Dr. Paul B. Chapman
Research presented at that same Meeting by Jedd D. Wolchok, MD, PhD, which examined ipilimumab plus dacarbazine versus ipilimumab plus placebo in a phase III trial, also moved the needle in the treatment of patients with melanoma.2 Dr. Wolchok is currently with Memorial Sloan Kettering Cancer Center.
“[The 2011] Plenary Session marked the beginning of the renaissance for melanoma,” Dr. Chapman said in an interview with the ASCO Daily News. “My research and the research presented by Dr. Wolchok changed the entire therapeutics for melanoma. Since that time, chemotherapy is almost never used to treat these patients.”
Dr. Kim Margolin
Dr. Steven J. O'Day, credit Casey Marx
“They ushered in the birth of modern immuno-oncology and molecular oncology in melanoma with BRAF inhibitors and the incredibly rapid responses to targeted molecular therapy,” Dr. O’Day said. Before 2010, melanoma was “a stepchild in oncology; very under the radar. But then the revolution was launched in terms of immuno-oncology and the ability to target BRAF,” he said.
Impact of the BRIM-3 Trial
Chemotherapy could shrink tumors in 12% to 15% of patients with melanoma, but there was no evidence of survival benefit, Dr. Chapman said. Results of the BRIM-3 trial showed an estimated 6-month survival rate of 84% with vemurafenib compared with 64% with dacarbazine, and an overall response rate of 48.4% with vemurafenib compared with 5.5% with dacarbazine. The median PFS with the oral targeted therapy was 7 months.
The data had an immediate effect on clinical practice, in part because the side effects of vemurafenib were not particularly severe and were easily managed. The most significant change that vemurafenib required for use in clinical practice was that oncologists and pathologists needed to genotype the melanoma to identify a BRAF mutation before beginning therapy.
“That was a change in paradigm,” Dr. Chapman said, adding that a BRAF mutation is found in approximately 40% of tumors.
Over time, Dr. Chapman said, the OS benefit has remained positive compared with dacarbazine, but the magnitude—as had been expected—decreased.
“With longer follow-up, we were starting to see the OS benefit decrease, but vemurafenib is clearly still better than chemotherapy.”
Melanoma Treatment Today
In current practice, a BRAF inhibitor—either vemurafenib or dabrafenib, the second BRAF inhibitor approved for melanoma treatment—is used in combination with a MAPK kinase (MEK) inhibitor rather than as single-agent therapy.
One combination, the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib, improved PFS and rates of complete or partial response when compared with vemurafenib monotherapy.4 Another combination, the BRAF inhibitor vemurafenib plus the MEK inhibitor cobimetinib, also showed improved results when compared with vemurafenib plus placebo in a phase III trial.5 In that trial, median OS significantly increased with the combination, including OS at 3 years (p = 0.005), as did median PFS (p < 0.0001). Another phase III trial, NCT01909453, is ongoing with a third and not yet approved BRAF inhibitor, encorafenib, in combination with the MEK inhibitor binimetinib, which is being compared with vemurafenib alone and encorafenib alone.
Combination therapy with a BRAF inhibitor plus a MEK inhibitor is now often considered second-line therapy for metastatic melanoma, according to Dr. O’Day, who was a coauthor on the BRIM-3 research.
“When vemurafenib first came out in 2011, there were dramatic responses by patients; however, with longer follow-up, we soon discovered that the responses were not as durable as the immune responses with a checkpoint inhibitor, such as ipilimumab,” he said.
First-line therapy for many patients with melanoma is now PD-1–directed therapy, either pembrolizumab or nivolumab, or a combination of nivolumab (PD-1 blockade) and ipilimumab (CTLA-4 blockade), Dr. O’Day said.
“I think there has been a general switch from using the BRAF drugs first, even with patients who have BRAF-positive disease, where we are now using the immune drugs in the first line and using BRAF and MEK combinations in the second line; however, the jury is still out,” he said.
Dr. Margolin said that questions remain for practitioners about which therapy should be used first and in which patients. A trial led by the ECOG-ACRIN Cancer Research Group may provide some answers, she said. The trial, NCT02224781, is randomly assigning patients with BRAF-mutant metastatic melanoma to one of two regimens: treatment first with combination dabrafenib/trametinib followed by combination ipilimumab/nivolumab therapy upon progression or treatment first with combination ipilimumab/nivolumab followed by combination dabrafenib/trametinib upon “definitive progression,” Dr. Margolin said.
“Immunotherapies given in combination work very fast but often not as fast as targeted therapies,” Dr. Margolin said. “There is a general sense that we should use targeted therapy in patients who need a remission right away and who have very aggressive disease.
“On the other hand, immunotherapy agents, although they may not work as fast, may create a better plateau in the long run. Therefore, they may be better for patients whose disease is not so aggressive,” she said.
Targeted agents also seem to have a plateau. “There may be a group of patients [with disease that is not quickly mutating], who are not developing resistance right away, and who may be served for long periods of time with the targeted agent,” she added. Answers to those questions await further research, she said.
BRAF mutations are present in other types of cancer. Investigators are looking at the efficacy of vemurafenib therapy for brain metastases in patients with a BRAF-mutated tumor. One open-label safety trial assessed vemurafenib in patients diagnosed with BRAF mutation–positive metastatic melanoma with nonresectable, previously treated brain metastases. The investigators reported that the agent can be safely used in these patients and can result in meaningful tumor regression.6
Vemurafenib is also being investigated for the treatment of patients with BRAF-mutant papillary thyroid cancer. In an off-label retrospective review reported from The University of Texas MD Anderson Cancer Center, the agent was shown to be potentially effective and well tolerated.7 Another study, a phase II trial conducted at 10 academic centers worldwide, showed antitumor activity with vemurafenib in patients with progressive, BRAF-mutant papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor.8 In their published report, those researchers said that vemurafenib “represents a potential new treatment option for these patients.”
–Kathy Holliman, MEd