Association of pembrolizumab with tumor response and survival among patients with advanced melanoma

Antoni Ribas, Omid Hamid, Adil Daud, F. Stephen Hodi, Jedd D. Wolchok, Richard Kefford, Anthony M. Joshua, Amita Patnaik, Wen Jen Hwu, Jeffrey S. Weber, Tara C. Gangadhar, Peter Hersey, Roxana S Dronca, Richard W Joseph, Hassane Zarour, Bartosz Chmielowski, Donald P. Lawrence, Alain Algazi, Naiyer A. Rizvi, Brianna HoffnerChristine Mateus, Kevin Gergich, Jill A. Lindia, Maxine Giannotti, Xiaoyun Nicole Li, Scot Ebbinghaus, S. Peter Kang, Caroline Robert

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Abstract

Importance: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. Objective: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. Design, Settings, and Participants: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. Exposures: Pembrolizumab 10mg/kg every 2weeks, 10mg/kg every 3weeks, or 2mg/kg every 3weeks continued until disease progression, intolerable toxicity, or investigator decision. Main Outcomes and Measures: The primary end pointwas confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. Results: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33%[95%CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45%[95%CI, 36%to 54%]). Overall, 74%(152/205) of responses were ongoing at the time of data cutoff; 44%(90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35%(95%CI, 31%-39%) in the total population and 52%(95%CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66%(95%CI, 62%-69%) and a 24-month survival rate of 49%(95%CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95%CI, 24 to not reached) with a 12-month survival rate of 73%(95%CI, 65%-79%) and a 24-month survival rate of 60%(95%CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. Conclusions and Relevance: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.

Original languageEnglish (US)
Pages (from-to)1600-1609
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume315
Issue number15
DOIs
StatePublished - Apr 19 2016

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Melanoma
Survival
Neoplasms
Survival Rate
Disease-Free Survival
Therapeutics
pembrolizumab
Population
France
Canada
Disease Progression
Monoclonal Antibodies
Research Personnel
Outcome Assessment (Health Care)
Clinical Trials
Safety

ASJC Scopus subject areas

  • Medicine(all)

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Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. / Ribas, Antoni; Hamid, Omid; Daud, Adil; Hodi, F. Stephen; Wolchok, Jedd D.; Kefford, Richard; Joshua, Anthony M.; Patnaik, Amita; Hwu, Wen Jen; Weber, Jeffrey S.; Gangadhar, Tara C.; Hersey, Peter; Dronca, Roxana S; Joseph, Richard W; Zarour, Hassane; Chmielowski, Bartosz; Lawrence, Donald P.; Algazi, Alain; Rizvi, Naiyer A.; Hoffner, Brianna; Mateus, Christine; Gergich, Kevin; Lindia, Jill A.; Giannotti, Maxine; Li, Xiaoyun Nicole; Ebbinghaus, Scot; Kang, S. Peter; Robert, Caroline.

In: JAMA - Journal of the American Medical Association, Vol. 315, No. 15, 19.04.2016, p. 1600-1609.

Research output: Contribution to journalArticle

Ribas, A, Hamid, O, Daud, A, Hodi, FS, Wolchok, JD, Kefford, R, Joshua, AM, Patnaik, A, Hwu, WJ, Weber, JS, Gangadhar, TC, Hersey, P, Dronca, RS, Joseph, RW, Zarour, H, Chmielowski, B, Lawrence, DP, Algazi, A, Rizvi, NA, Hoffner, B, Mateus, C, Gergich, K, Lindia, JA, Giannotti, M, Li, XN, Ebbinghaus, S, Kang, SP & Robert, C 2016, 'Association of pembrolizumab with tumor response and survival among patients with advanced melanoma', JAMA - Journal of the American Medical Association, vol. 315, no. 15, pp. 1600-1609. https://doi.org/10.1001/jama.2016.4059
Ribas, Antoni ; Hamid, Omid ; Daud, Adil ; Hodi, F. Stephen ; Wolchok, Jedd D. ; Kefford, Richard ; Joshua, Anthony M. ; Patnaik, Amita ; Hwu, Wen Jen ; Weber, Jeffrey S. ; Gangadhar, Tara C. ; Hersey, Peter ; Dronca, Roxana S ; Joseph, Richard W ; Zarour, Hassane ; Chmielowski, Bartosz ; Lawrence, Donald P. ; Algazi, Alain ; Rizvi, Naiyer A. ; Hoffner, Brianna ; Mateus, Christine ; Gergich, Kevin ; Lindia, Jill A. ; Giannotti, Maxine ; Li, Xiaoyun Nicole ; Ebbinghaus, Scot ; Kang, S. Peter ; Robert, Caroline. / Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 315, No. 15. pp. 1600-1609.
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title = "Association of pembrolizumab with tumor response and survival among patients with advanced melanoma",
abstract = "Importance: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. Objective: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. Design, Settings, and Participants: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. Exposures: Pembrolizumab 10mg/kg every 2weeks, 10mg/kg every 3weeks, or 2mg/kg every 3weeks continued until disease progression, intolerable toxicity, or investigator decision. Main Outcomes and Measures: The primary end pointwas confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. Results: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62{\%}] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33{\%}[95{\%}CI, 30{\%}-37{\%}]) and in 60 of 133 treatment-naive patients (45{\%}[95{\%}CI, 36{\%}to 54{\%}]). Overall, 74{\%}(152/205) of responses were ongoing at the time of data cutoff; 44{\%}(90/205) of patients had response duration for at least 1 year and 79{\%} (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35{\%}(95{\%}CI, 31{\%}-39{\%}) in the total population and 52{\%}(95{\%}CI, 43{\%}-60{\%}) among treatment-naive patients. Median overall survival in the total population was 23 months (95{\%} CI, 20-29) with a 12-month survival rate of 66{\%}(95{\%}CI, 62{\%}-69{\%}) and a 24-month survival rate of 49{\%}(95{\%}CI, 44{\%}-53{\%}). In treatment-naive patients, median overall survival was 31 months (95{\%}CI, 24 to not reached) with a 12-month survival rate of 73{\%}(95{\%}CI, 65{\%}-79{\%}) and a 24-month survival rate of 60{\%}(95{\%}CI, 51{\%}-68{\%}). Ninety-two of 655 patients (14{\%}) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4{\%}) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9{\%}). There were no drug-related deaths. Conclusions and Relevance: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33{\%}, 12-month progression-free survival rate of 35{\%}, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14{\%}.",
author = "Antoni Ribas and Omid Hamid and Adil Daud and Hodi, {F. Stephen} and Wolchok, {Jedd D.} and Richard Kefford and Joshua, {Anthony M.} and Amita Patnaik and Hwu, {Wen Jen} and Weber, {Jeffrey S.} and Gangadhar, {Tara C.} and Peter Hersey and Dronca, {Roxana S} and Joseph, {Richard W} and Hassane Zarour and Bartosz Chmielowski and Lawrence, {Donald P.} and Alain Algazi and Rizvi, {Naiyer A.} and Brianna Hoffner and Christine Mateus and Kevin Gergich and Lindia, {Jill A.} and Maxine Giannotti and Li, {Xiaoyun Nicole} and Scot Ebbinghaus and Kang, {S. Peter} and Caroline Robert",
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month = "4",
day = "19",
doi = "10.1001/jama.2016.4059",
language = "English (US)",
volume = "315",
pages = "1600--1609",
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TY - JOUR

