Adjuvant Therapy for Melanoma Prolongs RFS

The PD-1 inhibitor pembrolizumab (Keytruda; Merck) may be an effective adjuvant therapy for patients with advanced melanoma: The drug significantly reduces the risk of recurrence for patients with stage III melanoma, according to clinical trial data presented today at the American Association for Cancer Research 2018 Annual Meeting in Chicago, IL, and concurrently published in The New England Journal of Medicine.

Pembrolizumab received FDA approval in 2014 for metastatic melanoma, and it has since been greenlighted for certain forms of lung, head and neck, and gastric cancers, as well as urothelial carcinoma and Hodgkin lymphoma.

In the phase III KEYNOTE-054/EORTC 1325-MG trial, researchers enrolled 1,019 patients with stage IIIa, IIIb, and IIIc melanoma who were at high risk of recurrence after surgery—defined as having metastatic disease in one or more regional lymph nodes. Researchers randomly assigned patients to receive 200 mg of pembrolizumab or a placebo every 3 weeks for up to a year. Patients treated with the drug had a 12-month recurrence-free survival (RFS) rate of 75.4%, compared with 61% for patients who received a placebo, and RFS was consistently prolonged across subgroups. For example, PD-L1–positive and –negative patients were 46% and 53% less likely, respectively, to experience recurrence or death events than patients in the placebo group.

“The significance of these results is that what works in advanced melanoma also works in the adjuvant setting,” explained Alexander Eggermont, MD, PhD, of the Institut Gustave Roussy in Villejuif, France. He noted that pembrolizumab is generally associated with less severe immune-related adverse effects than the CTLA4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb), another adjuvant therapy for melanoma.

However, Eggermont said the trial's crossover design, in which patients in the placebo group who relapse can access the drug, will eventually allow it to answer an even bigger question: “Do we need to provide adjuvant therapy to the whole patient population, or would it be just as effective to follow patients very closely and treat those who relapse immediately at time of relapse with that medication?”

For Evan Lipson, MD, of Johns Hopkins University in Baltimore, MD, the results are exciting, although not surprising. He pointed out that the FDA approved the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) as an adjuvant therapy for melanoma in December 2017 based on similar study results.

“There doesn't seem to be a huge difference between what was reported with nivolumab and what's been reported with pembrolizumab,” he said. “I think this further solidifies the place of anti–PD-1 generally as the new adjuvant therapy standard of care for patients with high-risk resected melanoma.”

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, agreed, adding that the pembrolizumab trial builds on the nivolumab results by including patients with stage IIIa disease. However, both trials have yet to answer what he views as the major clinical question: “Is there overall survival benefit to giving adjuvant PD-1 therapy versus PD-1 therapy in the metastatic setting?”

“I think the most impact this trial can have in our field is yet to be seen, when the overall survival results come in,” he said. “It's a nice study, but we really need more time.” –Catherine Caruso