Background
Phase 2, multicenter, randomized, double-blind trial. 230 patients with locally advanced BCC (laBCC) not amenable to curative surgery or radiation, or metastatic BCC (mBCC). Sonidegib (LDE225/Odomzo) is an oral Smoothened (SMO) inhibitor of the hedgehog signaling pathway, similar in mechanism to vismodegib. Patients were randomized 1:2 to 200 mg vs 800 mg daily, stratified by disease type, histological subtype, and geographic region. The study was designed to identify the optimal dose (200 mg vs 800 mg) rather than compare to placebo.
Interventions and follow up
Arm A: Sonidegib 200 mg orally once daily (n=79)
Arm B: Sonidegib 800 mg orally once daily (n=151)
Primary endpoint: ORR in primary efficacy analysis population (fully assessable laBCC + all mBCC) by central review at 6 months post last randomizatio
mFollow up: 13.9 months (IQR 10.1–17.3)
Arm B: Sonidegib 800 mg orally once daily (n=151)
Primary endpoint: ORR in primary efficacy analysis population (fully assessable laBCC + all mBCC) by central review at 6 months post last randomizatio
mFollow up: 13.9 months (IQR 10.1–17.3)
Results
ORR (primary efficacy population) — 200 mg vs 800 mg: 36% (20/55; 95% CI 24–50) vs 34% (39/116; 95% CI 25–43)
ORR laBCC — 200 mg vs 800 mg: 43% (18/42; 95% CI 28–59) vs 38% (35/93; 95% CI 28–48)
ORR mBCC — 200 mg vs 800 mg: 15% (2/13; 95% CI 2–45) vs 17% (4/23; 95% CI 5–39)
ORR laBCC — 200 mg vs 800 mg: 43% (18/42; 95% CI 28–59) vs 38% (35/93; 95% CI 28–48)
ORR mBCC — 200 mg vs 800 mg: 15% (2/13; 95% CI 2–45) vs 17% (4/23; 95% CI 5–39)
Adverse events
Main adverse events: Both doses produced class-effect Hh inhibitor toxicities (muscle spasms, alopecia, dysgeusia, weight loss). Grade 3–4 CK elevation: 200 mg 6% vs 800 mg 13%. Treatment discontinuation: 200 mg 22% vs 800 mg 36%. Dose interruptions or reductions: 200 mg 32% vs 800 mg 60%. Better tolerability profile strongly favors 200 mg.
Conclusions
Sonidegib at both doses achieved comparable ORRs (~36–43% in laBCC), but the 200 mg dose demonstrated a markedly superior benefit-risk profile with fewer grade 3–4 toxicities, fewer discontinuations, and fewer dose reductions. BOLT established 200 mg as the approved dose and confirmed hedgehog inhibition as effective in advanced BCC with a 43% laBCC response rate.
Key Limitations
Key Limitations: Neither arm had a placebo control — this was a dose-comparison design, not a superiority trial vs no treatment. Small mBCC subgroups (N=13 and N=23) limit conclusions in metastatic disease. ORR in mBCC was only ~15–17%, considerably lower than in laBCC. Median DOR at primary analysis was short due to limited follow-up; updated analyses showed median DOR ~22 months (200 mg). Long-term data from 5-year follow-up (Dummer, JCO 2020) confirm durability in sustained responders.
Clinical Context
Sonidegib (Odomzo) received FDA approval for locally advanced BCC (not metastatic) in July 2015, based on BOLT 200 mg arm data. Unlike vismodegib (ERIVANCE), sonidegib's approval is limited to laBCC — not mBCC, due to modest activity in mBCC in BOLT. The 5-year BOLT update (Dummer JCO 2020) showed mDOR of ~22 months in laBCC responders with 200 mg, supporting durable benefit. Cemiplimab (EMPOWER-BCC-1) is now approved after Hh inhibitor progression.
References