5-Year Follow-up of KEYNOTE-006 Trial of Pembrolizumab vs Ipilimumab in Advanced Melanoma

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In a post hoc 5-year follow-up of the KEYNOTE-006 trial reported in The Lancet Oncology, Caroline Robert, MD, of Institut Gustave Roussy, Université Paris-Sud, and colleagues found that pembrolizumab maintained overall and progression-free survival benefits over ipilimumab in advanced melanoma.1 In the prior protocol-specified analyses from the trial, both pembrolizumab regimens significantly prolonged overall survival and progression-free survival vs ipilimumab.2,3

Caroline Robert, MD

Caroline Robert, MD

In the open-label trial, 834 patients with advanced melanoma with known BRAF V600 status and up to one previous systemic therapy from 87 sites in 16 countries were randomly assigned 1:1:1 between September 2013 and March 2014 to receive pembrolizumab at 10 mg/kg every 2 weeks (n = 279) or every 3 weeks (n = 277) or 4 doses of ipilimumab at 3 mg/kg every 3 weeks (n = 278).

Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued pembrolizumab with stable disease or better after receiving at least 24 months of treatment or discontinued treatment with a complete response after at least 6 months of treatment and then had disease progression could receive an additional 17 cycles of pembrolizumab. Data cutoff for this post hoc analysis was in December 2018.1

The median follow-up in the current analysis was 57.7 months in surviving patients.1 The median time on treatment was 6.0 months for pembrolizumab and 2.1 months for ipilimumab. Overall, 103 patients who received pembrolizumab (19%) completed 2 years of treatment, and 13 patients received a second course.

Outcomes in All Patients

  • No significant differences were observed between the 2-week and 3-week pembrolizumab groups in terms of median overall survival (31.1 and 34.2 months) or median progression-free survival (8.4 and 9.7 months). Thus, results for the two groups were combined for comparison with ipilimumab.
  • The median overall survival was 32.7 months in the combined pembrolizumab groups vs 15.9 months in the ipilimumab group (hazard ratio [HR] = 0.73, P = .00049). Overall survival was 55.2% vs 42.4% at 24 months, 48.1% vs 37.8% at 36 months, 42.3% vs 33.6% at 48 months, and 38.7% vs 31.0% at 5 years.
  • The median progression-free survival was 8.4 months vs 3.4 months (HR = 0.57, P < .0001). Progression-free survival was 32.7% vs 14.0% at 24 months, 28.8% vs 11.7% at 36 months, and 23.0% vs 7.3% at 4 years.

Outcomes by Treatment: First-Line or Second-Line Setting

  • Among the 368 patients who received pembrolizumab and the 181 patients who received ipilimumab in the first-line setting in the trial, the median overall survival was 38.7 months vs 17.1 months (HR = 0.73, P = .0036). Overall survival was 58.0% vs 44.7% at 24 months, 51.1% vs 40.8% at 36 months, 45.7% vs 36.9% at 48 months, and 43.2% vs 33.0% at 5 years.
  • Among the patients receiving first-line treatment in the trial, the median progression-free survival was 11.6 months vs 3.7 months (HR = 0.54, P < .0001). Progression-free survival was 37.3% vs 17.5% at 24 months, 33.1% vs 14.5% at 36 months, and 26.9% vs 8.0% at 4 years.
  • In patients who previously received chemotherapy (14% and 10%), BRAF or MEK inhibitors (17% and 20%), or immunotherapy (3% and 4%), second-line treatment in the trial yielded a median overall survival of 23.5 months vs 13.6 months (HR = 0.75, P = .036).

Outcomes by BRAF Mutation Status

  • In patients with BRAF V600 wild-type disease, the median overall survival was 28.1 months vs 13.9 months (HR = 0.73, P = .0048).
  • In patients with BRAF V600E–mutant or BRAF V600K–mutant disease previously treated with a BRAF or MEK inhibitor, the median overall survival was 20.4 months vs 11.9 months (HR = 0.71, P = .054).
  • In patients with BRAF V600E–mutant or BRAF V600K–mutant disease not previously treated with a BRAF or MEK inhibitor (patients with a normal baseline lactate dehydrogenase level), the median overall survival was not reached vs 26.2 months (HR = 0.70, P = .065).

Outcomes in Patients Completing 2 Years of Pembrolizumab

  • Among 103 patients completing 2 years of pembrolizumab treatment, with a median follow-up of 34.2 months from completion of therapy, estimated 24-month progression-free survival from the time of completion was 78.4%, 24-month overall survival was 95.9%, and 36-month overall survival was 93.8%.
  • Estimated 24-month progression-free survival was 85.4% among patients with a best response of a complete response, 82.3% among those with a partial response, and 39.9% among those with stable disease.

Outcomes in Patients Receiving Second Course of Pembrolizumab

  • Among 13 patients receiving a second course of pembrolizu­mab after disease progression, the best response to the first course was a complete response in 6, a partial response in 6, and stable disease in 1. The median duration of second-course pembrolizumab was 9 months, with four patients completing the course and five having ongoing treatment at the time of analysis. Best response to second-course pembrolizumab was complete response in three, partial response in four, stable disease in three, and progressive disease in one, with response assessment not yet performed in two patients at the time of analysis. Durations of response in responders with available data were 8.0, 8.9, > 3, > 3.7, > 7.5, > 8.3, and > 8.5 months.
  • Immune-mediated adverse events occurred in 10 patients during the first course and 4 patients during the second course; all adverse events were grade 1 or 2.

The investigators concluded: “Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of pembrolizumab in patients with advanced melanoma.” 

DISCLOSURE: The KEYNOTE-006 trial was funded by Merck Sharp & Dohme. Dr. Robert has served as a consultant or advisor to Amgen, Bristol-Myers Squibb, Merck, Merck Serono, Novartis, Pierre Fabre, and Roche. For full disclosures of the other study authors, visit


1. Robert C, Ribas A, Schachter J, et al: Pembrolizumab vs ipilimumab in advanced melanoma (KEYNOTE-006). Lancet Oncol 20:1239-1251, 2019.

2. Schachter J, Ribas A, Long GV, et al: Pembrolizumab vs ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase III study (KEYNOTE-006). Lancet 390:1853-1862, 2017.

3. Robert C, Schachter J, Long GV, et al: Pembrolizumab vs ipilimumab in advanced melanoma. N Engl J Med 372:2521-2532, 2015.


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