Clinical trialPhase 3Melanoma (skin cancer)

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

N Engl J Med · 20181019 patients

Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al. N Engl J Med. 2018. 378:1789-1801

A newer report of this study has been published: Seven-year analysis of adjuvant pembrolizumab versus placebo in stage III melanoma in the EORTC1325 / KEYNOTE-054 trial (2024)

Study type: Clinical trial
Study name: KEYNOTE-054 (EORTC 1325)
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial
Sample size: 1019 patients
Source: N Engl J Med · 2018
Trial registration: NCT02362594

In plain words

After complete removal of a melanoma that has reached the lymph nodes (stage III), the risk of the disease coming back is high. In this study, one year of pembrolizumab infusions (every 3 weeks) lowered the risk of the cancer coming back by about 43% compared with a placebo (dummy drug). About 15 out of every 100 patients had a serious side effect related to the drug.

Key results

75.4% vs 61.0%

1-year recurrence-free survival (overall population)

HR for recurrence or death 0.57; 98.4% CI 0.43–0.74; P<0.001

77.1% vs 62.6%

1-year recurrence-free survival (PD-L1-positive, 853 patients)

HR 0.54; 95% CI 0.42–0.69; P<0.001

Drugs in this study:Pembrolizumab (Keytruda)

Dose and schedule cards

Adjuvant pembrolizumab (KEYNOTE-054 and KEYNOTE-716)

Stage IIB, IIC or III melanoma after complete resection (adults and children aged 12 years and older)On the page “Melanoma (skin cancer)” · Resectable melanoma: neoadjuvant and adjuvant

Stage IIB, IIC or III melanoma after complete resection (adults and children aged 12 years and older)

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 mg)	IV, 30-minute infusion	Day 1 every 3 weeks (400 mg dose: every 6 weeks)

Cycle length: Every 21 days (or every 42 days with the 400 mg dose)
Duration: Up to 12 months, or until recurrence or unacceptable toxicity (KEYNOTE-054: 200 mg every 3 weeks, 18 doses; KEYNOTE-716: 17 cycles)

Per the FDA label; children aged 12 years and older: 2 mg/kg every 3 weeks (maximum 200 mg). Evidence:.

On the page “Melanoma (skin cancer)” · Resectable melanoma: neoadjuvant and adjuvant

Adjuvant pembrolizumab

High-risk resected melanomaCycle length: Every 3 weeksOn the page “Adjuvant pembrolizumab in melanoma”

High-risk resected melanoma

Drug	Dose	Route	Schedule
Pembrolizumab	200 mg (or 400 every 6 weeks)	IV	Every 3 weeks

Cycle length: Every 3 weeks
Duration: 18 doses (about one year)

As in KEYNOTE-054.

Dose source:.

On the page “Adjuvant pembrolizumab in melanoma”

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab

Pembrolizumab 200 mg IV on day 1 of each 21-day cycle, 18 doses in total (about 1 year) or until recurrence or unacceptable toxicity (514 patients). In part 2, patients with recurrence could receive pembrolizumab every 3 weeks for up to 2 years or until further progression.

2Placebo

Placebo (saline) IV on day 1 of each 21-day cycle for up to 18 doses (505 patients); patients with recurrence could receive pembrolizumab for up to 2 years in part 2.

Source of the regimen details: Abstract of the paper and ClinicalTrials.gov NCT02362594

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with completely resected high-risk stage III melanoma (excluding mucosal or ocular melanoma), with ECOG 0 or 1, tumour tissue available for PD-L1 assessment and no prior melanoma treatment other than surgery (or interferon for a thick primary melanoma without lymph node involvement); patients with active autoimmune disease, a history of pneumonitis requiring steroids or use of immunosuppressants were excluded. Stratification by stage and geographical region (ClinicalTrials.gov NCT02362594).

Endpoints

Primary endpoints: recurrence-free survival in the overall intention-to-treat population and in the subgroup with PD-L1-positive tumours. Safety was also assessed.

Safety and side effects

Treatment-related grade 3 to 5 adverse events: 14.7% with pembrolizumab versus 3.4% with placebo; one treatment-related death (myositis) occurred in the pembrolizumab group.

Clinical significance and place in guidelines

KEYNOTE-054 led to FDA approval of adjuvant pembrolizumab for resected stage III melanoma (2019) and, together with nivolumab (CheckMate 238) and dabrafenib–trametinib (COMBI-AD), established the standard adjuvant options. Today, in resectable macroscopic stage III disease, a neoadjuvant approach (NADINA, SWOG S1801) is preferred over adjuvant therapy alone.

Limitations

The initial report was based on short follow-up (15 months); an overall survival benefit was not reported in this paper; patients with stage IIIA disease with nodal involvement of less than 1 mm were not enrolled; many patients had undergone complete lymph node dissection, which is no longer routine.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.