Efficacy and safety of vismodegib in advanced basal-cell carcinoma

Adults aged 18 or older with adequate organ function and ECOG 2 or less. Metastatic: measurable disease by RECIST with histological diagnosis from a metastatic lesion. Locally advanced: at least one lesion of 10 mm or more that a Mohs, head and neck or plastic surgeon considered inoperable or for which surgery was inappropriate (recurrence after 2 or more operations with a low likelihood of surgical cure, or substantial morbidity or deformity); prior radiotherapy was required unless contraindicated or inappropriate. Patients with Gorlin syndrome (21%) were also enrolled. Exclusions: major organ dysfunction, pregnancy, breastfeeding, life expectancy below 12 weeks and inability to swallow capsules. 8 locally advanced patients were excluded from the efficacy analysis because independent review did not confirm BCC.

Primary endpoint: objective response rate by independent review facility; hypothesis: above 20% in locally advanced and above 10% in metastatic disease. In locally advanced disease, response was defined as a 30% or greater reduction in lesion size or complete resolution of ulceration, and complete response as no BCC on biopsy. Secondary endpoints: duration of response, progression-free survival, overall survival and safety.

All patients had at least one adverse event and more than half (57%) had only grade 1 or 2 events. Most common: muscle spasms 68%, alopecia 63%, dysgeusia 51%, weight loss 46%, fatigue 36%, nausea 29%, decreased appetite 23% and diarrhoea 22%. Serious adverse events in 25% and discontinuation because of adverse events in 12%. 7 deaths from adverse events (3 of unknown cause and one each from hypovolaemic shock, myocardial infarction, meningeal disease and ischaemic stroke), which the investigators judged unrelated to the drug. In the final update, grade 3 or higher adverse events occurred in 55.8% (mostly weight loss 8.7% and muscle spasms 5.8%), with no drug-related deaths.

The first approved hedgehog pathway inhibitor (FDA, 2012) and the basis of the vismodegib indication in metastatic BCC or locally advanced BCC that has recurred after surgery or in patients who are not candidates for surgery and radiotherapy. The 2023 EADO guideline recommends hedgehog inhibitors (vismodegib or sonidegib) for locally advanced and metastatic BCC and considers cemiplimab second line.

Single-arm, non-randomised trial without a comparator; the composite response definition in locally advanced disease was specific to this study. Duration of response was short in the first analysis, and many patients stopped treatment because of persistent low-grade side effects (such as dysgeusia and muscle cramps) or personal choice. The relationship of the deaths to the drug was reported as unknown.