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Clinical Trial
. 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

Caroline Robert  1 , Antoni Ribas  2 , Jedd D Wolchok  3 , F Stephen Hodi  4 , Omid Hamid  5 , Richard Kefford  6 , Jeffrey S Weber  7 , Anthony M Joshua  8 , Wen-Jen Hwu  9 , Tara C Gangadhar  10 , Amita Patnaik  11 , Roxana Dronca  12 , Hassane Zarour  13 , Richard W Joseph  14 , Peter Boasberg  5 , Bartosz Chmielowski  2 , Christine Mateus  15 , Michael A Postow  3 , Kevin Gergich  16 , Jeroen Elassaiss-Schaap  16 , Xiaoyun Nicole Li  16 , Robert Iannone  16 , Scot W Ebbinghaus  16 , S Peter Kang  16 , Adil Daud  17
Affiliations
Clinical Trial

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

Caroline Robert et al. Lancet. .

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.

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