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Caroline Robert - One of the best experts on this subject based on the ideXlab platform.
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Pembrolizumab versus ipilimumab in advanced melanoma keynote 006 post hoc 5 year results from an open label multicentre randomised controlled phase 3 study
Lancet Oncology, 2019Co-Authors: Caroline Robert, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Jacob Schachter, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. Methods KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous Pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two Pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued Pembrolizumab with stable disease or better after receiving at least 24 months of Pembrolizumab or discontinued with complete response after at least 6 months of Pembrolizumab and then progressed could receive an additional 17 cycles of Pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive Pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7–59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5–41·6) in the combined Pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6–11·3) in the combined Pembrolizumab groups versus 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p Interpretation Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of Pembrolizumab in patients with advanced melanoma. Funding Merck Sharp & Dohme.
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durable complete response after discontinuation of Pembrolizumab in patients with metastatic melanoma
Journal of Clinical Oncology, 2017Co-Authors: Wenjen Hwu, Caroline Robert, Omid Hamid, Adil Daud, Antoni Ribas, Jedd D Wolchok, Anthony M Joshua, Jeffrey S Weber, Tara C GangadharAbstract:Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after Pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with Pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of Pembrolizumab. Eligible patients who received Pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued Pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of Pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
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patient reported outcomes in keynote 006 a randomised study of Pembrolizumab versus ipilimumab in patients with advanced melanoma
European Journal of Cancer, 2017Co-Authors: Teresa M Petrella, Caroline Robert, Celeste Lebbe, Erika Richtig, Wilson H Miller, Giuseppe Masucci, Euan Walpole, Neil Steven, Mark R Middleton, Darcy A HilleAbstract:Objective Report results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of Pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma. Patients and methods Patients received Pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis. Results The PRO analysis population included 776 patients: Pembrolizumab Q2W (n = 270); Pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the Pembrolizumab Q2W, Pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with Pembrolizumab than with ipilimumab (decrease of −1.9 and −2.5 for Pembrolizumab versus −10.0 for ipilimumab; p < 0.001 for each Pembrolizumab arm versus ipilimumab). Fewer patients treated with Pembrolizumab experienced deterioration in GHS at week 12 (31% for Pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales. Conclusions HRQoL was better maintained with Pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma. ClinicalTrials.gov identifier NCT01866319.
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final analysis of a randomised trial comparing Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory advanced melanoma
European Journal of Cancer, 2017Co-Authors: Omid Hamid, Caroline Robert, Reinhard Dummer, Jacob Schachter, Adil Daud, Igor Puzanov, Dirk Schadendorf, Christian U Blank, Lee D Cranmer, Anna C PavlickAbstract:Abstract Aim To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study ( NCT01704287 ) of Pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. Methods In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to Pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p Results A total of 180 patients were randomised to Pembrolizumab 2 mg/kg, 181 to Pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5), 368 patients died and 98 (55%) crossed over to Pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus 11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with Pembrolizumab versus chemotherapy, regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. Conclusion Improvement in OS with Pembrolizumab was not statistically significant at either dose versus chemotherapy.
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Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory melanoma keynote 002 a randomised controlled phase 2 trial
Lancet Oncology, 2015Co-Authors: Antoni Ribas, Stephen F Hodi, Caroline Robert, Reinhard Dummer, Omid Hamid, Jacob Schachter, Igor Puzanov, Dirk Schadendorf, Anna C Pavlick, Karl D LewisAbstract:Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 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 BRAF V600 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 BRAF V600 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 Interpretation These findings establish Pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
Antoni Ribas - One of the best experts on this subject based on the ideXlab platform.
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Pembrolizumab versus ipilimumab in advanced melanoma keynote 006 post hoc 5 year results from an open label multicentre randomised controlled phase 3 study
Lancet Oncology, 2019Co-Authors: Caroline Robert, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Jacob Schachter, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. Methods KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous Pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two Pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued Pembrolizumab with stable disease or better after receiving at least 24 months of Pembrolizumab or discontinued with complete response after at least 6 months of Pembrolizumab and then progressed could receive an additional 17 cycles of Pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive Pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7–59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5–41·6) in the combined Pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6–11·3) in the combined Pembrolizumab groups versus 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p Interpretation Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of Pembrolizumab in patients with advanced melanoma. Funding Merck Sharp & Dohme.
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durable complete response after discontinuation of Pembrolizumab in patients with metastatic melanoma
Journal of Clinical Oncology, 2017Co-Authors: Wenjen Hwu, Caroline Robert, Omid Hamid, Adil Daud, Antoni Ribas, Jedd D Wolchok, Anthony M Joshua, Jeffrey S Weber, Tara C GangadharAbstract:Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after Pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with Pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of Pembrolizumab. Eligible patients who received Pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued Pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of Pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
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Pembrolizumab versus ipilimumab for advanced melanoma final overall survival results of a multicentre randomised open label phase 3 study keynote 006
The Lancet, 2017Co-Authors: Jacob Schachter, Georgina V Long, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of Pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. Methods In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of Pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous Pembrolizumab every 2 weeks (n=279), intravenous Pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the Pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either Pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53–0·87 for Pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53–0·86 for Pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. Interpretation Substantiating the results of the interim analyses of KEYNOTE-006, Pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between Pembrolizumab dosing schedules. These conclusions further support the use of Pembrolizumab as a standard of care for advanced melanoma. Funding Merck & Co.
