ADJUVANT THERAPY with pembrolizumab (Keytruda) significantly prolonged recurrence-free survival compared with placebo for patients with resected high-risk stage III melanoma, according to the results of the EORTC 1325/KEYNOTE-054 trial.1 Patients who received pembrolizumab had a 43% reduction in the risk of disease recurrence compared with placebo, a highly significant difference (P < .0001). No new safety signals related to pembrolizumab emerged in the trial.
For the co-primary endpoint of recurrence-free survival in the overall study population, the 1-year recurrence-free survival rate was 75.4% for pembrolizumab vs 61% for placebo, reducing the risk of recurrence by 43% (P < .001). In patients with programmed cell death ligand 1 (PD-L1)–positive tumors, 1-year recurrence-free survival rates were 77.1% vs 62.6%, respectively, with adjuvant pembrolizumab reducing the risk of relapse by 46% (P < .001). Similar results were observed in the subgroup of PD-L1–negative tumors.
“To get the benefit of pembrolizumab, it doesn’t matter whether you are PD-L1–positive or –negative.”— Alexander M.M. Eggermont, MD, PhD
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The study was published online in The New England Journal of Medicine to coincide with Dr. Eggermont’s presentation at the 2018 American Association for Cancer Research (AACR) Annual Meeting.2
Reduced Risk of Recurrence
“IN THE OVERALL intention-to-treat population, the estimated between-group difference in the 18-month rate of recurrence-free survival was 18.2 percentage points. These data provide more evidence that drugs effective in advanced melanoma also have effectiveness as adjuvant therapy,” stated lead author Alexander M.M. Eggermont, MD, PhD, Director General of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France.
“We were pleased to see that adjuvant pembrolizumab given as a flat dose of 200 mg 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,” he added.
As background, Dr. Eggermont said, “Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes. 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 the case of a single positive node, the diameter must be greater than 1 mm.”
Other phase III adjuvant trials in advanced melanoma include EORTC 18071 (ipilimumab [Yervoy] vs placebo in high-risk stage IIIA melanoma)3,4; COMBI-AD (dabrafenib [Tafinlar] plus trametinib [Mekinist] vs placebo in stage III BRAF-mutated melanoma)5; and CheckMate 238 (nivolumab [Opdivo] vs ipilimumab in stage III melanoma).6
KEYNOTE-054
- Pembrolizumab vs placebo after complete resection of high-risk stage III melanoma
- Within 13 weeks of surgery, 1,019 patients were randomized to receive adjuvant pembrolizumab or placebo every 3 weeks for 1 year.
- In cases of recurrence, patients receiving placebo could receive pembrolizumab until disease progression or for up to 2 years.
- Drug-related grade 3 to 5 adverse events were reported in 14.7% of the pembrolizumab group and 3.4% of the placebo group.
Study Details
THE CURRENT STUDY, KEYNOTE-054, included 1,019 patients with high-risk stage IIIA (at least 1 metastasis > 1 mm), IIIB, and IIIC melanoma. Patients were recruited from 123 centers in 23 countries. All patients had completely resected melanoma and histologically confirmed metastasis to a lymph node.
Within 13 weeks of surgery, patients were randomized 1:1 to receive adjuvant pembrolizumab at 200 mg intravenously every 3 weeks for 1 year or placebo every 3 weeks for 1 year. Those patients on placebo with a recurrence could receive pembrolizumab until disease progression or for up to 2 years.
“KEYNOTE-054 is the only adjuvant trial to offer crossover therapy at recurrence,” Dr. Eggermont said. “In 2.5 years, we will have the answer to a crucial question: Do you get a bigger benefit if you start with adjuvant pembrolizumab or wait until recurrence.”
In the intention-to-treat analysis, recurrence-free survival was 75.4% at 1 year for adjuvant pembrolizumab vs 61% for placebo. At 18 months, recurrence-free survival was 71.4% vs 53.2%, respectively—a 43% reduction in recurrence favoring adjuvant pembrolizumab.
