Novel drug shows efficacy in basal cell carcinoma

AACR 102nd Annual Meeting

ORLANDO, Fla. — Patients with basal cell nevus syndrome who were treated with GDC-0449, a novel hedgehog pathway inhibitor, were significantly less likely to develop new carcinomas than patients in a placebo group, according to findings presented here at the American Association for Cancer Research 102nd Annual Meeting.

Ervin H. Epstein, MD, senior scientist at Children’s Hospital Oakland Research Institute, said GDC-0449 (Genentech) has demonstrated efficacy in reducing locally advanced or metastatic basal cell carcinomas.

“This trial was conducted based on the fundamental knowledge that hedgehog signaling is pivotal to all basal cell carcinomas, including patients who inherit a defective copy of the gene that inhibits hedgehog signaling,” Epstein said. “This is the first drug that replaces the function of the missing gene.”

The current randomized, double blind, placebo-controlled trial involved 41 patients with basal cell nevus syndrome. Thirty-six of those patients have been enrolled for more than 1 month. Twenty-four of those 36 patients received 150 mg GDC-0449 once daily orally, and 12 patients received placebo.

Efficacy

The independent data safety monitoring board closed the placebo arm of the trial at the interim analysis due to statistically significant differences in outcome measures between the two groups. Patients in the treatment arm developed 0.07 new basal cell carcinomas per month vs. 1.74 new carcinomas per month in the placebo group (P<.0001).

“Indeed, we saw that GDC-0449 does prevent new basal cell carcinomas,” Epstein said. “Fundamentally, the curve for the study drug is flat.”

Compared with baseline measurements, the aggregate size of existing carcinomas changed –24 cm in the treatment arm and –3 cm in the placebo arm (P=.006).

“There is a clear reduction in existing tumor size,” Epstein said. “Tumors that were large enough for surgical excision markedly decreased in size.”

He said the drug works in single large tumors and groups of smaller tumors.

Molecular analysis was conducted in 23 basal cell carcinoma tumors. The study drug was linked to on-target reduction of the hedgehog pathway, yielding 200-fold decreases in Gli1 mRNA (P<.001) after 1 month of treatment for basal cell carcinomas. Patients in the placebo group experienced no change in Gli1 mRNA levels.

The study drug decreased tumor proliferation (Ki67) but did not affect apoptosis (CC3), according to the results. Three-month data indicated that GDC-0449 was associated with histological clearance in seven of 11 lesions available for analysis.

Adverse event profile

The study drug was associated with higher rates of common grade 1-2 adverse events, including taste loss (83% vs. 8%), muscle cramps (67% vs. 8%) and weight loss (50% vs. 8%). One patient in the study drug arm attempted suicide and another experienced severe muscle cramps, which the researchers said were the two instances of grade 3-4 adverse events reported.

The discontinuation rate due to adverse events was 20% in the GDC-0449 arm.

“GDC-0449 does have some adverse events, which makes it not tolerable for the usual patient with one tumor,” Epstein said. “We saw hair loss, muscle cramps and taste loss, which was accompanied by weight loss.”

Many patients dropped out by 1 year, and the tumors recurred. “We do not yet know about long-term adverse events,” he said. “We do not know if we can improve tolerance by intermittent dosing.”

The trial ran from September 2009 to January 2011 and involved patients from three clinical centers in the US.

The main objective was to assess the number of new surgically eligible basal cell carcinomas per month after 3 months of treatment. Change in size of existing carcinomas and safety and tolerability were secondary endpoints.

Epstein said many of these patients have dozens, hundreds or thousands of tumors. “Because of this proliferation, it is possible to get a lot of statistically significant data from a few patients over a short period of time,” he said.

Dr. Epstein reports being a paid consultant for Novartis and Genentech, and stock in Curis.

For more information:

• Epstein E. #LB-1. Presented at: AACR 102nd Annual Meeting; April 2-6, 2011; Orlando, Fla.

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