NEW ORLEANS - An oral inhibitor of the hedgehog pathway proved dramatically effective for the treatment and prevention of basal cell carcinomas in patients with basal cell nevus syndrome in a phase II study.
Indeed, the randomized double-blind trial was halted early for ethical reasons because patients assigned to vismodegib, formerly known as GDC-0449, demonstrated a 25-fold reduction in the rate of new basal cell carcinomas (BCCs), compared with placebo-treated controls, Dr. Jean Y. Tang reported at the annual meeting of the American Academy of Dermatology.
"We're really excited by these results as dermatologists because we're sick of just chopping up these poor patients' skin, and we’re excited to offer something better," said Dr. Tang of Stanford (Calif.) University.
Basal cell carcinomas are most commonly treated by surgical excision. That;s a traumatic therapy for patients with the genetic disease known as basal cell nevus syndrome (BCNS) because they experience many hundreds of BCCs during their lifetime.
The phase II study involved 41 patients at three medical centers who were randomized 2:1 to vismodegib at 150 mg once daily or placebo for a planned 18 months.
At baseline, the participants collectively had 2,000 existing BCCs. During a median 8 months of follow-up before halt of the study, the patients developed 694 new BCCs. The incidence of new BCCs was 0.07 cancers per month in the vismodegib arm, compared with 1.74 per month in controls.
In addition to preventing new skin cancers, treatment with vismodegib typically began shrinking existing tumors within the first month or two. Sixty percent of biopsied tumors that appeared clinically clear showed histologic clearance.
A side benefit seen after several months of vismodegib therapy was the "remarkable" clearance of the palmar and plantar pits which are a characteristic part of BCNS, Dr. Tang observed.
"Our patients are really struck by this. They’ve lived with this condition all their lives and now they can comfortably shake the hands of strangers," she explained.
Side effects were mild to moderate but sufficiently frequent that the investigators believe 18 months of daily therapy is unlikely to be tolerable. As patients from the placebo arm of the halted phase II study are crossed over to vismodegib, they are being dosed on an intermittent regimen consisting of repeated cycles of 3 months on daily therapy, then 2 months off, with the aim of minimizing side effects.
Eighty-three percent of patients on vismodegib experienced taste loss, typically starting in the first month. Seventy percent reported muscle cramping, again beginning in the first month or two. Half of treated patients experienced significant hair loss which occurred months later than the other side effects. Thirty percent of vismodegib-treated subjects dropped out of the study, because of adverse events. All side effects were completely reversed 1 month after stopping therapy.
Thus far, no tumor resistance has been seen. Patients who stopped the drug after a few months have not experienced a return of tumors to baseline size or number during the next 6 months.
Vismodegib is an oral small molecule antagonist of the smoothened receptor. In binding to smoothened, the drug turns off the hedgehog-signaling pathway, which is inappropriately activated in patients with BCNS, leading to tumor cell growth and proliferation.
Dr. Tang and coworkers became interested in evaluating vismodegib in patients with BCNS after other investigators reported the drug to be effective in a study involving 33 non-BCNS patients with locally aggressive or metastatic BCCs (N. Engl. J. Med. 2009; 361:1164-72).
Remaining questions involving treatment of BCNS patients include the best vismodegib dosing regimen, and whether the tumors will eventually come back after the drug is stopped, she noted.
Dr. Tang is considering conducting a study of vismodegib in non-BCNS patients with a large BCC burden. One audience member suggested including patients with post–radiation therapy BCCs. "I have postradiation patients with 400 BCCs," he said.
Another audience member, a dermatologist involved in the BCNS Network, commented that the buzz circulating among members of the patient support group is focused mainly on the spectacular improvement in quality of life resulting from vismodegib therapy.
Dr. Tang agreed. "The patients say that this medication has completely changed their lives," she said. "These patients have terrible phobias after undergoing tons and tons of biopsies and surgeries, so they're really incredibly grateful for this drug. Obviously there are some side effects, but I think the positive effects of this drug on quality of life cannot be adequately quantitated."
The investigator-initiated phase II study was sponsored by Genentech. Dr. Tang reporting having no commercial financial relationships.