Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)
- PMID: 28822576
- DOI: 10.1016/S0140-6736(17)31601-X
Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)
Abstract
Background: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis.
Methods: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319.
Findings: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group.
Interpretation: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma.
Funding: Merck & Co.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Comment in
-
KEYNOTE-006: a success in melanoma, but a long way to go.Lancet. 2017 Oct 21;390(10105):1816-1817. doi: 10.1016/S0140-6736(17)31816-0. Epub 2017 Aug 16. Lancet. 2017. PMID: 28822577 No abstract available.
Similar articles
-
Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study.Lancet Oncol. 2019 Sep;20(9):1239-1251. doi: 10.1016/S1470-2045(19)30388-2. Epub 2019 Jul 22. Lancet Oncol. 2019. PMID: 31345627 Clinical Trial.
-
Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial.Lancet Oncol. 2017 Sep;18(9):1202-1210. doi: 10.1016/S1470-2045(17)30428-X. Epub 2017 Jul 17. Lancet Oncol. 2017. PMID: 28729151 Clinical Trial.
-
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.Lancet Oncol. 2015 Aug;16(8):908-18. doi: 10.1016/S1470-2045(15)00083-2. Epub 2015 Jun 23. Lancet Oncol. 2015. PMID: 26115796 Free PMC article. Clinical Trial.
-
Pembrolizumab: A Review in Advanced Melanoma.Drugs. 2016 Mar;76(3):375-86. doi: 10.1007/s40265-016-0543-x. Drugs. 2016. PMID: 26846323 Review.
-
Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature.Ann Oncol. 2017 Feb 1;28(2):377-385. doi: 10.1093/annonc/mdw558. Ann Oncol. 2017. PMID: 28426103 Review.
Cited by
-
Impact of cemiplimab treatment duration on clinical outcomes in advanced cutaneous squamous cell carcinoma.Cancer Immunol Immunother. 2024 Jun 8;73(8):160. doi: 10.1007/s00262-024-03728-z. Cancer Immunol Immunother. 2024. PMID: 38850335 Free PMC article.
-
BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist.Adv Ther. 2024 Jul;41(7):2576-2585. doi: 10.1007/s12325-024-02883-0. Epub 2024 May 28. Adv Ther. 2024. PMID: 38806993 Free PMC article.
-
Regulatory mechanisms of PD-1/PD-L1 in cancers.Mol Cancer. 2024 May 18;23(1):108. doi: 10.1186/s12943-024-02023-w. Mol Cancer. 2024. PMID: 38762484 Free PMC article. Review.
-
Toll-like receptors in health and disease.MedComm (2020). 2024 Apr 29;5(5):e549. doi: 10.1002/mco2.549. eCollection 2024 May. MedComm (2020). 2024. PMID: 38685971 Free PMC article. Review.
-
The immune response-related genomic alterations in patients with malignant melanoma.Medicine (Baltimore). 2024 Apr 26;103(17):e37966. doi: 10.1097/MD.0000000000037966. Medicine (Baltimore). 2024. PMID: 38669390 Free PMC article.
Publication types
MeSH terms
Substances
Associated data
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials