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Targeted therapies becoming a treatment option for advanced basal cell carcinoma
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NEW YORK — Most basal cell carcinomas are treatable with local therapy but for locally advanced or metastatic disease, new targeted molecular therapies show promise for treating patients, said Karl D. Lewis, MD.
Lewis, associate professor of medical oncology at the University of Colorado, addressed the audience Sunday at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
Basal cell carcinoma is one of the most common cancers in the United States. The actual incidence is unclear because there is no registry for the disease but a report from the American Cancer Society released in 2000 estimated that there were as many as 975,000 diagnoses annually and Lewis said that number is likely more than a million today.
There is no approved, systemic treatment for patients with locally advanced or metastatic basal cell carcinoma, but therapies targeting the Hedgehog pathway have shown efficacy in clinical trials.
“The hedgehog inhibitors are showing encouraging responses in both sporadic basal cell carcinomas as well as basal cell nevus syndrome patients,” he said. “This further supports the concept of molecular targeted therapy in cancer, and this is likely to become a valid treatment option for this disease in the near future.”
There are several Hedgehog inhibitors under trial including LDE225 from Novartis, which is in phase 2 testing, and drugs from AstraZeneca, BMS and Infinity which are in phase 1 trials. The drug farthest along in testing is Genentech’s GDC-0449, an oral, small molecule Hedgehog pathway inhibitor that binds to SMO1-3.
A phase 1 study released in 2009 evaluated GDC-0449 in 15 patients with locally advanced BCC and 18 patients with metastatic disease. The results showed a 60% response rate for patients with locally advanced disease and a 50% response rate for those with metastatic disease. Median duration of response was 8.8 months.
Phase 2 results from a randomized, placebo controlled trial released by Tang et al at the AACR 102nd Annual Meeting showed similarly encouraging results, Lewis said. Twenty-four patients with basal cell nevus syndrome were assigned to GDC-0449 and 12 others were assigned to placebo. The primary endpoint was number of new, surgically eligible BCCs per month.
The data safety monitoring board ended the placebo arm early after researchers observed 0.07 new carcinomas per month in the experimental arm vs. 1.7 in the placebo arm. Tumor size shrank 24 cm in the treatment arm vs. just 3 cm in the placebo group.
In ERIVANCE BCC, a pivotal phase 2 study of GDC-0449 in advanced basal cell carcinoma, all patients were assigned to 150 mg daily GDC-0449 until progression. There were 33 patients with locally advanced disease and 63 with metastatic disease.
ORR=30.3% by independent review in the metastatic arm and 46% according to investigators. Another 64% of patients had stable disease. For patients with locally advanced disease, ORR was 43% according to independent review and 60% according to investigators. Another 38.1 % of patients had stable disease.
Median PFS was 9.5 months in both groups. Clinical benefit rate was 76% in the metastatic arm and 75% in the locally advanced arm.
“But there is a cost,” Lewis said. “These drugs can be somewhat toxic.”
In the Tang study, 20% of patients discontinued due to adverse events associated with GDC-0449 including taste loss (83%), muscle cramps (67%) and significant weight loss (50%). The most common toxicities in ERIVANCE BCC were muscle spasms (68%), alopecia (64%) and dysgeusia (50%).
“This is a disease population that is not going to be cured; this is a lifelong problem,” Lewis said. “If we remove drugs, the BCC will return.” – by Jason Harris
Disclosure: Dr. Lewis reported receiving research funding from Genentech and Novartis.
The 2012 HemOnc Today Melanoma and Cutaneous Malignancies Meeting will be held April 13-14 at the Grand Hyatt, New York, NY. Learn more at HemOncToday.com/melanoma.
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