T1 - Association of pembrolizumab with tumor response and survival among patients with advanced melanoma

AU - Ribas, Antoni

AU - Hamid, Omid

AU - Daud, Adil

AU - Hodi, F. Stephen

AU - Wolchok, Jedd D.

AU - Kefford, Richard

AU - Joshua, Anthony M.

AU - Patnaik, Amita

AU - Hwu, Wen Jen

AU - Weber, Jeffrey S.

AU - Gangadhar, Tara C.

AU - Hersey, Peter

AU - Dronca, Roxana S

AU - Joseph, Richard W

AU - Zarour, Hassane

AU - Chmielowski, Bartosz

AU - Lawrence, Donald P.

AU - Algazi, Alain

AU - Rizvi, Naiyer A.

AU - Hoffner, Brianna

AU - Mateus, Christine

AU - Gergich, Kevin

AU - Lindia, Jill A.

AU - Giannotti, Maxine

AU - Li, Xiaoyun Nicole

AU - Ebbinghaus, Scot

AU - Kang, S. Peter

AU - Robert, Caroline

PY - 2016/4/19

Y1 - 2016/4/19

N2 - Importance: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. Objective: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. Design, Settings, and Participants: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. Exposures: Pembrolizumab 10mg/kg every 2weeks, 10mg/kg every 3weeks, or 2mg/kg every 3weeks continued until disease progression, intolerable toxicity, or investigator decision. Main Outcomes and Measures: The primary end pointwas confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. Results: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33%[95%CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45%[95%CI, 36%to 54%]). Overall, 74%(152/205) of responses were ongoing at the time of data cutoff; 44%(90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35%(95%CI, 31%-39%) in the total population and 52%(95%CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66%(95%CI, 62%-69%) and a 24-month survival rate of 49%(95%CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95%CI, 24 to not reached) with a 12-month survival rate of 73%(95%CI, 65%-79%) and a 24-month survival rate of 60%(95%CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. Conclusions and Relevance: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.

AB - Importance: The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab. Objective: To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma. Design, Settings, and Participants: Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013). Median duration of follow-up was 21 months. The study was performed in academic medical centers in Australia, Canada, France, and the United States. Eligible patients were aged 18 years and older and had advanced or metastatic melanoma. Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]). Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses. Exposures: Pembrolizumab 10mg/kg every 2weeks, 10mg/kg every 3weeks, or 2mg/kg every 3weeks continued until disease progression, intolerable toxicity, or investigator decision. Main Outcomes and Measures: The primary end pointwas confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review. Secondary end points included toxicity, duration of response, progression-free survival, and overall survival. Results: Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline. An objective response was reported in 194 of 581 patients (33%[95%CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45%[95%CI, 36%to 54%]). Overall, 74%(152/205) of responses were ongoing at the time of data cutoff; 44%(90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months. Twelve-month progression-free survival rates were 35%(95%CI, 31%-39%) in the total population and 52%(95%CI, 43%-60%) among treatment-naive patients. Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66%(95%CI, 62%-69%) and a 24-month survival rate of 49%(95%CI, 44%-53%). In treatment-naive patients, median overall survival was 31 months (95%CI, 24 to not reached) with a 12-month survival rate of 73%(95%CI, 65%-79%) and a 24-month survival rate of 60%(95%CI, 51%-68%). Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE. Treatment-related serious AEs were reported in 59 patients (9%). There were no drug-related deaths. Conclusions and Relevance: Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.

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