Therapeutic field has been revolutionized by genetics of melanoma

Banff, Alberta - Numerous therapies are making a significant difference in the management of metastatic melanoma, according to an expert who spoke at the annual Canadian Melanoma Conference.

Steven J. O’Day, M.D., medical oncologist and clinical associate professor of medicine, University of Southern California, Los Angeles, says genetic research has made huge strides in the treatment of metastatic disease.

“The field has been revolutionized by the genetics of melanoma, which is driving these oral targeted drugs,” says Dr. O’Day, who is a medical oncologist and clinical associate professor of Medicine, University of Southern California, and an adjunct member, John Wayne Cancer Institute, Santa Monica, Calif. “We now have targeted agents and immunotherapy that are game-changers in melanoma in terms of demonstrating overall survival benefit in randomized trials. We have never had this before.”

Therapeutic selections

Citing vemurafenib, a BRAF enzyme inhibitor - which is designed to treat unresectable or metastatic melanoma in patients who carry the BRAFV600E mutation and is administered by mouth - and ipilumumab, a type of immunotherapy and humanized antibody that blocks the cytotoxic T-lymphocyte antigen molecule and is administered intravenously, Dr. O’Day says various factors influence the decision to use one therapy or another.

“There is no one right answer in terms of what to use,” Dr. O’Day says. “It depends on how much tumor they (patients) have, how fast the disease is advancing, how many different sites are affected, and how many symptoms the patients have.”

Other therapies are being studied to treat advanced disease such as mitogen-activated, extracellular signal-regulated kinase 1 (MEK1) inhibitors, one of which is known as trametinib, and is targeting BRAF mutant tumors, and another is a PD-1 inhibitor, BMS-936558, which would act similarly to ipilumumab.

The research aimed at treating advanced melanoma has applications for other cancers such as non-small cell lung cancer and renal carcinoma, Dr. O’Day says.

Age can play a factor in clinical decisions, as older patients are more likely to present with comorbidities and that information may affect the choice of medical therapy, according to Dr. O’Day.

“Clinicians have to make decisions about (using) oral agents that work quickly or determine if they (patients) have time to wait and see if they can generate an immune response,” he says. “Once that happens (an immune response is generated), it is a home run. These are the kinds of decisions we are making.”

If patients are very ill and cannot afford to wait for treatment, an immune response is not a judicious choice, he says.

Oral medications

Oral therapy such as a BRAF inhibitor is highly effective, with immediate tumor reduction seen in about 90 percent of patients, but the limitation is the development of resistance after some months of treatment, Dr. O’Day says. Given the likelihood of resistance, researchers are currently exploring different avenues to forestall this problem.

“It (the BRAF inhibitor) is not a long-term fix,” Dr. O’Day says. “While immune therapy works on many fewer patients, about 20 to 30 percent, the therapy is more durable over time.

Patients who have pre-existing autoimmune diseases such as lupus or Crohn’s disease are not candidates for immune therapies, he says.

In terms of adverse events, more skin toxicities and joint problems are seen with oral therapies to treat advanced melanoma while colitis and diarrhea can occur with immune therapies that treat metastatic melanoma.

“There have been deaths associated with severe toxicity from the immune agents,” Dr. O'Day says, noting patients who are administered immune therapies should be closely monitored.

It’s in the best interest of community dermatologists, and their patients, to stay current with the range of therapies to treat metastatic disease, according to Dr. O’Day.

“It’s important to ensure that they know metastatic melanoma is not as helpless and as futile to treat,” he says. “We have much better therapies for advanced melanoma, and we are moving those therapies to earlier stage (of disease). We really need to encourage dermatologists and patients to seek out oncologists that specialize in melanoma fairly early in their diagnosis, so that they can be well-positioned to benefit (from therapy).”

Disclosures: Dr. O’Day has conducted research, consulting, and is a speaker for Bristol-Myers Squibb. He has conducted research and is a speaker for Merck and Roche. He has also conducted research for GlaxoSmithKline.