Erivedge (vismodegib) is the new orally administered hedgehog-pathway inhibitor.
Its results in Basal Cell Nevus Syndrome (Gorlin syndrome) are impressive as shown by Tang, Mackay, Aszterbaum et al in the June issue of New England Journal of Medicine ( 366;23, page 2180). Of 41 patients studied with a combined 2700 basal cell cancers tracked, all tumors responded to vismodegib with nearly complete clinical remission in some patients. However, most basal cell carcinomas regrew once treatment was stopped. Histologic correlation of clinically resolved lesions discovered residual tumors present in only 17% of biopsy samples.
Two significant conclusions were drawn from the study. First, the lack of development of resistance in BCCa’s during treatment and the rarity of metastases correlate with the genomic stability of these cancers. The second conclusion addressed the temporary nature of the response to vismodegib. Drug-tolerant tumor stem cells exist from which regrowth occurs.
Another disappointing feature of the drug is the side effects. 54% of patients discontinued the drug due to side effects within 18 months. These included dysgeusia (alteration or loss of taste), muscle cramps, hair loss, and weight loss. All symptoms reversed within 3 months of stopping the drug.
Sekulic et al study in the same issue of New England Journal of Medicine (366,23; page 2171) evaluated response to vismodegib in advanced basal cell carcinomas – the non-inherited version of the disease. Although majority of patients had responded to treatment, of the patients with locally advanced BCCa’s 60% had a clinical response and 32% had complete response. 54% of biopsies had no residual BCCa. Metastatic BCCa response rate was lower at 45%. Mean duration of response was 11 months. Half the patients had stopped the drug during the study either due to the side effects or due to disease progression.
Unlike the Basal Cell Nevus Syndrome (BCNS) lesions, not all non-inherited advanced BCCa’s respond to treatment, although majority do. In both studies, the duration of response was temporary. The non-inherited BCCa regrew while on vismodegib, while the BCNS BCCa’s regrew after discontinuation of treatment. In both groups, half the patients stopped the drug for various reasons within 18 months of treatment. Histology findings were also similar – with no BCCa found in lesions that recurred at a later time.
A few clinical implications can be drawn from these findings. Treatment with vismodegib means chronic suppression of Basal cell carcinomas and not cure. The limitation of treatment in Basal Cell Nevus Syndrome are primarily side effects. While in non-inherited advanced BCCa’s, the limitation to chronic use is also cancer progression while on therapy. The average duration of response is only a year in advanced BCCa’s.
More research in inhibition of the the hedgehog pathway at different points is needed if medical cure for basal cell carcinoma is to be achieved.
Basal cell nevus syndrome patient
5 months after treatment with vismodegib - complete response achieved. Note the alopecia.
Basal cell nevus syndrome patient
5 months after treatment with vismodegib - significant response achieved.