Investigators found that for patients with melanoma who have a mutation in the BRAF gene, specifically a BRAF V600 mutation, immunotherapy is the better initial approach than drugs that specifically target this mutated pathway.
Advances in Treating Metastatic Melanoma Have Been ‘Nothing Short of Remarkable’
Melanoma is the fifth most common cancer in the United States, and it develops in about 1 in 38 white people, 1 in 1,000 Black people, and 1 in 167 Hispanic people, according to the American Cancer Society (ACS). Not too long ago, before the therapies we have today were available, patients with advanced melanoma, meaning melanoma that a surgeon couldn’t remove surgically, almost always died of the cancer, says Andrew Pecora, MD, a coauthor of the study and an oncologist and researcher at Hackensack Meridian’s John Theurer Cancer Center in New Jersey. Almost all deaths caused by skin cancer are from melanoma; an estimated 99,780 new cases will be diagnosed and 7,650 deaths from melanoma will occur in 2022, according to the American Academy of Dermatology Association (AAD). “While still a potentially devastating disease, advances in treatment for patients with metastatic melanoma have been nothing short of remarkable this past decade,” said the lead author, Michael Atkins, MD, the deputy director of Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, in a press release. A significant drop in melanoma deaths occurred from 2015 to 2019 — about 4 percent per year — a trend that experts attribute to advances in treatment. One of those advances is immune-based therapy, which cured about half the patients, says Dr. Pecora. “And then we learned that about 50 percent of the patients with melanoma have a mutation in the melanoma called a BRAF-mutation, and the FDA-approved therapies to treat that put about 50 percent of those patients into remission,” he says. Those were very meaningful and important advancements, says Pecora. “We went from everyone dying of melanoma to about half of the people being cured. But it opened up a question: If a patient has a BRAF-mutation, does it matter if you give them the targeted drugs first — the drugs targeted against that mutation — or do you first give them immunotherapy?” he says.
Administering Immunotherapy First Improves 2-Year Survival Rate
That’s the question this new trial was designed to answer. At the start of the trial in 2015, 265 trial participants with metastatic melanoma were randomly assigned to two groups: one group received a targeted drug combination (dabrafenib and trametinib) followed by an immunotherapy combination (ipilimumab and nivolumab) in the participants whose cancer resisted the first combination; the other group received the immunotherapy combination first and the targeted therapy if necessary. Researchers found an impressive 20 percent advantage in the two-year overall survival rate for people with advanced melanoma who first received immunotherapy (72 percent survival rate) versus those who initially got targeted therapies (52 percent survival rate). Progression-free survival, which is when the cancer is stable or improving, was also trending in favor of those who started on immunotherapy. The trial was stopped early because of the clear evidence of benefit when immunotherapy was given first. This study clearly determined which therapy should be administered first, says Pecora. “It turns out it matters, and it matters a lot. More people will stay alive if they get immunotherapy first, followed by targeted therapy if the immunotherapy doesn’t work, versus starting targeted therapy and going to immunotherapy if the targeted therapy doesn’t work,” he says.
The New Findings Will Change the Way Doctors Treat Melanoma
“The findings are changing the way that doctors around the world are practicing medicine as it relates to melanoma,” says Pecora. This new information will mean more people diagnosed with advanced melanoma who have the BRAF-mutation will live a long and healthy life, he adds. After further analyzing the findings, researchers better understand why patients with metastatic BRAF-mutant melanoma in general do better when combination immunotherapy is administered before combination targeted therapy. “Specifically, combination immunotherapy, in contrast to targeted therapy, produces more long-lasting tumor shrinkage, reduces the risk of disease progression in the central nervous system, and doesn’t interfere with the subsequent effectiveness of the alternative treatment approach,” said Dr. Atkins. The results of this study suggest that in comparison to first-line targeted therapies, the longer-lasting effects of immunotherapy may reduce the risk of tumors in challenging metastatic sites, such as the brain, says Christin Burd, PhD, an assistant professor and scientist with the Ohio State University Comprehensive Cancer Center Molecular Carcinogenesis and Chemoprevention Research Program in Columbus, who was not involved in this research. “Equally important, the study shows that targeted therapies can still be effective in patients who experience relapse after first-line immunotherapy,” says Dr. Burd.
Order of Treatment Matters for People With BRAF-Mutant Metastatic Melanoma
With multiple options available to treat BRAF-mutant, metastatic melanoma, it has been up to the patient and physician to select the best first-line therapy. “Results from this trial show, for the first time, that the order of these treatments matters. Knowing that first-line immunotherapy may prolong patient survival better than first-line targeted therapy will help providers select the best option for their patients,” says Burd.
Researchers Are Still Investigating Which Immunotherapy Regimen Is Best for Each Patient
What this study does not resolve is which immunotherapy regimen is the best initial treatment. That question is being addressed in other clinical trials, said Atkins. Burd agrees, saying, “This study compared specific drug combinations. Whether patient survival differs between single-agent immunotherapies and alternative BRAF and MEK inhibitors remains to be seen.” These findings could be strengthened even more with follow-up studies expanding these trials to a larger patient population, and possibly including additional BRAF-mutant tumor types, she adds. Despite these findings and the other breakthroughs and medications in treating melanoma, there are still some people whose cancer will progress, says Pecora. “Cancer researchers are now working on the next generation of immune-based therapies, which includes combining immune-based therapies and targeted therapies up front,” he says. “Those trials are ongoing, and we hope that by doing this, we’ll take the next step forward so that even more patients with advanced melanoma who have this BRAF-mutation can enjoy long-term benefits and survival,” says Pecora.
