Progress in Advanced Basal-cell Carcinoma: Exploring Hedgehog Pathway Inhibition

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 21st Congress of the European Academy of Dermatology and Venereology (EADV)

Prague, Czech Republic / September 27-30, 2012

Prague - Basal-cell carcinoma (BCC) is the most commonly diagnosed human cancer worldwide. Most BCCs are readily treated by surgery, but some lesions progress to an advanced state (locally advanced BCC) or spread to distant sites (metastatic BCC) and are no longer operable or amenable to radiation therapy. Advanced BCC is associated with significant morbidity. Once metastasized, it is highly malignant and is associated with a poor prognosis, with a median survival of 8 to 14 months. Until recently there has been no approved therapy for advanced BCC. However promising clinical studies have been carried out with targeted therapy based on inhibition of the hedgehog signalling pathway, which is aberrantly activated in most BCCs. A number of small-molecule hedgehog pathway inhibitors are in development for the treatment of advanced BCC and the first, vismodegib, became available in the US early in 2012. At the EADV congress, the latest clinical data on the efficacy of the hedgehog pathway inhibitor were reviewed and global safety data were presented.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Almost all basal-cell carcinomas (BCCs) contain genetic alterations that disrupt the hedgehog signalling pathway, resulting in aberrant pathway activation and uncontrolled proliferation of basal cells. Dr. Aleksandar Sekulic, Mayo Clinic College of Medicine, Scottsdale, Arizona, explained that the hedgehog signalling pathway plays an important role in the regulation of cell differentiation and organ formation during normal vertebrate embryonic development, but it is inactive in most adult tissues aside from maintenance and repair. The hedgehog pathway consists of 2 proteins, patched (PTCH) 1 and smoothened (SMO), and over 90% of BCCs show either activation of SMO or functional loss of PTCH1. The hedgehog signalling pathway was therefore identified as a potential therapeutic target for new anticancer treatments, notably BCC.

Hedgehog Pathway Inhibition

Most small-molecule inhibitors of the hedgehog pathway being investigated in BCC directly inhibit the SMO protein. The most widely studied is vismodegib, the first-in-class, oral, selective hedgehog pathway inhibitor. Dr. Sekulic, lead investigator of the ERIVANCE BCC study, reviewed the pivotal data which led to the drug’s recent approval in the US. “The results provided strong evidence that hedgehog pathway inhibition has significant efficacy in locally advanced BCC (laBCC) and metastatic BCC (mBCC) and this is supported by follow-up data,” he stated. The non-randomized study enrolled 71 patients with laBCC and 33 with mBCC (median age 62 years) who had inoperable disease or for whom surgery was unlikely because of ≥2 recurrences and curative resection and/or anticipated substantial morbidity and/or anticipated disfigurement from surgery. All patients received vismodegib 150 mg orally once daily until progression or intolerable toxicity.

The primary end point of ERIVANCE BCC was objective response rate by independent review facility (IRF). The reviewers were given photographs of the patients and radiographic images to assess the change in tumour size. “They showed clearly that the study met the primary end point and we saw significant efficacy,” Dr. Sekulic noted. The objective response rates by IRF were 30.3% for mBCC and 42.9% for laBCC, both significantly greater (P=0.001) than the hypothesized response rates of 10% and 20%, respectively (N Engl J Med 2012;366:2171-9). Most patients had tumour shrinkage. The hedgehog pathway inhibitor has since become available in the US for the treatment of adults with mBCC or with laBCC that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation therapy.

A 6-month update of investigator-assessed end points confirmed the efficacy of the treatment (EADV 2012. Poster 8579). Median duration of response (DOR) remained unchanged in patients with mBCC (12.9 months). Median progression-free survival (PFS) increased by 1.6 months (11.3 to 12.9 months) in laBCC patients and was 9.3 months for the mBCC cohort, similar to the primary analysis.

