Elsevier

The Lancet

Volume 384, Issue 9948, 20–26 September 2014, Pages 1109-1117
The Lancet

Articles
Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial

https://doi.org/10.1016/S0140-6736(14)60958-2Get rights and content

Summary

Background

The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma.

Methods

In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827.

Findings

173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses—21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI −14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient.

Interpretation

The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.

Funding

Merck Sharp and Dohme.

Introduction

Despite recent advances such as the anti-cytotoxic T-lymphocyte-associated-antigen-4 (CTLA-4) antibody ipilimumab and the mitogen-activated protein kinase pathway inhibitors vemurafenib, dabrafenib, and trametinib, melanoma treatment remains a challenge because there are few effective treatment options for patients who relapse or do not respond to these therapies. Response has been reported in about 25% and 50% of patients treated with MEK and BRAF inhibitors, respectively, and these agents are associated with a survival advantage compared with chemotherapy.1, 2, 3, 4, 5 However, their use is restricted to the roughly 50% of patients with BRAF V600-mutant melanoma,6 and the median duration of response is about 6–7 months.2, 3 Combination therapy with BRAF and MEK inhibitors results in an objective response rate of 76% and extends progression-free survival (PFS), but most patients develop resistance to these inhibitors.7 Thus, there is an urgent need to develop effective treatment options for patients who progress on these agents. The distinct mechanism of action of anti-programmed-death-receptor-1 (PD-1) antibodies, which increase tumour cell killing peripherally by cytotoxic T lymphocytes,8 might have activity in patients with ipilimumab-refractory melanoma.

PD-1 is expressed on antigen-stimulated T cells and induces downstream signalling that inhibits T-cell proliferation, cytokine release, and cytotoxicity.8, 9, 10 Many tumours, including melanoma, suppress cytotoxic T-cell activity11, 12 by expressing PD-1 ligand (PD-L1) on the cell surface. Anti-PD-1 and PD-L1 antibodies can reverse this T-cell suppression and induce long-lasting antitumour responses in patients with advanced solid tumours, including advanced melanoma.13, 14, 15, 16, 17, 18, 19, 20

Pembrolizumab (MK-3475, previously known as lambrolizumab) is a highly selective, humanised monoclonal IgG4-kappa isotype antibody against PD-1 that has shown robust clinical activity with an acceptable safety profile. In 135 patients with advanced melanoma who were enrolled in non-randomised cohorts of the large, phase 1 study KEYNOTE-001 (ClinicalTrials.gov, number NCT01295827), pembrolizumab resulted in long-lasting objective responses as assessed per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) in 31–51% of patients treated with doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks, and 81% of patients survived for at least 1 year after starting treatment.15, 16 Of note, promising antitumour activity and acceptable safety were noted in the 48 patients previously treated with ipilimumab; however, the sample size was insufficient to assess clinical benefit accurately, and lack of randomisation between doses and schedules restricted the ability to assess a dose-response relation.

In this study, an expansion cohort of KEYNOTE-001, we assessed further the clinical benefit of pembrolizumab in patients whose advanced melanoma progressed after ipilimumab and who were previously treated with a BRAF or MEK inhibitor, or both, a clinical scenario for which there is no effective treatment.

Section snippets

Study design and patients

This trial is a multicentre, international (Australia, Canada, France, and the USA), randomised expansion cohort of the phase 1 KEYNOTE-001 study. Eligible patients were aged 18 years or older, had progressive, measurable, unresectable melanoma that was previously treated with at least two doses of ipilimumab 3 mg/kg or higher administered every 3 weeks; had confirmed disease progression using immune-related response criteria21 within 24 weeks of the last dose of ipilimumab; and had adequate

Results

Between Aug 28, 2012, and April 5, 2013, 178 patients with ipilimumab-refractory advanced melanoma who were enrolled at 15 sites in four countries were randomly assigned to the pembrolizumab 2 mg/kg (n=91) or pembrolizumab 10 mg/kg group (n=87), and 173 received treatment (89 and 84 patients, respectively; figure 1). At baseline, 110 (64%) of 173 patients were stage M1c, 68 (39%) had elevated lactate dehydrogenase concentrations, 31 (18%) had BRAF mutations, and 15 (9%) had a history of brain

Discussion

The anti-PD-1 antibody pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks had similar and substantial anticancer activity and an acceptable safety profile in patients with advanced melanoma whose disease had progressed on ipilimumab, and in those with BRAF-mutant disease, who were previously treated with BRAF or MEK inhibitors, or both. This study is the largest reported of anti-PD-1 therapy in patients with melanoma and the first reported randomised comparison of an anti-PD-1 agent (

References (33)

  • ME Keir et al.

    PD-1 and its ligands in tolerance and immunity

    Annu Rev Immunol

    (2008)
  • DM Pardoll

    The blockade of immune checkpoints in cancer immunotherapy

    Nat Rev Cancer

    (2012)
  • LM Francisco et al.

    The PD-1 pathway in tolerance and autoimmunity

    Immunol Rev

    (2010)
  • SL Topalian et al.

    Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

    N Engl J Med

    (2012)
  • SL Topalian et al.

    Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab

    J Clin Oncol

    (2014)
  • O Hamid et al.

    Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma

    N Engl J Med

    (2013)
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