STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.
"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."
The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.
Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.
Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.
"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).
"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.
"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."
Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.
Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.
The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.
Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.
Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.
Median progression-free survival by independent review was 9.5 months in both cohorts.
The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.
In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.
"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.
Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.