Roxanne Nelson

April 04, 2011

April 4, 2011 (Orlando, Florida) — A novel agent has shown efficacy in the treatment of basal cell nevus syndrome, according to new data presented here at the American Association for Cancer Research (AACR) 102nd Annual Meeting.

Results from a phase 2 trial showed that GDC-0449, a new hedgehog pathway inhibitor that is being developed by Genentech, showed that it reduced the number of lesions and prevented the occurrence of new ones. Some of the patients even achieved near complete remission without developing resistance. However, adverse effects seen with the drug will restrict its use to a small targeted patient population, the researchers told meeting attendees.

Stellar Findings

This is a great breakthrough for these patients — with a capital B.

The drug has a lot of promise, and these findings are stellar, Daniel D. Von Hoff, MD, physician-in-chief and distinguished professor at the Translational Genomics Research Institute in Phoenix, Arizona, told Medscape Medical News. "From a clinical standpoint, having taken care of a fair number of patients with this particular syndrome, I do believe that this is a great breakthrough for these patients — with a capital B."

Dr. Von Hoff was not involved in the study, but moderated a press briefing where highlights of the study were presented ahead of the presentation.

Locating the PTCH Gene

Dr. Ervin Epstein Jr

Basal cell carcinoma is the most common of human cancers, and very rarely metastasizes, explained lead author Ervin Epstein Jr, MD, senior scientist at the Children's Hospital of Oakland Research Institute, California, who presented the results at a plenary session.

Most basal cell carcinomas occur sporadically, and primarily in middle-aged and older adults, he explained. However, in the rare heritable form known as basal cell nevus syndrome, or Gorlin syndrome, the lesions occur in adolescents and even children.

Patients with this syndrome get dozens, hundreds, or even thousands of tumors, he said. "It is these patients that we are studying for a variety of reasons, among which is that we can get statistically significant data from a relatively small population in a short amount of time."

Nevoid basal cell carcinoma syndrome represents a series of multiorgan abnormalities known to be the consequence of abnormalities in the PTCH gene. A decade and a half ago, Dr. Epstein and colleagues identified the PTCH gene, which encodes a primary inhibitor of the hedgehog signaling pathway.

Phase 1 data previously showed that GDC-0449 reduced locally advanced/metastatic basal cell carcinomas.

In the phase 2 study reported at the meeting, Dr. Epstein and colleagues randomized 41 patients, in a 2:1 ratio, to either GCD-0449 150 mg or placebo from September 2009 to January 2011.

The primary end point was to assess the number of new surgically eligible lesions per month after 3 months of treatment. Secondary end points included assessment of the change in size of existing lesions and the safety and tolerability of the agent.

Patients who were treated with GDC-0449 developed 0.07 new lesions per month, compared with 1.74 lesions for those receiving placebo (P < .0001). The size of existing basal cell carcinomas decreased significantly among patients who received GDC-0449 (lesion size decreased 24 cm from baseline), but remained essentially unchanged in the placebo group (decreased 3 cm) (P = .006).

In addition, none of the patients who received GDC-0449 required surgical removal of any basal cell carcinoma lesion during the study period.

Unsuitable for Sporadic Basal Cell Carcinoma

Molecular analysis showed that the antibasal cell carcinoma efficacy of GDC-0449 was associated with on-target reduction of the hedgehog pathway, in that Gli1 messenger (m)RNA levels declined 200-fold (P < .001) after 1 month. In contrast, Gli1 mRNA levels did not change in lesions from patients on placebo.

In addition, the researchers observed that GDC-0449 reduced tumor proliferation (Ki67) but had no effect on apoptosis (CC3). In lesion biopsies obtained after 3 months of GDC-0449 treatment, histologic clearance was evident in 7 of 11 samples.

However, Dr. Epstein pointed out that the agent was associated with a degree of toxicity that made it unsuitable for patients with sporadic basal cell carcinoma. The most common grade 1/2 adverse events were taste loss (83% vs 8%), muscle cramps (67% vs 8%), and weight loss (50% vs 8%).

Grade 3/4 adverse events experienced by 2 patients who received GDC-0449 included muscle cramp and suicide attempt. Overall, 20% of all patients who received GDC-0449 discontinued the drug because of adverse events.

"I do think that the drug is too toxic for the millions of patients with sporadic tumors for which the best surgery now cures about 98% to 99% of them," said Dr. Epstein. "It's going to be very useful for this small population, but we don't know about long-term adverse events, or if we can improve tolerance by intermittent dosing."

The study was funded by Genentech.

American Association for Cancer Research (AACR) 102nd Annual Meeting. Abstract LB 1. Presented April 3, 2011.


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