KEYNOTE-054 Trial/EORTC-1325

Background

Phase III RCT of 1,019 patients with resected high-risk stage IIIA, IIIB, or IIIC melanoma. Stage IV was excluded, unlike CheckMate 238. Evaluated adjuvant pembrolizumab vs placebo.

Interventions and follow up

Arm A: Pembrolizumab 200mg IV q3wk x18 cycles (~1yr) or until progression/unacceptable toxicity
Arm B: Placebo
Primary endpoint: RFS in the overall population and in PD-L1-positive tumors
Median follow-up: ~3yr

Results

3-yr RFS (overall): 63.7% vs 44.1% (pembrolizumab vs placebo); HR 0.56, 95%CI 0.47-0.68
3-yr RFS (PD-L1-positive): HR 0.57, 99%CI 0.43-0.74
RFS by BRAF V600E/K: HR 0.51, 99%CI 0.36-0.73
RFS by BRAF wild-type: HR 0.66, 99%CI 0.46-0.95
OS: NR (not yet mature at this analysis)

Adverse events

Any-grade irAEs (pembro vs placebo): 37.7% vs 9.0%; grade 3-4 irAEs 7.7% vs 0.6%
Endocrine: any endocrine disorder 23.4% vs 5.0%; hypothyroidism 14.5% vs 2.6%; hyperthyroidism 10.0% vs 1.0% (mostly grade 1-2); hypophysitis 0.6% vs 0%; type 1 diabetes 1.0% vs 0%
GI/other: colitis 2.2% vs 0.2%; sarcoidosis 1.2% vs 0%

Conclusions

Adjuvant pembrolizumab significantly prolonged RFS across the overall and PD-L1-positive populations and irrespective of BRAF status; OS impact was not yet established at this analysis.

Key Limitations

Placebo comparator rather than active control; OS immature; crossover/cross-over design (placebo patients could receive pembrolizumab at recurrence) confounds OS interpretation.

Clinical Context

FDA approved adjuvant pembrolizumab for resected stage III melanoma (2019). EMA approved in the same setting. A pillar of adjuvant anti-PD-1 therapy alongside CheckMate 238 nivolumab. ESMO endorses adjuvant anti-PD-1 for resected stage III disease.

References