1. Simoneaux, Richard

Article Content

CHICAGO-A 1-year course of 18 doses of adjuvant pembrolizumab was shown to significantly reduce the risk of recurrence for stage III melanoma patients that were at high risk of recurrence after surgery, according to data from the KEYNOTE-054/EORTC 1325-MG phase III clinical trial (N Engl J Med, 2018; doi:10.1056/NEJMoa1802357).


"Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes," explained Alexander M. M. Eggermont, MD, PhD, Director General, Gustave Roussy Cancer Campus Grand Paris in Villejuif, France. "A patient's risk of recurrence depends on the number of lymph nodes affected and the tumor load. Those classified as having a high risk of recurrence have one or more regional lymph nodes with melanoma metastasis." In cases where there is a single positive node, it must be larger than 1 mm in diameter.


Commenting on the results, Eggermont noted, "We were pleased to see that adjuvant pembrolizumab, given as a flat dose of 200 milligrams every 3 weeks after surgery for up to a year, which is 18 doses, significantly reduced the risk of recurrence for patients with high-risk stage III melanoma that has been completely resected."


Previously, the FDA had approved two other checkpoint-based immunotherapies for the treatment of completely resected stage III melanoma in the adjuvant setting: the anti-CTLA4 monoclonal antibody ipilimumab in October 2015 and the anti-PD-1 antibody nivolumab in December 2017.



Between August 2015 and November 2016, 1,019 completely resected stage III melanoma patients at 123 treatment centers in 23 countries were randomized in roughly a 1:1 ratio to either the pembrolizumab group (n=514) or the placebo group (n=505). The patient characteristics at baseline were similar for both groups. Stratification was performed using both disease stage (stage IIIA, stage IIIB, stage IIIC with 1-3 positive nodes, or stage IIIC with >=4 positive nodes) and geographic region (17 regions consisting of 1-3 countries each).


The primary endpoints for this study were the recurrence-free survival (RFS) in the overall intention-to-treat population and in the subgroup of patients having PD-L1-positive disease. For the purposes of this study, RFS was defined as the time between randomization and the date of first recurrence (local, regional, or distant metastasis) or death from any cause. The RFS distribution was estimated using Kaplan-Meier methodology.



Of the 509 patients who started pembrolizumab, 70 discontinued the regimen owing to an adverse event; of these, 66 were deemed to be drug-related by the investigators. Among the 502 patients who received placebo, 11 discontinued treatment because of an adverse event, and of these, eight were considered placebo related. Treatment discontinuation because of disease recurrence was noted for 109 patients in the pembrolizumab group and 179 patients in the placebo group. The full 1-year treatment period was completed by 282 patients in the pembrolizumab group and 294 in the placebo group.


The 12-month rate of RFS in the overall intent-to-treat population was 75.4 percent (95% CI, 71.3-78.9) in the pembrolizumab group and 61.0 percent (95% CI; 56.5-65.1) in the placebo group. RFS was significantly longer for the pembrolizumab participants than those in the placebo group, with a hazard ratio (HR) for recurrence or death of 0.57 (98.4% CI: 0.43-0.74; P<0.001). Rates of RFS at 18 months in the intention-to-treat population were 71.4 percent (95% CI: 66.8-75.4) and 53.2 percent (95% CI: 47.9-58.2) in the pembrolizumab and placebo groups, respectively.


For the 853 patients who had PD-L1-positive tumors, the 12-month RFS rate was 77.1 percent (95% CI: 72.7-80.9) and 62.6 percent (95% CI, 57.7 to 67.0) in the pembrolizumab (n=428) and placebo (n=425) groups, respectively. The results for this subpopulation afforded an HR for recurrence or death of 0.54 (95% CI: 0.42-0.69; P<0.001). Pembrolizumab also appeared to show benefit in those patients having PD-L1-negative disease (n=116) or disease of indeterminate PD-L1 status (n=50) with HR values of 0.60 and 0.80, respectively, although the value of such figures are somewhat questionable given the small size of these sub-populations.



When discussing the results for this study, Eggermont noted, "The risk of recurrence or death in the total population was 43 percent lower in the pembrolizumab group than in the placebo group; the risk was 46 percent lower in the pembrolizumab group than in the placebo group among patients with PD-L1-positive tumors, with similar results in the subgroup with PD-L1-negative tumors."


When asked about patient crossover, Eggermont explained, "An important aspect of this trial is that patients randomized to the placebo group who have recurrence are offered access to pembrolizumab. This crossover design is unique in the world of adjuvant trials in melanoma and will permit us to analyze if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse.


"The main limitation of the study is that we need more time before we can determine whether these positive RFS results will lead to improvement in overall survival for the patients," Eggermont noted. The overall survival results are expected to be published within the next 2 years or so.


"We hope that these data will lead to regulators in the U.S. and Europe approving pembrolizumab as a new treatment option for these patients," Eggermont concluded.


Richard Simoneaux is a contributing writer.