# KEYNOTE-006 (Robert 2015): pembrolizumab versus ipilimumab in advanced melanoma

Source: https://onco.cc/key-papers/paper-keynote-006-pembrolizumab-ipilimumab-melanoma-nejm-2015/  
OnCo record `paper-keynote-006-pembrolizumab-ipilimumab-melanoma-nejm-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Head to head, the PD-1 antibody pembrolizumab held melanoma back longer, prolonged life and caused fewer severe side effects than ipilimumab, the CTLA-4 antibody that had been the first immunotherapy to extend survival.

## Summary

KEYNOTE-006 randomised 834 patients with advanced melanoma, most untreated with immunotherapy, to pembrolizumab every two weeks, pembrolizumab every three weeks, or ipilimumab. Both pembrolizumab schedules improved progression-free and overall survival and roughly tripled the response rate compared with ipilimumab, with fewer grade 3 to 5 treatment-related adverse events. The trial made PD-1 blockade the first-line immunotherapy standard in melanoma and showed the three-weekly schedule was as effective as the two-weekly one.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2015
- DOI: 10.1056/NEJMoa1503093
- Authors: Robert C, Schachter J, Long GV, et al.
- Findings: 834 patients with advanced melanoma; pembrolizumab every 2 weeks, every 3 weeks, or ipilimumab.; Six-month progression-free survival 47.3% and 46.4% vs 26.5%; hazard ratios 0.58.; Twelve-month overall survival 74.1% and 68.4% vs 58.2%; hazard ratios 0.63 and 0.69.; Response rates 33.7% and 32.9% vs 11.9%; grade 3 to 5 treatment-related adverse events 13.3% and 10.1% vs 19.9%.
- What it means: This trial settled which checkpoint to block first in melanoma and set the pattern for PD-1 antibodies displacing ipilimumab across cancers. Long-term follow-up later showed that many responders remained free of progression years after stopping treatment.
- Caveats: Open-label design.; Ipilimumab was given at 3 mg/kg for four doses; the comparison does not cover combination therapy.; Most patients had received no prior systemic therapy, so results apply mainly to first-line use.

## Sources

- Full text (DOI): https://doi.org/10.1056/NEJMoa1503093
- ClinicalTrials.gov NCT01866319: https://clinicaltrials.gov/study/NCT01866319

## Connected records

- key papers: [Hodi 2010: ipilimumab, the first checkpoint inhibitor, extends survival in metastatic melanoma](https://onco.cc/key-papers/paper-hodi-ipilimumab-melanoma-nejm-2010/)
- cancers: [Advanced melanoma (unresectable stage III and stage IV)](https://onco.cc/cancers/advanced-melanoma/), [Melanoma](https://onco.cc/cancers/melanoma/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- companies: [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- terms: [Objective response rate (ORR)](https://onco.cc/terms/orr/), [Overall survival (OS)](https://onco.cc/terms/os/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- trials: [KEYNOTE-006](https://onco.cc/trials/keynote-006/)
- people: [Caroline Robert](https://onco.cc/people/caroline-robert/)
- ideas: [Treat the draining lymph node before removing it](https://onco.cc/ideas/idea-bio2-lymph-node-immune-priming/)

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