PracticeUpdate Dermatology Best of 2018

TOP STORIES 2018 8

Melanoma Hot Topics By Jane Grant-Kels MD

M elanoma continued to be a hot topic in 2018, with reported successes in new com- binations of targeted therapy and updates regarding the somewhat controversial role of com- plete lymph node dissection after a sentinel lymph node biopsy (SLNB) revealed a micro-metastasis. In my opinion, there were three stories that were the hottest! Those of us treating high-risk melanoma patients have experienced how difficult it has been for patients and their providers to “wait and see” if they will progress after they are discovered to have a positive SLNB. Until recently, systemic targeted therapies were only available to those of our patients with stage IV disease. An article by Eggermont et al published this year was long awaited and changed this scenario dramatically . 1 These authors conducted a phase III double-blinded trial to evaluate pembrolizumab (a PD-1 inhibitor) as adjuvant therapy in randomly selected patients with resected stage III melanoma. Approximately half of the patients received 200mg of pembrolizumab, and the other half received placebo intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxic effects occurred. The authors evaluated safety and recurrence-free survival. At a median follow-up of 15 months, pembrolizumab was associated with signif- icantly longer recurrence-free survival than placebo (1-year rate of recurrence-free survival, 75.4–77.1% in the pembrolizumab group and 62.6% in the placebo group). Adverse events of grades 3 to 5 that were related to the trial regimen were reported in 14.7% of the patients in the pembrolizumab group but only 3.4% of patients in the placebo group. The authors concluded, much to the applause of melanoma cli- nicians and patients, that 200 mg of pembrolizumab therapy given every 3 weeks for up to a year in high-risk, stage III melanoma patients resulted in significantly longer recurrence-free survival than pla- cebo, with no new toxic effects identified. This is a long-awaited therapy for our stage III patients and far better than let’s “wait and see what happens.” President Jimmy Carter highlighted the horrors of melanoma brain metastases. Despite his newsworthy medical situation, previous studies of nivolumab com- bined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. Consequently, a group of authors decided to evaluate the efficacy and safety of nivolumab plus ipilimumab in patients withmelanomawith untreated, nonirradi- ated brainmetastases in an open-label, multicenter, phase II study . 2 These patients had a brain metas- tasis that was of a tumor diameter between 0.5 and 3 cm without neurologic symptoms. They received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for up to four doses, followed by nivolumab

(3 mg/kg) every 2 weeks until progression or unac- ceptable toxic effects. The authors then evaluated the percentage of patients who had stable intracranial disease for at least 6 months, a complete response, or a partial response. The rate of intracranial clinical benefit was 57%, including a 26% rate of complete response, 30% rate of partial response, and 2% rate of stable disease. The overall rate of extracranial clin- ical benefit was calculated to be 56%. Grade 3 or 4 adverse events secondary to the therapy were iden- tified in 55% of patients. This safety profile matched that reported in patients with melanoma who do not have brain metastases. The authors therefore con- cluded that nivolumab plus ipilimumab had clinically meaningful intracranial efficacy for our patients with melanoma with untreated brain metastases. Finally, an oral presentation at the 2018 American Society of Clinical Oncology Annual Meeting in Chi- cago, Illinois, this past June reported that c omplete lymph node dissection (CLND) does not improve survival outcomes among patients with malignant melanoma who have a positive SLNB compared with observation or watchful waiting . 3,4 In the phase III DeCOG-SLT study, 473 patients with melanoma thickness of at least 1 mm and a positive SLNB with micro-metastases with a maximum of 2 mm in diam- eter were randomly assigned to undergo CLND (240 patients) or clinical monitoring only (233 patients) between January 2006 and December 2014. The authors evaluated distant metastasis–free survival (DMFS), recurrence-free (RFS), and overall survival (OS). After a median follow-up of 72 months, the fol- lowing were demonstrated: • The 5-year DMFS rate was 67.6% among patients who only underwent monitoring versus 64.9% among patients in the CLND arm. • There were no significant differences in the 5-year OS, with 71.4% in the observation group compared with 72.3% in the CLND group.

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