According to phase III results from the EORTC 1325-MG/KEYNOTE-054 trial presented at the 2018 AACR Annual Meeting and published in the <em>New England Journal of Medicine, </em>adjuvant pembrolizumab (Keytruda) reduced the risk of recurrence or death by 43% in patients with resected, high-risk stage III melanoma.
Alexander M. M. Eggermont, MD, PhD
According to phase III results from the EORTC 1325-MG/KEYNOTE-054 trial presented at the 2018 AACR Annual Meeting and published in theNew England Journal of Medicine,adjuvant pembrolizumab (Keytruda) reduced the risk of recurrence or death by 43% in patients with resected, high-risk stage III melanoma.1,2
At a median follow-up of 15 months, the 1-year recurrence-free survival (RFS) rate with the PD-1 inhibitor was 75.4% (95% CI, 71.3-78.9) versus 61.0% (95% CI, 56.5-65.1) with placebo (HR, 0.57; 98.4% CI, 0.43-0.74;P<.0001). The RFS benefit was observed regardless of PD-L1 orBRAFmutation status.
“We were pleased to see that adjuvant pembrolizumab…significantly reduced the risk of recurrence for patients with high-risk stage 3 melanoma that has been completely resected. We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients,” lead author Alexander M. M. Eggermont, MD, PhD, director general of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, said in a statement.
The EORTC 1325/KEYNOTE-054 trial enrolled 1019 patients with stage III melanoma who were at high risk of recurrence after complete resection of their tumors. Patients had stage IIIA (if N1a, at least 1 metastasis >1 mm), stage IIIB, or stage IIIC (no in transit meta) disease. No prior systemic therapy for melanoma was allowed and randomization had to occur within 12 weeks of surgery.
Patient were randomized to 200 mg of pembrolizumab (n = 514) or placebo (n = 505) intravenously every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. Except in the case of brain metastases, patients on placebo with recurrence were unblinded and could cross over to receive pembrolizumab. Additionally, patients randomized to pembrolizumab who had recurrence more than 6 months following completion of 1 year of initial treatment could rechallenge with pembrolizumab.
Patient characteristics were well balanced between the 2 arms. In the pembrolizumab arm, 63.0% of patients were male and the median age was 54 years (range 19-88). The breakdown of disease stage at randomization was 15.6% with stage IIIA, 46.1% with stage IIIB, 18.5% with stage IIIC with 1 to 3 positive lymph nodes, and 19.8% with stage IIIC with ≥4 positive lymph nodes.
Also in the pembrolizumab arm, 83.3% of patients were PD-L1 positive (melanoma score, ≥2), 11.5% were PD-L1 negative, and the status could not be determined for 5.3% of patients. RegardingBRAFstatus, 40.9% had a V600E or V600K mutation, 6.8% had another mutation, 45.3% were wild-type, and the status was unknown for 7.0%.
The primary endpoint was RFS in the overall population and in PD-L1positive patients. The 18-month RFS rate was 71.4% (95% CI, 66.8-75.4) with pembrolizumab versus 53.2% with placebo (95% CI, 47.9-58.2). An RFS benefit with the PD-1 inhibitor was observed across patients with either stage IIIA, IIIB, or IIIC disease.
In the PD-L1positive group, the 1-year RFS rate was 77.1% (95% CI, 72.7-80.9) in the pembrolizumab group and 62.6% (95% CI, 57.7-67.0) in the placebo group (HR, 0.54; 95% CI, 0.42-0.69;P<.001). The 18-month RFS rates were 74.2% versus 54.5%, respectively.
Among PD-L1negative patients, the 1-year RFS rates were 72.2% (95% CI, 58.6-82.0) in the pembrolizumab arm versus 52.2% (95% CI, 38.2-64.5) in the placebo group (HR, 0.47; 95% CI 0.26-0,85;P= .01). The 18-month RFS rates were 60.6% versus 52.2%, respectively.
InBRAF600E/Vpositive patients, the 1-year RFS rate was 72.5% with pembrolizumab versus 58.6% with placebo (HR, 0.57; 99% CI, 0.37-0.89;P= .0009). The 18-month RFS rates were 69.2% versus 52.4%, respectively.
AmongBRAFwild-type patients, the 1-year RFS rate was 73.0% with pembrolizumab versus 59.7% with placebo (HR, 0.64; 99% CI, 0.42-0.96;P= .0039). The 18-month RFS rates were 66.7% versus 48.8%, respectively.
Grade 3 to 5 treatment-related adverse events (AEs) occurred in 14.7% of the pembrolizumab arm versus 3.4% of the placebo group. In the pembrolizumab arm, there was 1 treatment-related death due to myositis.
All-grade immune-related AEs were reported in 37.3% of the pembrolizumab group and 9.0% of the placebo group. The incidence of endocrine disorders was higher with pembrolizumab (23.4% vs 5.0), with the most common endocrine disorders being hypothyroidism (14.3% vs 2.8%) and hyperthyroidism (10.2% vs 1.2%). The incidence of these 2 AEs was mostly grade 1 or 2, except for 1 case of grade 3 hyperthyroidism. Sarcoidosis also occurred at a low rate (1.4% vs 0%), with all cases being grade 1 or 2.
Grade 3/4 immune-related AEs occurred in 7.1% versus 0.6% of patients in the pembrolizumab versus placebo arms respectively. Events occurring at rates >1% included colitis (2.0% vs 0.2%), pneumonitis (0.8% vs 0%), and hepatitis (1.4% vs 0.2%).
“The EORTC 1325 trial will continue to its secondary end points, distant metastasis-free survival and overall survival. We recently found that the effects of treatment on recurrence-free survival correlate very well with the effects on overall survival in trials of adjuvant therapy with interferon alfa and with ipilimumab in high-risk melanoma,” Eggermont et al wrote in theNEJMpublication of their findings.
“Therefore, one may reasonably expect that the benefit of pembrolizumab for relapse-free survival that we have found in our trial will translate into an overall survival benefit, unless effective post-relapse treatments compensate for the initial disadvantage; this is a question that may be answered by the crossover design of the trial,” continued Eggermont et al.