As reported in The Lancet Oncology by Alexander M.M. Eggermont, MD, of Princess Máxima Center, Utrecht, the Netherlands, 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.¹

Alexander M.M. Eggermont, MD

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

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 (AJCC-7) 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 (ITT) population and in patients with PD-L1–positive tumors.The secondary endpoint reported herein was distant metastasis–free survival in the ITT and PD-L1–positive populations. PD-L1 positive status was defined as tumor or tumor-associated immune cell expression > 1%.

Distant Metastasis–Free Survival

Among 71 patients in the pembrolizumab group and 94 in the placebo group with a first locoregional recurrence, 43.7% vs 74.2% received subsequent systemic therapy, the most common being a PD-1 or PD-L1 inhibitor (22.5% vs 69.9%) and a BRAF-MEK inhibitor (18.3% vs 8.6%).

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 ITT population (HR stratified by stage = 0.60, 95% CI = 0.49–0.73, P < .0001) and 66.7% (95% CI = 61.8%–71.2%) vs 51.6% (95% CI = 46.6%–56.4%) among 853 patients (428 vs 425) with PD-L1–positive tumors (stratified HR = 0.61, 95% CI = 0.49–0.76, P < .0001). In the ITT 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 patients (59 vs 57) 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 patients (27 vs 23) with PD-L1 indeterminate 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 AJCC-7 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.

In analysis with patients staged according to AJCC 8th edition classification, hazard ratios were 0.63 (95% CI = 0.19–2.04) among 42 vs 40 patients with stage IIIA, 0.60 (95% CI = 0.37–0.97) among 163 vs 190 with stage IIIB, 0.56 (95% CI = 0.40–0.78) among 267 vs 238 with stage IIIC, and 0.41 (95% CI = 0.13–1.30) among 20 vs 19 with stage IIID 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

Among 379 patients in the pembrolizumab group vs 289 in the placebo group who were alive and without recurrence at the time of final recurrence-free survival analysis, recurrence-free survival events occurred in 18% vs 25% of patients during the additional follow-up reflected in the current updated analysis.

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 ITT population (HR = 0.59, 95% CI = 0.49–0.70); 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. In the PD-L1–positive population, recurrence-free survival at 3.5 years was 61.4% (95% CI = 56.3%–66.1%) in the pembrolizumab group vs 44.1% (95% CI = 39.2%–48.8%) in the placebo group (HR = 0.59, 95% CI = 0.49–0.73). In the PD-L1–negative population, recurrence-free survival at 3.5 years was 55.2% (95% CI = 41.6%–66.9%) in the pembrolizumab group vs 30.1% (95% CI = 18.2%–43.0%) in the placebo group (HR = 0.46, 95% CI = 0.23–0.90).

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% (HR = 0.57, 95% CI = 0.46–0.72). Locoregional recurrence alone as a first event occurred in 14% vs 18% (HR = 0.73, 95% CI = 0.54–1.00); 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.” 

DISCLOSURE: The study was funded by Merck Sharp & Dohme. Dr. Eggermont holds stock or other ownership interests in RiverD and Skyline Diagnostics; has received honoraria from BIOCAD, BIOINVENT, BioNTech AG, CatalYm, Ellipses Pharma, GlaxoSmithKline, IO Biotech, ISA Pharmaceuticals, MSD, Nektar, Novartis, Pfizer, Sellas Life Sciences, and Skyline Diagnostics; has served as a consultant or advisor to BIOINVENT, CatalYm, Ellipses Pharma, GlaxoSmithKline, IO BIOTECH, ISA Pharmaceuticals, MSD, Nektar, Novartis, Pfizer, Sellas Life Sciences, and Skyline Diagnostics; and has participated in a speakers bureau for BIOCAD, BMSi, and MSD.

REFERENCE

1. Eggermont AMM, Blank CU, Mandalà M, et al: Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): Distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 22:643-654, 2021.