HEDGEHOG INHIBITORS FOR BASAL CELL CARCINOMA

(New Orleans, Louisiana) — The investigational hedgehog pathway inhibitor GDC-0449 (Genentech) has shown "dramatic" efficacy in reducing the number of new and existing basal cell skin cancers in patients with basal cell nevus syndrome (BCNS), according to research presented here at a late-breaking study session at the American Academy of Dermatology 69th Annual Meeting.
"Currently, surgery is the standard treatment for basal cell carcinoma [BCC]. However, surgery is not an option for patients with really bad BCCs, locally aggressive or metastatic disease, and certainly not for patients who suffer from this genetic disorder of basal cell nevus syndrome," said Jean Y. Tang, MD, from Stanford University in Palo Alto, California. "There is no treatment to prevent these tumors and these patients [undergo] hundreds of surgeries in their lifetime."
Patients with BCNS, also known as Gorlin syndrome, and BCC tumors have mutations in components of the hedgehog signaling pathway that keep it constantly turned on and lead to tumor cell growth and proliferation.
"Molecularly targeted therapies focus on turning this pathway off, and one way to do that is to antagonize the smoothened receptor, which would inactivate the pathway and stop BCC growth," Dr. Tang explained. "GDC-0449 is a small molecule that does just this. It targets the hedgehog pathway by binding to the smoothened receptor. Therefore, we hypothesized that it would stop BCC development in patients with BCNS."
Accordingly, Dr. Tang and her team initiated a phase 2 randomized double-blind placebo-controlled trial in which they enrolled 41 patients from 3 centers and assigned them in a 2:1 ratio to receive oral GDC-0449 150 mg or placebo once daily for 18 months.
The average age of the patients was 54 to 60 years, and they were balanced in terms of sex and weight. At baseline, both groups had 23 or 24 BCCs; they were followed for an average of 8 months.
The researchers found that subjects who were randomized to GDC-0449 had very few BCCs develop over time — 0.07 BCCs per month — compared with 1.74 BCCs per month for patients on placebo (P < .0001). GDC-0449 also significantly reduced the size of existing BCCs (P = .006).
Dr. Tang reported that some patients achieved a near-complete remission and that no resistance to the drug developed.
Palmar pits, a common feature of BCNS, disappeared among patients on the active drug. "Our patients are just struck by this. They've lived with this all their lives and now they can comfortably shake the hands of strangers," she noted.
Because of the big difference in the results, the data safety and monitoring board voted to end the placebo group. The investigators are currently converting participants in the placebo group to the active drug and testing different regimens.
"We're really excited as dermatologists because we're sick of just chopping up these poor patients' skin and we're excited to offer something better," she said.
In an interview with Medscape Medical News, Dr. Tang admitted she is elated with these results. "It is fantastic to us. It feels like this drug could really change the treatment and management of BCCs in these unfortunate patients. For the first time ever, there's something that works besides surgery."
Adverse Effects a Problem for Some
The adverse effects — most notably loss of taste, muscle cramps, and hair thinning — caused 20% of patients to stop treatment.
"These side effects may limit the drug's usefulness. I would tell a patient with this syndrome that if they have a big burden of disease — we're talking 50 or more BCCs — the side-effect profile is worth it, but if they have less than 10 or 20, I'm not sure the side effects are worth it," she said. "But these kinds of discussions need to be made on an individual patient-by-patient basis."
The researchers want to determine whether GDC-0449 can be given intermittently.
"I think because of the side-effect profile, most patients probably won't tolerate taking it every single day for the rest of their lives. Most likely this medication would be given in low doses, or perhaps patients can be on it for 6 or 12 months every few years just to clean up and reduce the burden of BCC tumors on their skin," she said.
The response from the patients has been extremely positive, Dr. Tang said.
"Basically, all of the BCNS patients are connected to each other on Facebook now. One of the first came back to us in tears and told us 'Doctor, this is the first month I've never had a biopsy in 10 years'. The patients are incredibly grateful for this treatment," she said.
The adverse effects are impossible to hide; as a result, patient advocacy groups have been questioning the ethics of having a placebo group, Dr. Tang added.
"Going forward, we won't have one anymore, but it was important to establish our statistical end points," she said.
"This is the first ever molecularly targeted drug against the hedgehog pathway for basal cells, and it basically opens up a new era for treatments of basal cell cancers," Dr. Tang said. "There are a lot of other tumors that are hedgehog-driven, and we hope that whatever we learn in this trial can help other patients with hedgehog-driven tumors."
Richard L. Gallo, MD, PhD, told Medscape Medical News that he found the results of this study "exciting."
"This is a great example of the benefit of understanding the molecular pharmacology of some of these drugs and the pathophysiology behind the origin of these diseases, so the results are very encouraging," he said after the presentation.
"It appears that the side-effect profile so far is very tolerable in this patient population," noted Dr. Gallo, who moderated the late-breaking abstract session. "Clearly, the comments from the patient advocates support what the investigators are saying. I think there will be only good things to say about this in the future."
This study was supported by Genentech. Dr. Tang has disclosed no relevant financial relationships. Dr. Gallo reports financial relationships with Allergan, Ceregenex, Galderma, Inimex, Intendis, Johnson and Johnson, Novartis, and Skin Epibiotics.