TY - JOUR
T1 - Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma
T2 - A randomised dose-comparison cohort of a phase 1 trial
AU - Robert, Caroline
AU - Ribas, Antoni
AU - Wolchok, Jedd D.
AU - Hodi, F. Stephen
AU - Hamid, Omid
AU - Kefford, Richard
AU - Weber, Jeffrey S.
AU - Joshua, Anthony M.
AU - Hwu, Wen Jen
AU - Gangadhar, Tara C.
AU - Patnaik, Amita
AU - Dronca, Roxana
AU - Zarour, Hassane
AU - Joseph, Richard W.
AU - Boasberg, Peter
AU - Chmielowski, Bartosz
AU - Mateus, Christine
AU - Postow, Michael A.
AU - Gergich, Kevin
AU - Elassaiss-Schaap, Jeroen
AU - Li, Xiaoyun Nicole
AU - Iannone, Robert
AU - Ebbinghaus, Scot W.
AU - Kang, S. Peter
AU - Daud, Adil
N1 - Funding Information:
KG, JE-S, XNL, RI, SWE, and SPK are employees of Merck Sharp and Dohme, a subsidiary of Merck, Whitehouse Station, NJ, and might own stock or hold stock options in the company. CR has served on advisory boards for Merck, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, and Amgen. AR has received research funding, served on advisory boards, and received honoraria from or for Merck. JDW has received research funding and non-financial support from Merck and Bristol-Myers Squibb and has served on advisory boards for Merck. FSH has received funding from Merck for doing clinical research studies and has served as a non-paid consultant to Merck. OH has received research funding and has served as a consultant to Merck. RK has had travel paid by Merck, Bristol-Myers Squibb, Roche, and Novartis; has served on advisory boards for Merck, Bristol-Myers Squibb, GlaxoSmithKline, Roche, and Novartis; and has received honoraria from Merck. JSW has received research funding and personal fees from Merck. W-JH has received funding from Merck for clinical research, clinical trial support, and study drug. TCG has received personal fees from Merck. AP has received research funding from Merck. HZ has received research funding from Merck. PB has received research funding from Merck and speaker's fees from Bristol-Myers Squibb. BC has served on advisory boards for Merck, Genentech, Bristol-Myers Squibb, Prometheus, Morphotek, GlaxoSmithKline, and CytRx Corporation; has received research funding from Merck; and is a member of speaker's bureaus for Genentech, Bristol-Myers Squibb, and Prometheus. MAP has received research funding from Bristol-Myers Squibb. AD has received research funding from and served on advisory boards for Amgen, Genentech, GlaxoSmithKline, OncoSec, and Roche. The other authors declare no competing interests.
Funding Information:
This study was funded by Merck Sharp and Dohme, Whitehouse Station, NJ, a subsidiary of Merck, which provided the study drug and worked jointly with the senior academic authors to design the study and gather, analyse, and interpret the results. CR, AR, and AD had full access to the study data and worked with employees of the funder to analyse the results. All authors approved the decision to submit the manuscript for publication, affirm the accuracy and completeness of the data, and attest that the study was done in accordance with the protocol and all amendments. All drafts of the manuscript were written by the corresponding author and AD with input from the other authors. The funder provided assistance with manuscript preparation and funded medical writing support. Aside from the authors and those listed in the acknowledgements, no one else contributed to the preparation of the manuscript.
Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/9/20
Y1 - 2014/9/20
N2 - 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.
AB - 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.
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U2 - 10.1016/S0140-6736(14)60958-2
DO - 10.1016/S0140-6736(14)60958-2
M3 - Article
C2 - 25034862
AN - SCOPUS:84908354848
SN - 0140-6736
VL - 384
SP - 1109
EP - 1117
JO - The Lancet
JF - The Lancet
IS - 9948
ER -