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Hedgehog (HH) pathway inhibitors — vismodegib (Erivedge, FDA 2012) and sonidegib (Odomzo,...

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IDBMA-SMO-BCC
ArtTherapeutische Relevanz
Statusreviewed 2026-05-04 | pending_clinical_signoff | actionability review required
ErkrankungenDIS-BCC
QuellenSRC-ESMO-SARCOMA-2024 SRC-NCCN-SKIN-2025

Fakten zur Handlungsfähigkeit

BiomarkerBIO-SMO
VarianteSMO-Aktivierungsmutation — aktiviert den HH-Weg flussabwärts von PTCH1; alle BCC-HH-Streckenaktivierung; Biomarker-Tests für klinische Eignung nicht erforderlich; SMO Mutation identifiziert den HK-Wegfahrer
ErkrankungDIS-BCC
ESCAT-StufeIA
Empfohlene Kombinationenvismodegib 150 mg PO QD (continuous; break after 24 weeks if CR/near-CR to reduce cumulative toxicity; MIKIE study), sonidegib 200 mg PO QD with food (preferred over 800 mg arm — similar efficacy, less toxicity), cemiplimab 350 mg IV q3w — post-HHI progression or HHI-inappropriate patients
Kontraindizierte MonotherapieHHI (Vismodegib/Sonidegib) in der Schwangerschaft — teratogen (Embryo-fetale Toxizität Kategorie X); obligatorische Verhütung erforderlich, HHI bei Gorlin-Syndrom + vorheriger Strahlung — strahleninduziertes BCC-Außenfeld ist kein Hinweis; die Strahlung selbst ist bei Gorliner-Patienten relativ kontraindiziert
Zusammenfassung der BeweiseHedgehog (HH) pathway inhibitors — vismodegib (Erivedge, FDA 2012) and sonidegib (Odomzo, FDA 2015) — are approved for locally advanced BCC (laBCC) not amenable to surgery/radiation, and metastatic BCC (mBCC). Both are SMO antagonists; all BCC harbors HH pathway activation (PTCH1 loss ~90%, SMO mutation ~10–20%), so biomarker testing is not required for clinical eligibility. Key efficacy data: Vismodegib (ERIVANCE, Sekulic et al. NEJM 2012): laBCC ORR 43% (CR 13%), mBCC ORR 30%; mDOR ~7.6 months; CR in laBCC can be durable and enable resection. Sonidegib (BOLT, Migden et al. Lancet Oncol 2015): laBCC ORR 58% (200 mg arm); mBCC ORR 17%. Comparable efficacy; different toxicity profile. Cemiplimab (anti-PD-1, FDA 2021) is approved for laBCC/mBCC after HHI failure or in patients where HHI is not appropriate. SMO secondary mutations (D473H most common) drive acquired HHI resistance — clinical crossover between agents has limited efficacy.

Anmerkungen

ESCAT IA (multiple FDA approvals; phase II/III data). Drug-class toxicity (both HHIs): muscle cramps (~68%), alopecia (~60%), dysgeusia (~55%), weight loss (~45%), fatigue, nausea. A treatment holiday (12 weeks off after initial response) reduces cumulative toxicity without compromising efficacy (MIKIE study). Sonidegib has higher rate of elevated CPK (myopathy risk) than vismodegib — monitor CPK. HHI-to-HHI crossover: generally not effective; SMO D473H resistance mutation not blocked by either approved agent. Consider vismodegib for patients with multiple BCCs (Gorlin syndrome) — can dramatically reduce BCC burden, but long-term toxicity limits chronic use. Cemiplimab is effective post-HHI; PD-L1 testing not required (approved regardless of PD-L1 status).

Verwendet von

Therapeutische Relevanz