Investigational drug targeting hedgehog pathway yields response in basal-cell carcinoma

Phase-1 study results revealed that GDC-0449 — an orally active small molecule that targets the hedgehog pathway — demonstrated antitumor activity in advanced or metastatic basal-cell carcinoma.

Researchers conducted an open-label, multicenter, two-stage trial (n=68) to evaluate GDC-0449 in patients with various solid tumors refractory to standard therapy. Published results in The New England Journal of Medicine included data from 33 patients with basal-cell carcinoma. Preliminary data on nine patients with basal-cell carcinoma were presented at the 2008 Annual Meeting of the American Association for Cancer Research.

Patients were randomly assigned to receive oral GDC-0449 150 mg per day (n=17), 270 mg per day (n=15) or 540 mg per day (n=1). Study treatment duration was a median of 9.8 months. Eighteen patients demonstrated an objective response to treatment; seven were evident by imaging, 10 by physical examination and one by both imaging and physical exam.

Two patients had a complete response, or disappearance of a palpable or visible tumor; 16 patients had a partial response, defined as a reduction of more than half the tumor diameter. Of the remaining 15 patients, 11 had stable disease and four had progressive disease.

Patients with metastatic tumors had an overall response of 50% (95% CI, 29-71); those with locally advanced tumors demonstrated a 60% overall response.

Grade-3 adverse events, considered attributable to the study drug, occurred in six patients. The researchers also reported one grade-4 event of asymptomatic hyponatremia, but considered it unrelated to the study drug.

Hedgehog signaling was apparent in the tumors that responded to treatment, according to the researchers. “We found high levels of GLI1 mRNA expression in tumors from the patients, similar to the levels in more common resectable basal-cell carcinoma and consistent with constitutive activation of the hedgehog pathway,” the researchers wrote. “These results, combined with the responses of some tumors to treatment with GDC-0449, suggest that more advanced tumors rely on the activation of the hedgehog pathway for growth and maintenance.”

The researchers also noted that pharmacokinetic analyses indicated the larger doses of 270 mg or 540 mg per day did not increase plasma concentrations of GDC-0449.

Andrzej A. Dlugosz, MD, and Moshe Talpaz, MD, of the departments of dermatology and internal medicine at the University of Michigan, Ann Arbor, discussed these findings in an accompanying editorial. They wrote that the data “constitute compelling evidence that therapy directed against the hedgehog signaling pathway is a promising new approach for the treatment of advanced and metastatic basal-cell carcinoma, and set the stage for studies using hedgehog pathway inhibitors in other cancers. … The remarkable responses that are reported in the initial cases suggest that the hedgehog pathway can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology.”

Von Hoff DD. N Engl J Med. 2009;doi:10.1056/NEJMoa0905360.