Adjuvant Pembrolizumab Approved in EU for Stage III Melanoma

The European Commission has approved pembrolizumab as an adjuvant treatment for patients with resected, stage III melanoma with lymph node involvement.

Alexander M. M. Eggermont,


The European Commission has approved pembrolizumab (Keytruda) as an adjuvant treatment for patients with resected, stage III melanoma with lymph node involvement, according to Merck (MSD), the manufacturer of the PD-1 inhibitor.

The approval was based on findings from the phase III EORTC 1325-MG/KEYNOTE-054 trial. For its review, the European Medicines Agency requested an updated recurrence-free survival (RFS) analysis with 7 months’ of additional follow-up beyond the trial’s initial data cutoff. In this analysis, pembrolizumab reduced the risk of disease recurrence or death by 44% versus placebo in patients with resected, high-risk stage III melanoma (HR = 0.56; 98% CI, 0.44-0.72; P <.0001). The 1-year RFS rates were 76% versus 61%, and the 18-month rates were 72% versus 54%, respectively.1

“Melanoma patients, particularly those with stage III disease, often have a high risk of recurrence, and the collaborative study from EORTC and Merck demonstrated a significant reduction in the risk of cancer returning after surgery,” study chair Alexander M. M. Eggermont, MD, PhD, said in a statement.

“This approval in the adjuvant setting marks another important milestone in the treatment of melanoma,” added Eggermont, director general at the Gustave Roussy Cancer Institute, Professor of Oncology, University of Paris-Saclay.

In the United States, the FDA is currently evaluating a supplemental biologics license application for pembrolizumab in this setting based on the previously reported data from the EORTC 1325-MG/KEYNOTE-054 trial that were presented at the 2018 AACR Annual Meeting and published in the New England Journal of Medicine.2,3 In this earlier analysis, adjuvant pembrolizumab reduced the risk of recurrence or death by 43% in patients with resected, high-risk stage III melanoma.

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. Regarding BRAF status, 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-L1—positive 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-L1—positive 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-L1—negative 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.

In BRAF 600E/V—positive 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.

Among BRAF wild-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%).


  1. European Commission Approves Merck’s KEYTRUDA® (pembrolizumab) as Adjuvant Therapy for Adults with Resected Stage III Melanoma. Merck. Published online December 17, 2018. Accessed December 17, 2018.
  2. Eggermont AMM, Blank CU, Mandala M, et al. Pembrolizumab vs. placebo after complete resection of high-risk stage iii melanoma: efficacy and safety results from the EORTC 1325-MG/KEYNOTE-054 double-blinded phase 3 trial. Presented at 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT001.
  3. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma [published online April 15, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1802357.

At a median follow-up of 15 months, the 1-year RFS rate was 75.4% (95% CI, 71.3-78.9) with the PD-1 inhibitor 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 or BRAF mutation status.