An Overview of Melanoma's Major Milestones

Treatment for melanoma is not a one-size-fits all approach, and has multiple factors to consider, including stage, family health history and the genetic makeup of the tumor, explained Lynn Schuchter, M.D., at the Melanoma Action Coalition’s Fall Conference in Philadelphia.

“We know that different types of melanoma are associated with different genetic mutations,” Schuchter said, explaining that about 50 percent of melanomas have BRAF mutations, which could affect treatment optoins once the disease moves to be stage 3 or 4.

Stage 3 melanoma — meaning that it has spread to the lymph nodes – has had some major changes in recent years. For example, interferon – designed to target any lingering melanoma cells and prevent them from spreading and growing – is no longer used much in this space, as the paradigm is shifting toward checkpoint inhibitors, such as Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab), as well as BRAF and MEK inhibitors.

“I can’t stress enough the seismic changes in the field for patients who are stage 3,” said Schuchter, the C. Willard Robinson Professor of Hematology-Oncology and Melanoma Program Leader at Penn Medicine’s Abramson Cancer Center.

In years prior, immunotherapy trials were not very successful, as researchers were focused more on “stepping on the gas,” rather than “cutting the breaks,” said Schuchter, explaining that immunotherapy agents work by inhibiting the PD-1 or PD-L1 proteins, which prevent T cells — a type of white blood cell – from recognizing the cancer and attacking it.

This type of immune checkpoint blockade was originally developed by two researchers, James P. Allison, Ph.D., and Tasuku Honjo, M.D., Ph.D., who recently won the 2018 Nobel Prize in Physiology or Medicine.

“All that you heard about the Nobel Prize, this was advancing the cures of diseases by cutting the breaks,” Schuchter said.

BRAF/MEK inhibitor combination like Tanfinlar (dabrafenib) plus Mekinist (trametinib); Zelboraf (vemurafenib) plus Cotellic (cobimetinib); or Braftovi (encorafenib) plus Mektovi (binimetinib) have demonstrated clinical activitiy, while immunotherapy is also a promising option for these patients with late-stage disease.

The approved indication for BRAFTOVI + MEKTOVI is the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

However, it is important for patients and providers to consider the side effect profile of the regimen that they select. For example, the combination of Yervoy plus Nivolumab tends to be more efficacious, but often comes with more toxicity.

“Sometimes there’s a fine line between efficacy and side effects with these therapies,” Schuchter said. “There has to be really close communication between the patient and the care team. Most of the time patients do really well with [checkpoint inhibitors], but sometimes the side effects are really serious.”

Overall, Schuchter said that while there are still questions to be answered in treating melanoma — including mitigating side effects of immunotherapy and preventing or overcoming resistance to BRAF/MEK inhibitors – the field has drastically changed in the last eight years.

“It’s really remarkable the progress we’ve had,” she said. “I did not think in my lifetime that we’d see these kinds of advancements. But of course, we still have work to do.”