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CHICAGO -- Adjuvant pembrolizumab (Keytruda) for resected high-risk melanoma led to almost a 20% absolute improvement in recurrence-free survival (RFS), irrespective of a tumor's PD-L1 expression status, according to a study reported here.

Data for more than 1,000 patients showed an 18-month RFS of 71.4% among those randomized to pembrolizumab versus 53.2% for patients who had surgery and placebo. The differences translated into a 43% reduction in the hazard ratio for recurrence or death.

The results showed a consistent benefit for adjuvant pembrolizumab across all prespecified subgroups, reported Alexander Eggermont, MD, PhD, of Gustave Roussy Cancer Campus Grand Paris, at the American Association for Cancer Research (AACR) annual meeting.

"It is convincingly demonstrated that adjuvant pembrolizumab does have a very significant impact on relapse-free survival, both in the overall patient population and in the PD-L1-positive subgroup," Eggermont said during an AACR press briefing. "It is true across all subgroups and associated with a very favorable safety profile."

The results were published simultaneously in the .

The study provided a definitive answer to the question of whether adjuvant therapy could reduce the risk of recurrence after surgery for stage III melanoma, said press briefing moderator Louis Weiner, MD, of Georgetown Lombardi Cancer Center in Washington. Moreover, patients benefited from adjuvant pembrolizumab irrespective of PD-L1 expression status or BRAF mutation status.

"This is remarkable and it's really paradigm shifting," said Weiner. "One of the reasons why I think it will be very exciting for our field is that it is ushering in a new era of earlier use of these checkpoint antibodies in the life cycle of patients with cancer. It's going to change the management of this specific stage of cancer, and I think it's going to inform future efforts to extend this kind of strategy into other cancers where checkpoint antibodies may be useful."

The study added to recent research demonstrating a significant reduction in the risk of recurrence of resected stage III (high risk) melanoma with adjuvant therapy. In the absence of effective adjuvant therapy, recurrence rates range for patients with stage IIIC disease. Eggermont's group with a multicenter, randomized trial showing that ipilimumab (Yervoy) significantly improved RFS in resected stage III melanoma versus placebo.

At the 2017 European Society of Medical Oncology conference, one large randomized trial demonstrated superior RFS with nivolumab (Opdivo) versus ipilimumab. Investigators in a placebo-controlled trial showed that the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) significantly improved RFS in resected BRAF-mutated melanoma.

The availability of multiple approved drugs with demonstrated efficacy in the adjuvant setting leaves physicians and patients with multiple potential choices for treatment. Eggermont said convenience may play a role in the decision for patients with BRAF-mutated melanoma, as oral therapy with dabrafenib and trametinib might be attractive to patients who have to travel substantial distances to get infusions of anti-PD-1 antibodies.

Referring to data from the advanced-melanoma setting, Eggermont said response induction and durability of response, particularly beyond 2 years, favor the anti-PD-1 agents. For patients with BRAF wild type tumors, "there really is only one option -- adjuvant anti-PD-1." Whether targeted therapy followed by anti-PD-1 at relapse is superior to upfront adjuvant anti-PD-1 therapy for BRAF-mutated tumors remains to be seen and is the objective of several ongoing trials, he added.

Eggermont reported results of the trial, which involved 1,019 patients with stage III resected melanoma. They were randomized to pembrolizumab or placebo and followed until disease recurrence. Placebo-treated patients who had recurrence beyond 6 months could cross over to pembrolizumab. The primary endpoint was RFS

Results in the overall study population showed a 12-month RFS of 75.4% with pembrolizumab and 61.0% with placebo, increasing to the 18.2% absolute difference at 18 months (P<0.0001). The difference at 18 months was similar in patients with PD-L1-positive tumors (74.2% vs 54.5%, P<0.0001) and PD-L1-negative tumors (60.6% vs 52.2%, P=0.0111), although the latter group included only 116 patients.

The results were consistent across stages IIIA (HR 0.32, P=0.0217), IIIB (HR 0.56, P=0.0004), and IIIC (HR 0.58, P=0.0005). Patients with BRAF-positive (HR 0.57, P=0.0009) and BRAF wild-type tumors also derived similar benefit from the PD-1 inhibitor (HR 0.64, P=0.0039).

No new or unexpected adverse events occurred in pembrolizumab-treated patients. The most common adverse events (any grade) were thyroid abnormalities (20.8%), skin/rash (5.3%), colitis (3.7%), and pneumonitis (3.3%) Grade 3/4 adverse events were uncommon.