Elsevier

The Lancet Oncology

Volume 20, Issue 9, September 2019, Pages 1239-1251
The Lancet Oncology

Articles
Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study

https://doi.org/10.1016/S1470-2045(19)30388-2Get rights and content

Summary

Background

Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006.

Methods

KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two pembrolizumab dosing regimen groups was not protocol-specified. 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 pembrolizumab or discontinued with complete response after at least 6 months of pembrolizumab and then progressed could receive an additional 17 cycles of pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319.

Findings

Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7–59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5–41·6) in the combined pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6–11·3) in the combined pembrolizumab groups versus 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p<0·0001). Grade 3–4 treatment-related adverse events occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) of 256 patients in the ipilimumab group; the most common of these events were colitis (11 [2%] vs 16 [6%]), diarrhoea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Any-grade serious treatment-related adverse events occurred in 75 (14%) patients in the combined pembrolizumab groups and in 45 (18%) patients in the ipilimumab group. One patient assigned to pembrolizumab died from treatment-related sepsis.

Interpretation

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.

Funding

Merck Sharp & Dohme.

Introduction

Historically, advanced melanoma had a poor prognosis, with 5-year survival of less than 10% before the era of targeted therapy and immunotherapy.1 Approved treatment options for advanced melanoma have improved survival and include BRAF or MEK inhibitors, or both, for patients with BRAFV600-mutant disease, and immunotherapy with checkpoint inhibitors directed against cytotoxic T-lymphocyte-associated antigen 4 (CTLA4; ipilimumab) and PD-1 (pembrolizumab and nivolumab) for patients irrespective of their BRAF mutation status.1

Research in context

Evidence before this study

Immunotherapy using the PD-1 inhibitors pembrolizumab and nivolumab and the cytotoxic T-lymphocyte-associated antigen-4 inhibitor ipilimumab has improved survival in patients with advanced melanoma. For reports of clinical trials involving checkpoint inhibitors with long-term follow-up of patients with advanced melanoma, we searched PubMed on Feb 5, 2019, for papers published since database inception using the search terms “nivolumab AND melanoma”, “pembrolizumab AND melanoma”, and “ipilimumab AND melanoma”, without any language restrictions. We narrowed the search results to include reports of prospective trials in advanced melanoma with overall survival as a study endpoint. We found a phase 3 study of ipilimumab plus dacarbazine versus placebo plus dacarbazine showing 5-year overall survival of 18·2% and 8·8%, respectively. A report of the 4-year follow-up of the CheckMate 067 trial showed 4-year overall survival of 53% for nivolumab plus ipilimumab, 46% for nivolumab alone, and 30% for ipilimumab alone, respectively. We did not find any reports of 5 years of follow-up in a randomised controlled trial of nivolumab or pembrolizumab in advanced melanoma. We also searched PubMed for reports of second-course treatment or re-treatment in patients with advanced melanoma using the search terms “nivolumab AND re-treatment AND melanoma”, but we found no articles presenting results from randomised controlled trials of patients re-treated with nivolumab. We found a pooled analysis of six trials with different patient populations (previously treated or treatment naive) and doses of ipilimumab (3–20 mg/kg), which limited interpretation of results. The proportion of patients with an overall response was 23%. Grade 3–4 immune-related adverse events occurred in 5·9–25·0% of re-treated patients, depending on ipilimumab dose.

Added value of this study

This report of 5 years' follow-up of KEYNOTE-006 is, to our knowledge, the longest follow-up to date in a randomised phase 3 trial of pembrolizumab in patients with advanced cancer. Pembrolizumab continued to show superiority over ipilimumab, irrespective of line of therapy, BRAFV600 status, or exposure to previous BRAF or MEK inhibitors for those patients with BRAFV600E-mutant or BRAFV600K-mutant disease. We present outcomes in patients who completed 2 years of pembrolizumab treatment. Additionally, we present an exploratory analysis of best overall response in patients treated with a second course of pembrolizumab.

Implications of all the available evidence

Our results show that median overall survival in patients treated with pembrolizumab versus ipilimumab continued to show superiority in the overall population after almost 5 years of follow-up. Pembrolizumab conferred sustained disease control over a long period, whereby 78% of patients who completed 2 years of pembrolizumab treatment with at least stable disease remained progression free 24 months after pembrolizumab completion. The safety profile of pembrolizumab remained consistent with previous reports. Preliminary findings suggest that re-treatment with pembrolizumab after disease progression can provide additional antitumour activity and second-course pembrolizumab was generally well tolerated.