A 12-month update was presented by Dr. Sekulic shortly afterwards at the annual congress of the European Society for Medical Oncology (ESMO). Findings showed that for the mBCC cohort, median PFS and DOR were maintained at 9.3 months and 14.7 months, respectively. For the laBCC cohort, PFS was maintained at 12.9 months and DOR was non-evaluable due to censoring as a result of a large proportion of patients who continue to be responders at time of data cut-off (ESMO 2012. Poster 1112PD). With a median follow-up of 22.3 months, 1- and 2-year survival rates were 78.0% and 60.3%, respectively, for mBCC and 93.1% and 85.2%, for laBCC.

Treatment-associated Adverse Events

Most patients in ERIVANCE BCC experienced at least one adverse event, observed Dr. Sekulic. The most common ones, occurring in ≥20% of patients, were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, fatigue, nausea, decreased appetite and diarrhea. “Importantly the vast majority of these adverse events occurred as mild or moderate,” he emphasized. Serious adverse events were reported in 25% of patients, only 4% considered to be possibly related to study drug. Seven deaths occurred, none of which was considered to be related to therapy. “There was no common pattern among these deaths and they all occurred a long time after initiation of therapy,” Dr. Sekulic told delegates. The adverse event profile remained unchanged at 6 and 12 months updates.

Gorlin Syndrome

Hedgehog pathway inhibition is also being studied as treatment for Gorlin syndrome (basal cell nevus syndrome), a rare and heritable disease in which patients inherit one defective copy of PTCH1. Thousands of BCCs may occur in a single patient with this syndrome. A clinical trial with vismodegib 150 mg/day was carried out from September 2009 through January 2011 in 42 patients with Gorlin syndrome. “This was started as a randomized trial, but at interim analysis the data were so striking that the Data Safety and Monitoring Board demanded that the placebo arm be stopped and all patients be crossed over into the active treatment arm of the trial,” Dr. Sekulic explained. After 8 months, the mean per-patient rate of new surgically eligible BCCs was significantly lower in the vismodegib group vs. the placebo group (2 vs. 29, P<0.001), “So hedgehog pathway inhibition prevents onset of new disease” he observed. Treatment also significantly reduced lesion size, defined as mean diameter of existing BCCs. In some patients, all BCCs clinically regressed. No tumours progressed during treatment. “This population may not be large, but for these patients this really is a life-changing treatment,” Dr. Sekulic stated.

Global Safety Investigation

The latest data from an ongoing global safety study with vismodegib (STEVIE) show a safety profile similar to that seen in ERIVANCE BCC, reported Prof. Nicole Basset-Séguin, Hôpital Saint-Louis, Paris, France. STEVIE is a single-arm, open-label, phase II multicentre safety study carried out in patients with laBCC or mBCC receiving vismodegib 150 mg orally once daily until disease progression, intolerable toxicity or patient request to discontinue. As of September 2012, 423 patients had been enrolled in 15 countries, including Canada, toward an overall target of up to 800.

Presenting the results of the second interim sub-analysis in the first 150 patients with ≥3 months of follow-up (138 with laBCC and 12 with mBCC, median treatment duration 4.8 months), Prof. Basset-Séguin noted that 112 (74.7%) were still on study drug treatment. Adverse events were the main reason for discontinuation in 10 of the 38 other patients. The most common treatment-emergent adverse events were similar to ERIVANCE BCC, predominantly mild or moderate, Prof Basset Séguin reported. These were muscle spasms (53.3%), alopecia (42.7%), dysgeusia (36.0%). Twenty-two (14.7%) serious adverse events occurred, as well as 8 deaths (5.3%) that were considered unrelated to study medication.

At data-cutoff, with best response available for 124 patients, 24 (19.4%) had achieved complete response and 69 (55.6%) partial response according to RECIST criteria. Only 4 (3.2%) had progressive disease, which remains to be confirmed by further study. Prof Basset-Séguin cautioned that since the study is ongoing, these efficacy data should be considered preliminary, but are consistent with previous findings


Hedgehog pathway inhibition appears to have significant efficacy in laBCC and mBCC, as demonstrated in the ERIVANCE BCC study and updates. The STEVIE study to date confirms the safety of the first in-class inhibitor, vismodegib, in patients with laBCC and mBCC. Hedgehog pathway inhibition also appears effective in shrinking existing BCC and preventing new BCCs in Gorlin syndrome patients. Further trials of this targeted therapy are underway in operable and advanced BCC, including combinations with surgery.

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