Pembrolizumab Approved by FDA for Stage III Melanoma


The PD-1 inhibitor pembrolizumab has gained FDA approval as an adjuvant therapy for patients with high-risk stage III melanoma with lymph node involvement following complete resection.

The PD-1 inhibitor pembrolizumab (Keytruda) has gained FDA approval as an adjuvant therapy for patients with high-risk stage III melanoma with lymph node involvement following complete resection.1This is the first anti—PD-1 therapy to be investigated in the adjuvant setting across patients with stage IIIA, stage IIIB, and stage IIIC melanoma.

The agent was approved based on findings from the pivotal phase III EORTC 1325/KEYNOTE-054 trial. Findings from the trial showed adjuvant pembrolizumab led to a 43% reduction in the risk of disease recurrence or death compared with placebo in this patient population (HR, 0.57; 95% CI, 0.46-0.70;P<.001).2,3

&ldquo;As physicians, we are always looking to find ways to prevent cancer from returning in our patients,&rdquo; said Alain Algazi, MD, associate clinical professor of medicine, Department of Medicine, Hematology/Oncology, University of California, San Francisco, Medical Center, in a press release. &ldquo;Keytruda has demonstrated significant improvement in recurrence-free survival among stage III melanoma patients when compared to a placebo, and we now have a new option to help patients who have a high risk of recurrence.&rdquo;

In the multicenter, double-blind, placebo-controlled, randomized EORTC 1325/KEYNOTE-054 trial 1019 patients were enrolled who had 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, 62.0% of patients were male and the median age was 54 years (range 19-88). The breakdown of disease stage at randomization was 16% with stage IIIA, 46% with stage IIIB, 18% with stage IIIC with 1 to 3 positive lymph nodes, and 20% with stage IIIC with &ge;4 positive lymph nodes. The majority of patients (94%) had an ECOG performance status of 0; 6% had a score of 1.

Also in the pembrolizumab arm, 84% of patients were PD-L1 positive (melanoma score, &ge;2), 11.5% were PD-L1 negative, and the status could not be determined for 5.3% of patients. RegardingBRAFstatus, 50% had a V600E or V600K mutation, 6.8% had another mutation, 44% 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.

Results showed that, at a median follow-up of 15 months, the 1-year recurrence-free survival (RFS) rate was 75.4% (95% CI, 71.3-78.9) with pembrolizumab compared with 61.0% (95% CI, 56.5-65.1) with placebo.

The median RFS was not reached with adjuvant pembrolizumab versus 20.4 months (95% CI, 16.2-not reached) with placebo (HR, 0.57; 95% CI, 0.46-0.70;P<.001). The RFS benefit was observed regardless of PD-L1 expression orBRAFmutation status.

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.

InBRAF600E/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.

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.

Regarding safety, all-grade immune-related AEs were reported in 37.3% of the pembrolizumab group and 9.0% of the placebo group. The most common AE &ge;20% of patients was diarrhea (28%).

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 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.

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%).

&ldquo;In the fight against cancer, progress is made one step at a time, and today we&rsquo;re pleased to take another important step—making Keytruda available as an adjuvant therapy for patients with stage III melanoma,&rdquo; said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. &ldquo;At Merck, we are committed to transforming the treatment of cancer, as is exemplified by this important advance in the adjuvant treatment of melanoma.&rdquo;

The European Commission approved the PD-1 inhibitor for this indication in December 2018.


  1. FDA Approves Merck&rsquo;s KEYTRUDA&reg; (pembrolizumab) for the Adjuvant Treatment of Patients with Melanoma with Involvement of Lymph Node(s) Following Complete Resection. Merck. Published February 19, 2019. Accessed February 19, 2019.
  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.
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