KEYNOTE-006: What the Melanoma Trial Found

In brief

KEYNOTE-006 randomized 834 people with advanced melanoma to pembrolizumab or ipilimumab. At five years of follow-up, median overall survival was 32.7 months in the combined pembrolizumab groups versus 15.9 months with ipilimumab (hazard ratio 0.73, p=0.00049). Pembrolizumab roughly doubled median survival while causing fewer severe side effects than the drug it replaced.

Trial at a glance

Field	Detail
Trial	KEYNOTE-006 (NCT01866319)
Phase	Phase 3, randomized, open-label
Sites	87 institutions in 16 countries
Enrollment	834 patients, September 2013 to March 2014
Cancer type	Advanced (unresectable or metastatic) melanoma, ipilimumab-naive
Arms	Pembrolizumab 10 mg/kg every 2 weeks (n=279) or every 3 weeks (n=277); ipilimumab 3 mg/kg every 3 weeks for 4 doses (n=278)
Primary endpoints	Progression-free survival (RECIST 1.1) and overall survival

What the two drugs do

Both are immunotherapies, and both release a brake on your immune system rather than attacking the tumor directly. They release different brakes, at different points, and that difference explains most of the result.

Your T cells carry checkpoint proteins that shut them down so they do not attack healthy tissue. Ipilimumab blocks CTLA-4, a checkpoint that acts early, in the lymph nodes, while T cells are first being activated. Pembrolizumab blocks PD-1, a checkpoint that acts later, at the tumor itself, where cancer cells display a partner protein that tells arriving T cells to stand down.

Releasing the early, system-wide brake activates immune cells broadly, including against your own tissues. Releasing the late, local brake concentrates the effect nearer the tumor. That is why the toxicity profiles differ so sharply, and why this trial's safety result runs in the same direction as its efficacy result — unusual in oncology, where more benefit almost always costs more harm. Ipilimumab was the comparator because it was the standard of care for advanced melanoma when the trial opened in 2013: this was a new drug tested against a genuine advance, not against nothing.

What the trial found

The first report, published in the New England Journal of Medicine in 2015, covered the interim analysis. At that point the response rate was 33.7% for pembrolizumab every 2 weeks and 32.9% every 3 weeks, versus 11.9% for ipilimumab. Six-month progression-free survival was 47.3% and 46.4% versus 26.5%. Twelve-month overall survival was 74.1% and 68.4% versus 58.2%. Grade 3 to 5 adverse events occurred in 13.3% and 10.1% of pembrolizumab patients against 19.9% on ipilimumab.

The five-year analysis, published in Lancet Oncology in 2019 at a median follow-up of 57.7 months, is the one worth sitting with:

• Median overall survival: 32.7 months (95% CI 24.5–41.6) with pembrolizumab versus 15.9 months (13.3–22.0) with ipilimumab. Hazard ratio 0.73 (95% CI 0.61–0.88), p=0.00049.
• Median progression-free survival: 8.4 months (95% CI 6.6–11.3) versus 3.4 months (2.9–4.2). Hazard ratio 0.57 (95% CI 0.48–0.67), p<0.0001.
• Grade 3–4 treatment-related adverse events: 96 of 555 patients (17%) on pembrolizumab, 50 of 256 (20%) on ipilimumab.

The striking part is not the median. It is the shape of the curve behind it. As reported in coverage of that analysis, five-year overall survival was 38.7% with pembrolizumab versus 31.0% with ipilimumab — and among patients receiving it as their first treatment, 43.2% versus 33.0%.

A ten-year follow-up published in Annals of Oncology in 2024, at a median of 123.7 months from randomization, found 34.0% of the pembrolizumab group and 23.6% of the ipilimumab group still alive. Among patients who completed at least 94 weeks of pembrolizumab, the eight-year overall survival rate was 80.8%.

Why the tail matters more than the median

In most cancer trials, a survival curve declines steadily and a better drug shifts the whole curve right — everyone gets somewhat more time. Immunotherapy curves in melanoma do something different. They drop, then flatten. A group of patients stops dying at the expected rate and keeps not dying, for years, in some cases after stopping treatment entirely.

A median cannot show you that. Thirty-two point seven months describes the person in the middle; it says nothing about whether the people above the middle gained a few months or a decade. The ten-year figure is what answers it — a third of the pembrolizumab group still alive. That is not the same as a cure, and the trial cannot tell you who lands there. But it changes what a conversation about advanced melanoma can reasonably include.

What changed because of it

Pembrolizumab's first FDA approval, on September 4, 2014, was an accelerated approval and a narrow one: melanoma "and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor." The label said plainly that "an improvement in survival or disease-related symptoms has not yet been established."

In December 2015, with this trial in the label's clinical studies section, the FDA broadened the indication to "unresectable or metastatic melanoma" with no prior-treatment requirement. That is the practical translation of the result: pembrolizumab moved from a last-resort option to a first-line one, and the survival question the 2014 label had left open was answered.

What this trial cannot tell you

• Everyone enrolled was ipilimumab-naive and had advanced melanoma. It says nothing about earlier-stage disease, or about people already treated with a checkpoint inhibitor.
• It compared two single agents. Combination immunotherapy and BRAF-targeted therapy were not in this trial, and the options in melanoma have continued to change since.
• The trial used 10 mg/kg pembrolizumab. The approved dose has never been that — the 2014 label specified 2 mg/kg every 3 weeks — so dose is not something to read off a trial page.
• Averages describe groups. Neither the median nor the ten-year rate predicts what happens to any one person.

Questions worth asking

• Does my melanoma's stage and prior treatment match the group in this trial?
• What immunotherapy or targeted options apply to my tumor's testing results?
• What side effects would we watch for, and which ones mean calling immediately?

You may also find our plain-language guides to melanoma and immunotherapy useful, along with questions to ask about a clinical trial.

Sources

This article was written from the sources below, which were checked on the source-check date shown above.

• Robert C, et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results. Lancet Oncol. 2019;20(9):1239-1251 (primary)
• Robert C, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-32 (primary)
• Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study. Ann Oncol. 2024;35(12):1191-1199 (primary)
• FDA prescribing information: KEYTRUDA (pembrolizumab), December 2015 (melanoma indication expanded) (official)
• FDA prescribing information: KEYTRUDA (pembrolizumab), September 2014 (original accelerated approval) (official)
• ClinicalTrials.gov record NCT01866319 (KEYNOTE-006) (official)
• ASCO Post: 5-Year Follow-up of Pembrolizumab vs Ipilimumab in Advanced Melanoma (secondary)

How this article was prepared

Prepared by Cancer Explained's AI-assisted editorial system and checked against the sources listed below. This article has not been reviewed by a healthcare professional unless a named reviewer is specifically shown.

Cancer Explained is published by the National Cancer Information Foundation as a nonprofit-oriented public-interest education project. It is not a diagnostic service, does not recommend treatments, and is not for emergencies.

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