Evolving Treatment for Advanced Melanoma: More Questions Than Answers

Over the past 5 years, a number of new pharmacologic treatments for advanced melanoma have been introduced, including immunotherapy, targeted agents (BRAF and MEK inhibitors), and oncolytic viral therapy. Novel combination strategies are also being implemented and investigated.

In 2010, however, the treatment landscape looked very different from how it does today, explained April K. Salama, MD, of the Duke Cancer Institute in Durham, North Carolina, during the National Comprehensive Cancer Network (NCCN) Annual Conference, held March 22–24 in Orlando, Florida. At that time, patients with metastatic melanoma with good performance status could enter a clinical trial or receive high-dose interleukin-2 and chemotherapy. If the patient had poor performance status, then supportive care and/or referral to hospice was usually offered. “But there has been a dramatic change since then, and a rapid evolution of therapy for melanoma,” said Salama.

To understand options for second-line therapy, Salama explained that it is important to understand the ways in which first-line treatment has evolved over the years. In terms of the NCCN guidelines, there is general consensus that for patients whose melanomas do not have an activating mutation in BRAF, the frontline regimen should contain a programmed death 1 (PD-1) inhibitor.

The second group of patients are those with BRAF mutations. “We now know that over half of patients have melanomas that harbor a BRAF mutation, and we now have highly selective BRAF as well as MEK inhibitors,” she said. “Combination studies have shown improved outcomes in patients.”

A phase III trial published last year showed that dabrafenib combined with trametinib in patients with metastatic disease was superior to dabrafenib alone, in terms of progression-free survival (22% vs 12% at 3 years; hazard ratio [HR], 0.71) and overall survival (44% vs 32% at 3 years; HR, 0.75).

“This really established the combination therapy with a BRAF inhibitor as the standard, as opposed to single-agent therapy in patients who are candidates for these options,” said Salama. “An even more recent development, which I think is important to consider, are the new findings in adjuvant therapy.”

Previous options in adjuvant therapy were “controversial, to say the least,” she noted, since they were limited by efficacy and concerns about toxicity. A recent study, she said, looked at adjuvant nivolumab vs ipilimumab in patients with resected stage III or IV melanoma. At a very early follow-up, nivolumab treatment resulted in a statistically significant 12-month relapse-free survival rate compared with ipilimumab. Nivolumab also had a better toxicity profile.

Also in the adjuvant setting, BRAF-mutated patients treated with dabrafenib plus trametinib for 1 year after surgery had superior overall survival, compared with patients in the placebo group.

In the setting of second-line therapy, Salama discussed key factors to consider when selecting a treatment regimen. These include patient-related factors, such as the presence of BRAF-mutated vs wild-type disease, or NRAS and KIT mutations.

Also important is the patient’s best response to therapy, treatment administration in the adjuvant vs metastatic setting, the timing of relapse in relation to therapy, and prior toxicities that were experienced.

“I think it is reasonable for a patient who is progressing on a PD-1 inhibitor to consider dual checkpoint inhibitor therapy, and that is stated in NCCN guidelines,” Salama commented.

The guidelines also state that reinduction with the same agent/agents can be considered for patients who achieve disease control and do not experience toxicity, but subsequently experienced disease progression less than 3 months after the therapy was continued.

While some data exist on dual checkpoint-inhibitor therapy in the second-line setting, response rates are about half of those seen in the front line. “While there is activity, it is diminished, which is what would be expected in treating a less favorable patient population,” Salama said. “But of concern is that, despite the efficacy being cut in half, the toxicity is not.”

In one study of 64 patients who received combination therapy with nivolumab/ipilimumab, 91% had at least one clinically significant adverse event, while 40 patients had at least one emergency department visit because of treatment toxicity.

Studies have also investigated the sequencing of BRAF-targeted therapy and immunotherapy. In one series reported in 2014, when checkpoint therapy largely consisted of ipilimumab, “there were some challenges giving up front BRAF-inhibitor therapy and then trying to treat with immunotherapy,” said Salama.

Patients treated with immunotherapy first still derived some benefit from BRAF-inhibitor treatment in the second-line setting. However, among those who received ipilimumab after BRAF-inhibitor therapy, the vast majority derived almost no clinical benefit.

In 2018, with the availability of improved checkpoint inhibitors, a retrospective study of treatment sequencing compared outcomes in 58 patients who received BRAFi +/− MEKi therapy first with 56 patients who received an anti–PD-1 agent first. There was no statistical difference in overall survival between groups overall (40.3 months vs 27.5 months; (P = .7). Those who received second-line anti–PD-1 therapy had a lower overall response rate (25% vs 40%).

“Right now there are more questions than answers in BRAF-mutated melanoma,” said Salama. “There are more options than ever and there is no perfect therapy.”  More prospective data are needed to identify optimal combinations and sequencing, and investigation of these questions is ongoing.