Vismodegib Efficacy In Basal Cell Nevus Syndrome Hampered By Adverse Events

Tumour burden and the rate of new surgically eligible basal cell carcinomas are significantly reduced by vismodegib treatment in patients with basal cell nevus syndrome but side effects prevent continuous therapy

medwireNews: Vismodegib can reduce basal cell carcinoma (BCC) tumour burden in patients with basal cell nevus (Gorlin) syndrome but side effects mean continuous treatment is often not possible, indicate phase II study findings.

“Unfortunately, despite their efficacy, inhibitors of hedgehog signalling are associated with adverse events which necessitate treatment interruption in most patients, resulting in tumour recurrence”, the investigators write in The Lancet Oncology.

“To overcome this challenge, additional ongoing studies (eg, NCT01556009 and NCT01815840) are examining alternative dosing schedules, in particular intermittent dosing, of vismodegib.”

The final analysis of the trial confirms interim results showing that the 26 patients given a 150 mg/day dose of the smoothened inhibitor for 3 months developed fewer surgically eligible BCCs and had a reduced tumour burden compared with 15 placebo-treated controls.

During the subsequent open-label phase, 25 patients at two centres were treated for up to 36 months and a further 12 patients at a third centre were monitored for the same length of time, explain Ervin Epstein Jr, from the Children’s Hospital of Oakland Research Institute in California, USA, and co-investigators.

Vismodegib therapy was associated with a significantly reduced rate of new surgically eligible BCCs compared with placebo, at a rate of 2.0 versus 34.0 lesions per patient per year, they report.

Eleven patients crossed over from placebo to vismodegib treatment and this reduced the development of new surgically eligible tumours from 30.0 to 0.4 per patient per year.

The 16 patients who were “very compliant” with treatment, defined as taking at least 80% of vismodegib pills over 36 months, had the greatest benefit, with an average rate of new surgically eligible BCCs of just 0.6 per patient per year. This compared with an average rate of 1.7 lesions for the 14 patients who were “very incompliant” and taking less than 50% of pills.

“We noted that new surgically eligible basal-cell carcinomas recurred during drug breaks but did shrink in size and number after the patient restarted vismodegib”, the researchers write, adding that “patients treated with vismodegib continuously for longer periods of time seemed to have a longer duration of benefit after stopping the drug.”

Indeed, the 10 patients who took the drug continuously for at least 15 months did not return to their baseline BCC burden for 18 months after discontinuing treatment.

Of the 22 patients who stopped taking vismodegib for 6 months or longer, half had a BCC recurrence of at least 50% of baseline tumour burden over a median of 7.0 months. Three of 11 patients had a 90% recurrence over a median of 21.0 months and baseline tumour burden was reached by one patient after a 12-month drug interruption, followed by a second 7-month interruption 8 months later.

However, the researchers emphasize that only 13% of 40 patients overall, and just 17% of 18 patients scheduled to receive 36 months of treatment, were able to tolerate vismodegib therapy without a break.

The most common side effects associated with vismodegib were grade 1–2 symptoms of hair loss (100 vs 7% placebo), muscle cramps (100 vs 7%), dysgeusia (93 vs 7%), weight loss (63 vs 7%), gastrointestinal upset (65 vs 13%) and fatigue (48 vs 0%). Grade 3 adverse events in the vismodegib-treated patients included weight loss (15%), muscle cramps (8%), chest pain (8%) and pneumonia (8%).

The authors note that just 30% of patients who underwent 16–18 months of treatment had complete hair growth within 18 months of discontinuing treatment.

There was one death from laryngeal cancer and another from prostate cancer in patients who had discontinued vismodegib but these were considered probably unrelated to treatment.

Two patients had a BCC that did not shrink or continued to grow during vismodegib treatment but both had other lesions that were not resistant to treatment, the authors add.


Tang JY, Ally MS, Chanana AM, et al. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol; Advance online publication 9 November 2016. DOI:

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