As reported in The Lancet Oncology by Alexander M.M. Eggermont, MD, and colleagues, the pivotal phase III EORTC 1325/KEYNOTE-054 trial has shown significant improvement in the secondary endpoint of distant metastasis–free survival—as well as continued benefit in the primary endpoint of recurrence-free survival—with adjuvant pembrolizumab vs placebo in patients with resected high-risk stage III melanoma.

Pembrolizumab was approved in this setting in February 2019 on the basis of improved recurrence-free survival after a median 15-month follow-up (hazard ratio [HR] = 0.57, 98.4% confidence interval [CI] = 0.43–0.74, P < .0001).

Alexander M.M. Eggermont, MD

Study Details

In the double-blind trial, 1,019 patients from sites in 23 countries were randomly assigned between August 2015 and November 2016 to receive pembrolizumab at 200 mg (n = 514) or placebo (n = 505) every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Patients had American Joint Committee on Cancer staging system, 7th edition stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis) disease.

The co-primary endpoints were recurrence-free survival in the intention-to-treat population and in patients with PD-L1–positive tumors. The secondary endpoint reported herein was distant metastasis–free survival in the intention-to-treat and PD-L1–positive populations; PD-L1–positive status was defined as tumor or tumor-associated immune cell expression > 1%. 

Distant Metastasis–Free Survival

Median follow-up was 42.3 months (interquartile range = 40.5–45.9 months). Distant metastasis–free survival at 3.5 years was:

• 65.3% (95% CI = 60.9%–69.5%) in the pembrolizumab group vs 49.4% (95% CI = 44.8%–53.8%) in the placebo group in the intention-to-treat population (HR stratified by stage = 0.60, 95% CI = 0.49–0.73, P < .0001)
• 66.7% (95% CI = 61.8%–71.2%) vs 51.6% (95% CI = 46.6%–56.4%) among 853 (428 vs 425) patients with PD-L1–positive tumors (stratified HR = 0.61, 95% CI = 0.49–0.76, P < .0001).

In the intention-to-treat population, rates were 82.8% vs 69.8% at 1 year, 73.5% vs 56.0% at 2 years, and 68.2% vs 51.5% at 3 years. 

Among 116 (59 vs 57) patients with PD-L1–negative tumors, 3.5-year distant metastasis–free survival was 58.0% (95% CI = 44.1%–69.5%) in the pembrolizumab group vs 40.2% (95% CI = 27.0%–53.0%) in the placebo group (HR = 0.57, 99% CI = 0.29–1.15). Among 50 (27 vs 23) patients with indeterminate PD-L1 status, rates were 59.3% (95% CI = 38.6%–75.0%) vs 28.6% (95% CI = 11.7%–48.2%; HR = 0.49, 99% CI = 0.17–1.35). Hazard ratios according to disease stage were: 0.64 (99% CI = 0.27–1.53) among 77 vs 75 patients with stage IIIA, 0.58 (99% CI = 0.40–0.86) among 239 vs 232 with stage IIIB, and 0.61 (99% CI = 0.42–0.88) among 198 vs 198 with stage IIIC disease. Distant metastasis–free survival at 3 years was 67.0% vs 44.4% (HR = 0.53, 99% CI = 0.36–0.77) among 209 vs 231 patients with BRAF V600E– or BRAF V600K–mutant tumors and 65.0% vs 54.1% among 234 vs 215 patients with BRAF wild-type tumors (HR = 0.73, 99% CI = 0.50–1.07).

Updated Recurrence-Free Survival Outcomes

Recurrence-free survival at 3.5 years was 59.8% (95% CI = 55.3%–64.1%) in the pembrolizumab group vs 41.4% (95% CI = 37.0%–45.8%) in the placebo group in the intention-to-treat population (HR = 0.59, 95% CI = 0.49–0.70) and 61.4% (95% CI = 56.3%–66.1%) vs 44.1% (95% CI = 39.2%–48.8%) in PD-L1–positive population (HR = 0.59, 95% CI = 0.49–0.73). In the intention-to-treat population, rates were 75.3% vs 60.0% at 1 year, 68.0% vs 46.9% at 2 years, and 63.7% vs 43.5% at 3 years.

Distant metastasis was the first disease recurrence event in 25% vs 38% of patients, either alone (23% vs 33%) or together with locoregional recurrence (2% vs 6%). The 3.5-year cumulative incidence of distant metastasis as the first site of recurrence was 24.9% vs 39.5%. Locoregional recurrence only occurred in 14% vs 18%; locoregional recurrence alone or combined with distant metastasis occurred in 15% vs 24%.

The investigators concluded, “Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis–free survival at a 3.5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.”

Dr. Eggermont, of Princess Máxima Center, Utrecht, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.