In an initial study with ipilimumab, 15 (11%) of 137 patients with metastatic melanoma achieved an objective response, and median overall survival was 10·1 months (95% CI 8·0–13·8).2 First-line nivolumab led to an objective response in 43% or 45% of patients with advanced melanoma3, 4 and in 27% after progression on ipilimumab.5 Median overall survival was 36·9 months (95% CI 28·3–not reached) or 37·5 months (25·5–not reached) with first-line nivolumab, with 3-year survival and 4-year survival of 51% and 46%, respectively.3, 4 In patients with advanced melanoma, median overall survival with second-line nivolumab was 15·7 months (95% CI 12·9–19·9).5 In the phase 1b KEYNOTE-001 trial of pembrolizumab in patients with advanced melanoma, 194 (33%) of 581 patients in the overall population and 60 (45%) of 133 treatment-naive patients achieved an objective response, and median overall survival was 23 months (95% CI 20–29) and 31 months (24–not reached), respectively.6 5-year overall survival in the overall population was 34%.7 Despite the substantial progress brought by these therapies on overall survival, long-term survival rates are unknown, as are outcomes after treatment discontinuation.

In the protocol-specified final analysis of the phase 3 KEYNOTE-006 study in advanced melanoma, median overall survival was not reached with pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks and was 16·0 months (95% CI 13·5–22·0) with ipilimumab after a median follow-up of 22·9 months.8 Median progression-free survival was 5·6 months (95% CI 3·4–8·2) for pembrolizumab every 2 weeks and 4·1 months (2·9–7·2) for pembrolizumab every 3 weeks, compared with 2·8 months (2·8–2·9) for ipilimumab. The proportion of patients who achieved an objective response was also improved with pembrolizumab every 2 weeks or every 3 weeks, compared with ipilimumab (33·7% and 32·9% vs 11·9%).9 Pembrolizumab was associated with a lower frequency of grade 3–5 treatment-related adverse events compared with ipilimumab. Both efficacy and safety were similar between the pembrolizumab dose regimens.8, 9 On the basis of these results, pembrolizumab is now considered a standard of care for advanced melanoma.1 Health-related quality of life was also better maintained with pembrolizumab than with ipilimumab in patients with advanced melanoma in KEYNOTE-006.10

We report outcomes from KEYNOTE-006 after long-term follow-up of almost 5 years, including outcomes by line of therapy, BRAFV600 status, and previous treatment with BRAF or MEK inhibitors. Outcomes are also presented for patients who completed 2 years of pembrolizumab treatment and for those who had progression after completion of protocol-specified treatment and received second-course pembrolizumab.

Section snippets

Study design and participants

KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries that compared pembrolizumab with ipilimumab in ipilimumab-naive patients with histologically confirmed unresectable stage III or IV melanoma. The study protocol is available in the appendix (pp 26–167), and the methods have been published previously.8, 9 Eligible patients were aged 18 years or older, with an Eastern Cooperative

Results

Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled at 87 sites in 16 countries (appendix pp 5–7) and were randomly assigned to receive pembrolizumab (n=556) or ipilimumab (n=278; figure 1). Of these, 811 patients received at least one dose of study treatment (figure 1). 368 (66%) patients in the combined pembrolizumab groups and 181 (65%) patients in the ipilimumab group received the study drug as first-line therapy for advanced disease, and 195 (35%) and 107 (38%),

Discussion

Consistent with previous analyses with shorter follow-up,8, 9 the estimated 5-year survival outcome of KEYNOTE-006 presented here continued to show superiority of pembrolizumab over ipilimumab in patients with ipilimumab-naive advanced melanoma. Patients who were given pembrolizumab had longer overall survival and progression-free survival than did those given ipilimumab. These results were observed irrespective of BRAFV600 status, or exposure to previous BRAF or MEK inhibitors for those

Data sharing

Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co, Kenilworth, NJ, USA is committed to providing qualified scientific researchers access to anonymised patient-level data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. The company is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial

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