Great strides have been made in nonsurgical management of melanoma brain metastases, and more advances are on the horizon, according to a new review.1

Targeted therapies and immunotherapies have proven effective, new methods to improve central nervous system (CNS) penetration are being identified, and multimodality treatment approaches are showing promise, according to the review authors, Shalini Makawita, MD, and Hussein A. Tawbi, MD, PhD, both of MD Anderson Cancer Center in Houston.

“Melanoma brain metastases are absolutely treatable in 2021,” said Allison Betof Warner MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, who was not involved in the review.

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“Too many patients are told this is a universally fatal disease, so why bother doing treatment, [but] patients with melanoma brain metastases are not without options,” Dr Warner added.  

Immunotherapy and Targeted Therapies

Combination treatment with BRAF and MEK inhibitors has prolonged survival in patients with BRAF V600E-mutated metastatic melanoma and active CNS disease.1 However, the combinations have generally demonstrated better control of extracranial disease than intracranial disease.

For asymptomatic melanoma brain metastases, combination immunotherapy with ipilimumab and nivolumab has produced durable responses in 46% to 55% of patients.1

“Immunotherapy agents have revolutionized the field of oncology over the past decade and have shown proven and durable benefit in the treatment of melanoma brain metastases,” Dr Makawita said.

“Some historic challenges in treating brain metastases include [the] difficulty of many systemic therapies in penetrating through the blood-brain barrier,” she said. “Immunotherapies appear to have better penetration into the CNS and have shown concordance between responses intracranially and extracranially.”

Combination immunotherapy has led to improved response rates when compared with single-agent anti-PD-1 therapy, Dr Makawita said.

“The majority of the benefit has been noted in patients with asymptomatic melanoma brain metastases,” she noted. “Increased recruitment of patients with symptomatic brain metastases in clinical trials is needed.”

Dr Warner pointed out that toxicities can be a concern when combining immunotherapies.

“Patients with baseline autoimmune disease are more likely to have flares and other side effects to combination immunotherapy,” she said. “Those with poor performance status or who lack social support are less likely to tolerate side effects as well.” 

One cohort less likely to respond to immunotherapy is patients who require steroids for symptomatic brain metastases, Dr Warner said.

“This poses a challenge because immunotherapy is now our standard go-to for many patients,” she explained. “If a patient has a BRAF mutation, I prefer to use targeted therapy until the patient is off steroids, and then I change over to immunotherapy.”

“Other approaches using targeted therapy or radiation therapy are unlikely to lead to results in durable disease control without additional treatment,” Dr Warner said. “In melanoma, all roads generally lead back to immunotherapy, particularly in the brain.”   

Combining Approaches: Promise and Pitfalls

Combining immunotherapy and radiation therapy has been shown to cause regression of disease outside the target irradiated lesion, known as the abscopal effect.1

“Retrospective studies have shown likely synergism between such combinations,” Dr Makawita said. “Combining systemic therapy with immune checkpoint inhibitors or targeted therapies with stereotactic radiosurgery is currently under study.”  

“Other promising trials are examining a combination of targeted therapy with immune checkpoint inhibitors,” Dr Makawita added. “For instance, IMspire1502 showed significant improvement in progression-free survival with vemurafenib/cobimetinib with atezolizumab or placebo in patients with BRAF V600mutations.”
However, adding targeted therapy to immunotherapy raises the question about additional toxicity and the worry of burning through multiple lines of therapy at one time, according to Dr Warner.

“I’m less concerned about [the] duration of response of targeted therapy followed by immunotherapy or immunotherapy followed by targeted therapy, or better PFS with triplet therapy than any agent alone,” Dr Warner said. “Community oncologists say, ‘Throw the book at these tumors,’ but if we play all our cards at the same time and the patient progresses, we are left with limited options in melanoma.”