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, Antoni Ribas, Jedd D. Wolchok, F. Stephen Hodi, Omid Hamid, Richard Kefford, Jeffrey S. Weber, Anthony M. Joshua, Wen Jen Hwu, Tara C. Gangadhar, Amita Patnaik, Roxana S Dronca, Hassane Zarour, Richard W Joseph, Peter Boasberg, Bartosz Chmielowski, Christine Mateus, Michael A. Postow, Kevin Gergich, Jeroen Elassaiss-SchaapXiaoyun Nicole Li, Robert Iannone, Scot W. Ebbinghaus, S. Peter Kang, Adil Daud

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1109-1117
Number of pages9
JournalThe Lancet
Volume384
Issue number9948
DOIs
StatePublished - Sep 20 2014

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Death Domain Receptors
Melanoma
Therapeutics
Fatigue
Appointments and Schedules
Safety
pembrolizumab
ipilimumab
Pruritus
Exanthema
Drug-Related Side Effects and Adverse Reactions
Pharmaceutical Preparations
Disease Progression
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

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Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma : A randomised dose-comparison cohort of a phase 1 trial. / Robert, Caroline; Ribas, Antoni; Wolchok, Jedd D.; Hodi, F. Stephen; Hamid, Omid; Kefford, Richard; Weber, Jeffrey S.; Joshua, Anthony M.; Hwu, Wen Jen; Gangadhar, Tara C.; Patnaik, Amita; Dronca, Roxana S; Zarour, Hassane; Joseph, Richard W; Boasberg, Peter; Chmielowski, Bartosz; Mateus, Christine; Postow, Michael A.; Gergich, Kevin; Elassaiss-Schaap, Jeroen; Li, Xiaoyun Nicole; Iannone, Robert; Ebbinghaus, Scot W.; Kang, S. Peter; Daud, Adil.

In: The Lancet, Vol. 384, No. 9948, 20.09.2014, p. 1109-1117.

Research output: Contribution to journalArticle

Robert, C, Ribas, A, Wolchok, JD, Hodi, FS, Hamid, O, Kefford, R, Weber, JS, Joshua, AM, Hwu, WJ, Gangadhar, TC, Patnaik, A, Dronca, RS, Zarour, H, Joseph, RW, Boasberg, P, Chmielowski, B, Mateus, C, Postow, MA, Gergich, K, Elassaiss-Schaap, J, Li, XN, Iannone, R, Ebbinghaus, SW, Kang, SP & Daud, A 2014, 'Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial', The Lancet, vol. 384, no. 9948, pp. 1109-1117. https://doi.org/10.1016/S0140-6736(14)60958-2
Robert, Caroline ; Ribas, Antoni ; Wolchok, Jedd D. ; Hodi, F. Stephen ; Hamid, Omid ; Kefford, Richard ; Weber, Jeffrey S. ; Joshua, Anthony M. ; Hwu, Wen Jen ; Gangadhar, Tara C. ; Patnaik, Amita ; Dronca, Roxana S ; Zarour, Hassane ; Joseph, Richard W ; Boasberg, Peter ; Chmielowski, Bartosz ; Mateus, Christine ; Postow, Michael A. ; Gergich, Kevin ; Elassaiss-Schaap, Jeroen ; Li, Xiaoyun Nicole ; Iannone, Robert ; Ebbinghaus, Scot W. ; Kang, S. Peter ; Daud, Adil. / Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma : A randomised dose-comparison cohort of a phase 1 trial. In: The Lancet. 2014 ; Vol. 384, No. 9948. pp. 1109-1117.
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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.",
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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 S

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

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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