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Lancet. 2014 Sep 20;384(9948):1109-17. doi: 10.1016/S0140-6736(14)60958-2. Epub 2014 Jul 15.

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

Author information

1
Gustave Roussy and INSERM U981, Paris-Sud, France. Electronic address: caroline.robert@gustaveroussy.fr.
2
University of California Los Angeles, Los Angeles, CA, USA.
3
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
4
Dana-Farber Cancer Institute, Boston, MA, USA.
5
Angeles Clinic and Research Institute, Los Angeles, CA, USA.
6
Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Westmead, NSW, Australia; University of Sydney, Sydney, NSW, Australia.
7
H Lee Moffitt Cancer Center, Tampa, FL, USA.
8
Princess Margaret Cancer Centre, Toronto, ON, Canada.
9
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA.
11
South Texas Accelerated Research Therapeutics, San Antonio, TX, USA.
12
Mayo Clinic, Rochester, MN, USA.
13
University of Pittsburgh, Pittsburgh, PA, USA.
14
Mayo Clinic, Jacksonville, FL, USA.
15
Gustave Roussy and INSERM U981, Paris-Sud, France.
16
Merck, Whitehouse Station, NJ, USA.
17
University of California San Francisco, San Francisco, CA, USA.

Abstract

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.

PMID:
25034862
DOI:
10.1016/S0140-6736(14)60958-2
[Indexed for MEDLINE]
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