Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial

Antoni Ribas, Igor Puzanov, Reinhard Dummer, Dirk Schadendorf, Omid Hamid, Caroline Robert, F. Stephen Hodi, Jacob Schachter, Anna C. Pavlick, Karl D. Lewis, Lee D Cranmer, Christian U. Blank, Steven J. O'Day, Paolo A. Ascierto, April K S Salama, Kim A. Margolin, Carmen Loquai, Thomas K. Eigentler, Tara C. Gangadhar, Matteo S. CarlinoSanjiv S. Agarwala, Stergios J. Moschos, Jeffrey A. Sosman, Simone M. Goldinger, Ronnie Shapira-Frommer, Rene Gonzalez, John M. Kirkwood, Jedd D. Wolchok, Alexander Eggermont, Xiaoyun Nicole Li, Wei Zhou, Adriane M. Zernhelt, Joy Lis, Scot Ebbinghaus, S. Peter Kang, Adil Daud

Research output: Contribution to journalArticle

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Abstract

Background: Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p

Original languageEnglish (US)
Pages (from-to)908-918
Number of pages11
JournalThe Lancet Oncology
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2015

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Melanoma
Research Personnel
Drug Therapy
Disease-Free Survival
Carboplatin
temozolomide
Mitogen-Activated Protein Kinase Kinases
Paclitaxel
ipilimumab
pembrolizumab
Dacarbazine
Random Allocation
Prednisone
L-Lactate Dehydrogenase
Therapeutics
Safety
Mutation
Population

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002) : A randomised, controlled, phase 2 trial. / Ribas, Antoni; Puzanov, Igor; Dummer, Reinhard; Schadendorf, Dirk; Hamid, Omid; Robert, Caroline; Hodi, F. Stephen; Schachter, Jacob; Pavlick, Anna C.; Lewis, Karl D.; Cranmer, Lee D; Blank, Christian U.; O'Day, Steven J.; Ascierto, Paolo A.; Salama, April K S; Margolin, Kim A.; Loquai, Carmen; Eigentler, Thomas K.; Gangadhar, Tara C.; Carlino, Matteo S.; Agarwala, Sanjiv S.; Moschos, Stergios J.; Sosman, Jeffrey A.; Goldinger, Simone M.; Shapira-Frommer, Ronnie; Gonzalez, Rene; Kirkwood, John M.; Wolchok, Jedd D.; Eggermont, Alexander; Li, Xiaoyun Nicole; Zhou, Wei; Zernhelt, Adriane M.; Lis, Joy; Ebbinghaus, Scot; Kang, S. Peter; Daud, Adil.

In: The Lancet Oncology, Vol. 16, No. 8, 01.08.2015, p. 908-918.

Research output: Contribution to journalArticle

Ribas, A, Puzanov, I, Dummer, R, Schadendorf, D, Hamid, O, Robert, C, Hodi, FS, Schachter, J, Pavlick, AC, Lewis, KD, Cranmer, LD, Blank, CU, O'Day, SJ, Ascierto, PA, Salama, AKS, Margolin, KA, Loquai, C, Eigentler, TK, Gangadhar, TC, Carlino, MS, Agarwala, SS, Moschos, SJ, Sosman, JA, Goldinger, SM, Shapira-Frommer, R, Gonzalez, R, Kirkwood, JM, Wolchok, JD, Eggermont, A, Li, XN, Zhou, W, Zernhelt, AM, Lis, J, Ebbinghaus, S, Kang, SP & Daud, A 2015, 'Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial', The Lancet Oncology, vol. 16, no. 8, pp. 908-918. https://doi.org/10.1016/S1470-2045(15)00083-2
Ribas, Antoni ; Puzanov, Igor ; Dummer, Reinhard ; Schadendorf, Dirk ; Hamid, Omid ; Robert, Caroline ; Hodi, F. Stephen ; Schachter, Jacob ; Pavlick, Anna C. ; Lewis, Karl D. ; Cranmer, Lee D ; Blank, Christian U. ; O'Day, Steven J. ; Ascierto, Paolo A. ; Salama, April K S ; Margolin, Kim A. ; Loquai, Carmen ; Eigentler, Thomas K. ; Gangadhar, Tara C. ; Carlino, Matteo S. ; Agarwala, Sanjiv S. ; Moschos, Stergios J. ; Sosman, Jeffrey A. ; Goldinger, Simone M. ; Shapira-Frommer, Ronnie ; Gonzalez, Rene ; Kirkwood, John M. ; Wolchok, Jedd D. ; Eggermont, Alexander ; Li, Xiaoyun Nicole ; Zhou, Wei ; Zernhelt, Adriane M. ; Lis, Joy ; Ebbinghaus, Scot ; Kang, S. Peter ; Daud, Adil. / Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002) : A randomised, controlled, phase 2 trial. In: The Lancet Oncology. 2015 ; Vol. 16, No. 8. pp. 908-918.
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TY - JOUR

T1 - Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002)

T2 - A randomised, controlled, phase 2 trial

AU - Ribas, Antoni

AU - Puzanov, Igor

AU - Dummer, Reinhard

AU - Schadendorf, Dirk

AU - Hamid, Omid

AU - Robert, Caroline

AU - Hodi, F. Stephen

AU - Schachter, Jacob

AU - Pavlick, Anna C.

AU - Lewis, Karl D.

AU - Cranmer, Lee D

AU - Blank, Christian U.

AU - O'Day, Steven J.

AU - Ascierto, Paolo A.

AU - Salama, April K S

AU - Margolin, Kim A.

AU - Loquai, Carmen

AU - Eigentler, Thomas K.

AU - Gangadhar, Tara C.

AU - Carlino, Matteo S.

AU - Agarwala, Sanjiv S.

AU - Moschos, Stergios J.

AU - Sosman, Jeffrey A.

AU - Goldinger, Simone M.

AU - Shapira-Frommer, Ronnie

AU - Gonzalez, Rene

AU - Kirkwood, John M.

AU - Wolchok, Jedd D.

AU - Eggermont, Alexander

AU - Li, Xiaoyun Nicole

AU - Zhou, Wei

AU - Zernhelt, Adriane M.

AU - Lis, Joy

AU - Ebbinghaus, Scot

AU - Kang, S. Peter

AU - Daud, Adil

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Background: Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p

AB - Background: Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p

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