In PD-L1–positive patients, the 1-year recurrence-free survival rate was 77.1% vs 62.6%, respectively; at 18 months, the recurrence-free survival rate was 74.2% vs 54.5%, respectively—a 46% improvement. In PD-L1–negative patients, the 1-year rate of recurrence-free survival was 72.2% vs 52.2%, respectively, and at 18 months, the recurrence-free survival rate was 60.6% vs 52.2%, respectively—a 53% improvement with adjuvant pembrolizumab.
“To get the benefit of pembrolizumab, it doesn’t matter whether you are PD-L1–positive or –negative,” Dr. Eggermont noted.
Recurrence-Free Survival by Stage
LOOKING AT each stage separately, for patients with stage IIIA disease who have a good prognosis, 1-year recurrence-free survival was 93.4% for pembrolizumab vs 81.1% for placebo; at 18 months, recurrence-free survival was 89.8% vs 76.8%, respectively—a 68% improvement with adjuvant pembrolizumab.
Intermediate efficacy was observed in patients with stage IIIB disease. The 1-year recurrence-free survival rate was 75.8% for pembrolizumab vs 62.4% for placebo; at 18 months, recurrence-free survival was 71.4% vs 54.8%, respectively—a 44% reduction in relapse for adjuvant pembrolizumab. Patients with stage IIIC melanoma had a 42% reduction in the risk of relapse with adjuvant pembrolizumab.
Recurrence-free survival was similar in patients with BRAF-mutated and BRAF wild-type disease, all of whom benefited from adjuvant pembrolizumab. In fact, in a subgroup analysis, adjuvant pembrolizumab improved recurrence-free survival across all subgroups.
ADJUVANT THERAPY IN HIGH-RISK STAGE III MELANOMA
- Pembrolizumab improved relapse-free survival in the overall study population, in PD-L1–positive and PDL1–negative patients, and in all subgroups, including BRAF-mutated and BRAF wild-type tumors.
- The safety profile was consistent with other studies of pembrolizumab.
Additional Data
AN EXPLORATORY analysis showed that the cumulative incidence of distant metastasis as the first recurrence-free survival event was higher in the placebo arm: 29.7%, vs 16.7% with pembrolizumab, representing a 47% reduction in risk. More patients in the control arm had both distant and locoregional recurrences: 27.4%, vs 15.2% in the pembrolizumab arm.
Pembrolizumab had a favorable safety profile. Severe immune-related adverse events were rare but consistent with those observed in advanced melanoma. Drug-related grade 3 to 5 adverse events were reported in 14.7% of the pembrolizumab group and 3.4% of the placebo group.
The highest incidence of immune-related adverse events, mostly grade 1 to 2, were endocrine disorders (most commonly hypothyroidism [14.3%], hyperthyroidism [10.2%], and thyroiditis [3.1%]). The incidence of grade 3 to 5 immune-related adverse events was 7.1% and included colitis (2.0%), pneumonitis (0.8%), and hepatitis (1.4%). ■
DISCLOSURE: Dr. Eggermont has served on scientific advisory boards for and/ or received honoraria from Actelion, Agenus, Amgen, Bayer, BMS, GSK, Incyte, ISA Pharmaceuticals, HalioDX, Merck- Serono, MSD, Nektar, Novartis, Pfizer, and Sanofi.
REFERENCES
1. Eggermont AMM, Blank CU, Mandala M, et al: Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. 2018 AACR Annual Meeting. Abstract CT001. Presented April 15, 2018.
2. Eggermont AMM, Blank CU, Mandala M, et al: Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. April 15, 2018 (early release online).
3. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071). Lancet Oncol 16:522-530, 2015.
4. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al: Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 375:1845-1855, 2016.
5. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377:1813-1823, 2017.
6. Weber J, Mandala M, Del Vecchio M, et al: Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824-1835, 2017.
