An experimental drug targeting a common mutation in melanoma successfully shrank tumors that spread to the brain in nine out of 10 patients in part of an international phase I clinical trial reported in the May 18 issue of The Lancet.
The drug dabrafenib, which targets the Val600 BRAF mutation that is active in half of melanoma cases, also cut the size of tumors in 25 of 36 patients with late-stage melanoma that had not spread to the brain. The drug also showed activity in other cancer types with the BRAF mutation.
"Nine out of 10 responses among patients with brain metastases is really exciting. No other systemic therapy has ever demonstrated this much activity against melanoma brain metastases," said study co-lead author Gerald Falchook, M.D., assistant professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.
Melanoma patients whose disease has spread to their brains have a median overall survival of four or five months from the time of diagnosis, the researchers note. Drugs used to treat brain metastases have response rates of 10 percent or lower. Surgery and stereotactic or whole-brain radiation also are used.
Tumor shrinkage in the nine responders ranged from 20 percent to 100 percent. In four cases, the brain metastases disappeared.
These results will need to be validated in additional clinical trials with larger groups of patients, Falchook says.
All 10 of the metastasis patients eventually had their cancer progress, but the median time before progression was 4.2 months. Without treatment, many of them would likely have died by that point. Two survived for more than 12 months with one still on the trial at 19 months.
High response rate for those without brain metastases
Overall, 184 patients enrolled at eight sites in the United States and Australia. Of these, 156 patients had melanoma that had spread to other organs. MD Anderson enrolled 64 patients.
"This is a very non-toxic drug, which is common with these newer, targeted therapies," Falchook said.
In the second stage of the phase I trial, they tested a recommended dose of 150mg orally twice daily in:
- 36 patients with melanoma with the Val600 BRAF mutation without brain metastases,
- 10 patients with untreated melanoma brain metastases, and
- 28 patients with other BRAF-mutant cancers.
Among the 36 melanoma patients without untreated brain metastases:
- 25 (69 percent) had a partial or complete response, which is shrinkage of at least 30 percent as determined by measuring tumor shrinkage with radiographic imaging,
- 18 (50 percent) had a confirmed response, meaning the reduction in size was observed in a second imaging scan at least one month later,
The confirmed response rate was similar to that in a phase III study of vemurafenib, the first drug approved for treatment of BRAF-mutant melanoma. Among those with other types of cancers with the BRAF mutation, patients with papillary thyroid, non-small cell lung and colorectal cancers had partial responses. "This is further evidence that a tumor's molecular profile is as important, and possibly more important, than the organ where the cancer begins," Falchook said. "We need to screen for BRAF and other molecular abnormalities in our patients' tumors." he said.
Falchook has six melanoma patients still receiving dabrafenib, including five who are in complete remission. In addition, Falchook is still treating six papillary thyroid patients and one colorectal cancer patient whose tumors have not progressed on the treatment.
MD Anderson news release