EORTC 1325/KEYNOTE-054: trial | Bending the Curve: Trial by Trial

EORTC 1325/KEYNOTE-054

Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma

Population

Completely resected AJCC-7 stage IIIA (at least one lymph node metastasis larger than 1 mm), IIIB or IIIC (without in-transit metastasis) cutaneous melanoma

Design

Double-blind, randomised (1:1), placebo-controlled phase 3 trial. Pembrolizumab 200 mg or placebo every 3 weeks for 18 doses (about 1 year) or until recurrence or unacceptable toxicity. Coprimary endpoints: recurrence-free survival in the overall ITT population and in the PD-L1-positive subgroup.

Primary endpoint

RFS

Arms

Pembrolizumab (experimental, n = 514): Pembrolizumab 200 mg intravenously every 3 weeks, 18 doses
Placebo (control, n = 505): Placebo intravenously every 3 weeks, 18 doses

People

Eggermont AMM, senior author Robert C, EORTC

RFSHR 0.57Δ 12-month RFS+14.4 pointsRFSHR 0.56 (95% CI 0.47–0.68)Δ 36-month RFS+19.6 pointsDMFSHR 0.60 (95% CI 0.49–0.73)Δ 42-month DMFS+15.9 points

Show the numbers

Results reported for EORTC 1325/KEYNOTE-054
Endpoint	Analysis	Pembrolizumab	Placebo	Effect
RFS	primarymedian follow-up 15 monthsEggermont 2018	75.4% at 12 mo (71.3–78.9%)	61% at 12 mo (56.5–65.1%)	HR 0.57P<0.001Hazard ratio for recurrence or death 0.57 with a 98.4% confidence interval of 0.43 to 0.74 (not a 95% interval). PD-L1-positive subgroup (853 patients): 1-year RFS 77.1% vs 62.6%, HR 0.54 (95% CI 0.42 to 0.69). Grade 3 to 5 treatment-related adverse events 14.7% vs 3.4%; one treatment-related death (myositis) in the pembrolizumab group.
RFS	long term-updatemedian follow-up 3.05 yearsEggermont 2020	63.7% at 3 y	44.1% at 3 y	HR 0.56 (95% CI 0.47–0.68)190 vs 283 RFS events. The 3-year rates are given without confidence intervals in the abstract. PD-L1-positive subgroup HR 0.57 (99% CI 0.43 to 0.74).
DMFS	long term-updatemedian follow-up 42.3 monthsEggermont 2021	65.3% at 42 mo (60.9–69.5%)	49.4% at 42 mo (44.8–53.8%)	HR 0.60 (95% CI 0.49–0.73)P<0.0001Secondary endpoint (final DMFS results). 3.5-year RFS in the same report: 59.8% vs 41.4% (HR 0.59; 95% CI 0.49 to 0.70). PD-L1-positive subgroup (853 patients) DMFS 66.7% vs 51.6%, HR 0.61.
RFS	long term-updatemedian follow-up 6.9 yearsEggermont 2024	50% at 7 y (46–55%)	36% at 7 y (32–41%)	HR 0.63 (95% CI 0.53–0.74)Rounded percentages as published. DMFS at 7 years 54% (95% CI 50 to 59) vs 42% (95% CI 37 to 46), HR 0.64 (95% CI 0.54 to 0.76). Progression/recurrence-free survival 2 was exploratory (HR 0.69; 95% CI 0.57 to 0.84).

Results reported for EORTC 1325/KEYNOTE-054
Endpoint	Analysis	Pembrolizumab	Placebo	Effect
RFS	primarymedian follow-up 15 monthsEggermont 2018	75.4% at 12 mo (71.3–78.9%)	61% at 12 mo (56.5–65.1%)	HR 0.57P<0.001Hazard ratio for recurrence or death 0.57 with a 98.4% confidence interval of 0.43 to 0.74 (not a 95% interval). PD-L1-positive subgroup (853 patients): 1-year RFS 77.1% vs 62.6%, HR 0.54 (95% CI 0.42 to 0.69). Grade 3 to 5 treatment-related adverse events 14.7% vs 3.4%; one treatment-related death (myositis) in the pembrolizumab group.
RFS	long term-updatemedian follow-up 3.05 yearsEggermont 2020	63.7% at 3 y	44.1% at 3 y	HR 0.56 (95% CI 0.47–0.68)190 vs 283 RFS events. The 3-year rates are given without confidence intervals in the abstract. PD-L1-positive subgroup HR 0.57 (99% CI 0.43 to 0.74).
DMFS	long term-updatemedian follow-up 42.3 monthsEggermont 2021	65.3% at 42 mo (60.9–69.5%)	49.4% at 42 mo (44.8–53.8%)	HR 0.60 (95% CI 0.49–0.73)P<0.0001Secondary endpoint (final DMFS results). 3.5-year RFS in the same report: 59.8% vs 41.4% (HR 0.59; 95% CI 0.49 to 0.70). PD-L1-positive subgroup (853 patients) DMFS 66.7% vs 51.6%, HR 0.61.
RFS	long term-updatemedian follow-up 6.9 yearsEggermont 2024	50% at 7 y (46–55%)	36% at 7 y (32–41%)	HR 0.63 (95% CI 0.53–0.74)Rounded percentages as published. DMFS at 7 years 54% (95% CI 50 to 59) vs 42% (95% CI 37 to 46), HR 0.64 (95% CI 0.54 to 0.76). Progression/recurrence-free survival 2 was exploratory (HR 0.69; 95% CI 0.57 to 0.84).

Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.

Data table

Endpoint	HR	95% CI
RFS	0.56	0.47–0.68
DMFS	0.6	0.49–0.73
RFS	0.63	0.53–0.74

Appears in

2018 Adjuvant pembrolizumab: EORTC 1325/KEYNOTE-054 (2018)

Sources

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789-1801.
PubMed DOI
Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson VG, Dalle S, et al. Longer Follow-Up Confirms Recurrence-Free Survival Benefit of Adjuvant Pembrolizumab in High-Risk Stage III Melanoma: Updated Results From the EORTC 1325-MG/KEYNOTE-054 Trial. J Clin Oncol. 2020;38(33):3925-3936.
PubMed DOI
Eggermont AMM, Blank CU, Mandalà M, Long GV, Atkinson VG, Dalle S, 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. 2021;22(5):643-654.
PubMed DOI
Eggermont AM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V, et al. Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial. Eur J Cancer. 2024;211:114327.
PubMed DOI