Targeted Drug Combination Can Have Long-Lasting Results for Some With BRAF-Mutated Melanoma

For about half of patients with advanced melanoma, there is only one treatment choice: immunotherapy. But for those whose late-stage melanoma expresses a BRAF gene mutation, there’s another option — combinations of targeted drugs.

Figuring out which type of drug to take can be challenging for these patients and their doctors, but there are some rules of thumb that can guide them, said Dr. Adil Daud, co-director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco.

“It’s a controversial topic in our field, and there’s no easy way to decide,” he told CURE in an interview. However, he said, “We did a study in 2017 showing that the presence of liver metastases doesn’t give you a great response to immunotherapy.”

Another factor that might rule out immunotherapy is a high level of expression of the enzyme lactate dehydrogenase, Daud said. “Or, if there are multiple sites of metastatic disease or the presence of autoimmune disease like multiple sclerosis or Crohn’s, that might make you pause, because if you’re revving up the immune system, it could have autoimmune complications.”

He added that targeted drugs that inhibit the proteins BRAF and MEK “are given orally, so, for example, if you’re a working person, maybe you don’t want to come in every two or three weeks for infusion (of immunotherapy). That’s reasonable to consider, too.”

Daud cited new evidence that the targeted drugs Tafinlar (dabrafenib) and Mekinist (trametinib), when given together, generate about a 30% survival rate for eligible patients after five years on the drug. He added that, at the five-year mark, one-fifth of patients taking the combination have not experienced any disease progression. Those findings came out of a study, presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, that pooled the results of two randomized clinical trials, known as COMBI-d and COMBI-v. The trials tested the drug combination against single-agent targeted drug regimens.

Daud, who was not an investigator on the study, noted that the way the combination fared in comparison with targeted drugs given alone was not the main point of the research, as it’s already been established that pairs of these medications work best to prevent cancer from becoming resistant to treatment. He added that Tafinlar and Mekinist have been approved by the Food and Drug Administration (FDA) since 2014 for use together in this population.

Therefore, he said, the most important information from the study is that good results from using Tafinlar and Mekinist can be long-lasting for some patients.

That has been the case for Colleen, a patient who chose not to reveal her last name in order to preserve her privacy. She received a diagnosis seven years ago when a mole on the back of her calf was found to be melanoma. A year later, it had spread and become stage 4 cancer. “I was able to connect with Dr. Daud and get on the Mekinist and Tafinlar,” she said. He chose targeted drugs over immunotherapy for Colleen, he said, because her cancer had spread to her liver.

Despite some fevers, chills, fatigue and joint pain, the regimen “has been tolerable,” Colleen said. “I’ve been able to continue on with my lifestyle and I’m doing very well. I’m working at a winery I love and spending time with my teenage daughter and husband and two dogs, traveling, hiking and doing all the things I enjoyed before this happened.”

Colleen’s experience is an example of why it’s important for patients with melanoma that has spread to lymph nodes or more distant parts of the body to ask their care teams to genomically sequence their tumor tissue when it’s removed, Daud said. This laboratory test can tell patients if their cancers have BRAF mutations; express a lot of the protein PD-L1, making them likely to respond to immunotherapy; or are driven by other mutations, such as c-KIT, which could be treatable with the targeted drug Gleevec (imatinib) in a clinical trial, and NRAS, for which trial drugs may also be available.

Genomic testing is especially important when melanomas appear on sun-damaged skin, as 60% of these cancers express the BRAF mutation, Daud said.

Besides Tafinlar and Mekinist, there are two other pairs of targeted drugs approved by the FDA to treat people with BRAF-mutated metastatic melanoma: Zelboraf (vemurafenib)/Cotellic (cobimetinib) and Braftovi (encorafenib)/Mektovi (binimetinib).

Colleen’s side effects, which were fairly mild and controllable, are quite common in patients who take this regimen, as are skin rashes, Daud said. More serious side effects, such as heart, lung or vision problems, can also occur, as can other kinds of cancer, bleeding problems, intestinal tears and blood clots.

And side effects aren’t restricted to targeted drug combinations. The most common side effects of immunotherapies include skin rash, cough, diarrhea, fatigue and reactions to infusion such as dizziness or chills. More serious and rare side effects can include liver or kidney damage, hormonal problems, inflammation of the brain and attacks of healthy organs by the immune system.

When administering targeted drugs, “most of these side effects are reversible,” Daud noted. “For fevers and chills, we just stop and restart the medications. For vision (problems) or reduced injection fraction or pulmonary problems, we reduce the dose of Mekinist.”

Most of the side effects of immunotherapies are also reversible, some with courses of steroids.

Daud suggested that side effects should not be seen as an argument against using combination targeted regimens.

“We don’t recommend using a single drug, because a single drug has as many side effects as the combinations,” he said. “The combination doesn’t significantly ratchet up the adverse events, but a single agent has more risk of drug resistance.”