast, prostate)
22679179	2012	Review	Clin Cancer Res	Approval-era review of vismodegib pharmacology and Phase 2 basis for FDA approval
22653209	2012	Review	Nature Reviews Drug Discovery	Drug profile at initial FDA approval, MOA and development summary

Finland Market Information

Vismodegib currently has no marketing authorizations on file in this market (market status: 未上市 / Not Marketed; 0 licenses recorded).

Cytotoxicity

Item	Content
Cytotoxicity Classification	Targeted therapy (Hedgehog pathway / Smoothened inhibitor) — not a conventional cytotoxic agent
Myelosuppression Risk	Please refer to the package insert warnings and precautions
Emetogenicity Classification	Please refer to the package insert warnings and precautions
Monitoring Items	Please refer to the package insert warnings and precautions
Handling Protection	Please refer to the package insert warnings and precautions

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Vismodegib's mechanistic and clinical link to skin cancer (BCC) is well established internationally (large Phase 2 safety cohort of 1,232 patients, multiple completed trials, and current treatment guidelines), but the drug has no registration or marketing history in this jurisdiction, so local regulatory and safety data must be established before advancing.

To proceed, the following is needed:

TFDA package insert warnings/contraindications (DG001, Blocking) — required before any S1 safety assessment can proceed
Confirmed mechanism-of-action data via DrugBank API (DG002)
Local drug-drug interaction (DDI) data — current query returned no results
Formal regulatory pathway assessment given zero current market authorizations
Independent literature/trial search for the top-ranked but currently unevidenced candidate (medulloblastoma with extensive nodularity) before it can be scored beyond L5/Research Question
Disclaimer

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