A UCLA-led research team has pinpointed a three-drug combination that could prove to be an effective new therapy for people with a specific type of advanced melanoma.
Patients in this study received daily dosing with the BRAF inhibitor dabrafenib taken orally twice daily at 15 mg, the MEK inhibitor trametinib taken orally once daily at 2 mg and intravenous infusions of the anti-PD-1 antibody pembrolizumab every 3 weeks at 2 mg/kg.
Graphic: Courtesy of Dr. Antoni Ribas
The approach shows promise for extending the lives of people with a type of melanoma that contains a potent gene mutation, BRAF V600E. In clinical trials, it appeared not to cause the debilitating side effects that are caused by a combination of one targeted drug and an immunotherapy drug.
The researchers found that people with the melanoma survived longer without the cancer progressing or growing when they received a combination of two targeted inhibitors that block the BRAF mutation (dabrafenib and trametinib) and an immune checkpoint inhibitor drug (pembrolizumab) as the initial treatment for their disease.
“Utilizing the three drugs together sensitized the patient’s own immune system to bolster the power of immunotherapy and block the growth of two genes — BRAF and MEK — that cause cancer cells to reproduce and grow out of control,” says Dr. Antoni Ribas, MD (FEL ’98, ’01), PhD, professor of medicine and director of the UCLA Jonsson Comprehensive Cancer Center’s Tumor Immunology Program.
In the phase one trial, the scientists tested the three-drug combination for safety in 15 people with BRAF-mutated metastatic melanoma. In 11 of them, the tumors shrank and remained stable and did not grow again for 12 to 27 months. In the phase two trial, those who received the three-drug combination had progression-free survival — meaning that the disease did not worsen or progress — for an average of 16 months. Those who received trametinib, dabrafenib and a placebo lived for an average of 10.3 months without the disease progressing.
Previous studies have found that using one of the three drugs alone can dramatically shrink tumors in a small percentage of people with melanoma. A majority of people on the treatment, however, do not see any benefit or end up experiencing a relapse. Two-drug combinations also have been tested, but they, too, have had limited success. “Earlier attempts to combine a targeted agent with an immune checkpoint inhibitor as a double-combination therapy had debilitating side effects for patients, and it was just too toxic to continue testing, so we went back to the drawing board,” says Dr. Ribas, who also is director of the Parker Institute for Cancer Immunotherapy Center at UCLA. “We found that by using two targeted inhibitors, instead of just one, in combination with a checkpoint inhibitor, we could safely and effectively treat the cancer.”
— Denise Heady
“Combined BRAF and MEK Inhibition with PD-1 Blockade Immunotherapy in BRAF-mutant Melanoma,” Nature Medicine, June 6, 2019.
“Dabrafenib, Trametinib and Pembrolizumab or Placebo in BRAF-mutant Melanoma,” Nature Medicine, June 6, 2019.
