Combination of two therapies holds promise in treating melanoma

Allan C. Halpern, MD, MSc

Allan C. Halpern, MD, MSc

Two approaches to treating melanoma — pathway-targeted therapy and immunotherapy — have upsides and downsides, but a combination of the two may yield better outcomes. Those approaches and a nonmelanoma skin cancer treatment using a Hedgehog pathway inhibitor were examined during Friday’s Hot Topics presentation “Melanoma and Nonmelanoma Skin Cancer.”

“After decades of no new drugs approved in melanoma, four new drugs have been approved in less than four years. It is a real sea change in the availability of treatments, with some impact on survival in patients with advanced metastatic melanoma,” said Allan C. Halpern, MD, MSc, chief of the dermatology service at Memorial Sloan Kettering Cancer Center, New York.

“It is an exciting development in the larger scope of the field of cancer because it is the most impressive first demonstration of the efficacy of immunotherapy and Checkpoint Blockade,” he said. “It also is a glowing example of the ability to target tumors with small-molecule inhibitors of specific pathways that are mutated in the individual patient’s tumor.”

Pathway-targeted therapy for melanoma has zeroed in on the BRAF gene because as many as half of patients with advanced melanoma have tumors mutated in the same location within the BRAF gene, Dr. Halpern said.

“What we have learned is that by shutting down this pathway you can have dramatic clinical responses,” he said. “When you shut down the pathway in only one place, those responses can actually be paradoxically associated with the development of keratoacanthoma-type squamous cell carcinomas. But if you shut down the pathway in two places, then it would appear you might have increased efficacy while eliminating that paradoxical side effect.”

This pathway-targeted therapy acts quickly, but the tumor eventually recurs almost as quickly, in a matter of months, which is called “acquired resistance.” Researchers are trying to better understand the mechanisms of acquired resistance, Dr. Halpern said.

Immunotherapy has the opposite effect in treating melanoma. The response to therapy is not as fast or dramatic as in pathway-targeted therapy, but it appears to last longer.

“In a percentage of patients, immunotherapy appears to be durable, with people living years with either stable disease or actual regression of their disease after just a short course of treatment,” Dr. Halpern said. “The news here is that the one approved immunotherapy has been well received, but associated with some concerning toxicities. However, medical oncologists are getting better at managing these.”

A second immunotherapy has a different target and holds promise. One treatment option combines the two agents, but the combination has resulted in significant toxicity, he said.

“The current ongoing clinical work is to better understand how to use the pathway-targeted therapies and the immunotherapies optimally as individual approaches, but also to figure out how to combine them,” Dr. Halpern said, adding that reducing side effects is key in those studies.

In nonmelanoma skin cancer, the use of a pathway-targeted inhibitor is a treatment most being studied.

“The exciting story here is the availability of Hedgehog inhibitors for advanced, surgically inoperable primary tumors and metastatic tumors for whom the responses in some patients have been dramatic,” Dr. Halpern said. “It clearly has a place in our armamentarium. Unfortunately, the side-effect profile has stood in the way of the persistent use of this drug in most patients.”

Return to index