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standard dose Pembrolizumab in combination with reduced dose ipilimumab for patients with advanced melanoma keynote 029 an open label phase 1b trial
Lancet Oncology, 2017Co-Authors: Georgina V Long, Catriona M Mcneil, Victoria Atkinson, Jonathan Cebon, Michael B Jameson, Bernie M Fitzharris, Andrew G Hill, Antoni RibasAbstract:Summary Background Reduced-dose nivolumab in combination with standard-dose ipilimumab improves objective response and progression-free survival compared with standard-dose ipilimumab alone, but increases toxicity. We assessed the safety and anti-tumour activity of standard-dose Pembrolizumab in combination with reduced-dose ipilimumab. Methods In this open-label, phase 1b trial, we recruited patients from 12 medical centres in Australia, New Zealand, and the USA. Eligible patients were aged at least 18 years, had advanced melanoma, had an Eastern Coooperative Oncology Group performance status of 0 or 1, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, had adequate organ function, had resolution of toxic effects of the most recent previous chemotherapy to grade 1 or less, had no active autoimmune disease requiring systemic steroids or immunosuppressive agents, had no active non-infectious pneumonitis, had no uncontrolled thyroid dysfunction or diabetes, had no active brain metastases, and had not received previous immune checkpoint inhibitor therapy. Patients received intravenous Pembrolizumab 2 mg/kg plus intravenous ipilimumab 1 mg/kg every 3 weeks for four doses, followed by intravenous Pembrolizumab 2 mg/kg every 3 weeks for up to 2 years or disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was safety and tolerability. The proportion of patients achieving an objective response assessed per RECIST version 1.1 by independent central review and overall survival were secondary endpoints. We also assessed progression-free survival. The primary endpoint was assessed in all patients who received at least one dose of combination therapy. Activity was assessed in all enrolled patients. This trial is registered with ClinicalTrials.gov, number NCT02089685. Enrolment into this cohort is closed, but patients are still being monitored for safety and anti-tumour activity. Findings Between Jan 13, 2015, and Sept 17, 2015, we enrolled and treated 153 patients. As of the Oct 17, 2016, cutoff date, median follow-up was 17·0 months (IQR 14·8–18·8). 110 (72%) of 153 patients received all four Pembrolizumab plus ipilimumab doses; 64 (42%) remained on Pembrolizumab monotherapy. 110 grade 3–4 treatment-related adverse events occurred in 69 (45%) patients. No treatment-related deaths occurred. Treatment-related adverse events led to discontinuation of Pembrolizumab and ipilimumab in 22 (14%) patients, including 17 (11%) who discontinued both treatments for the same event and five (3%) who discontinued ipilimumab for one event and later discontinued Pembrolizumab for another. 12 (8%) patients discontinued ipilimumab only and 14 (9%) discontinued Pembrolizumab only because of treatment-related adverse events. 158 immune-mediated adverse events of any grade occurred in 92 (60%) patients, and 50 immune-mediated adverse events of grade 3–4 occurred in 42 (27%) patients; the most common immune-mediated adverse events were hypothyroidism (25 [16%]) and hyperthyroidism (17 [11%]). 93 (61% [95% CI 53–69]) patients achieved an objective response. Estimated 1 year progression-free survival was 69% (95% CI 60–75), and estimated 1 year overall survival was 89% (95% CI 83–93). Interpretation Standard-dose Pembrolizumab given in combination with four doses of reduced-dose ipilimumab followed by standard-dose Pembrolizumab has a manageable toxicity profile and provides robust anti-tumour activity in patients with advanced melanoma. These data suggest that standard-dose Pembrolizumab plus reduced-dose ipilimumab might be a tolerable, efficacious treatment option for patients with advanced melanoma. A randomised phase 2 trial of alternative dosing strategies of this combination is underway. Funding Merck & Co, Inc.
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Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory melanoma keynote 002 a randomised controlled phase 2 trial
Lancet Oncology, 2015Co-Authors: Antoni Ribas, Stephen F Hodi, Caroline Robert, Reinhard Dummer, Omid Hamid, Jacob Schachter, Igor Puzanov, Dirk Schadendorf, Anna C Pavlick, Karl D LewisAbstract:Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 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 BRAF V600 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 BRAF V600 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 Interpretation These findings establish Pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
Jacob Schachter - One of the best experts on this subject based on the ideXlab platform.
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Pembrolizumab versus ipilimumab in advanced melanoma keynote 006 post hoc 5 year results from an open label multicentre randomised controlled phase 3 study
Lancet Oncology, 2019Co-Authors: Caroline Robert, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Jacob Schachter, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. Methods KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous Pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two Pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued Pembrolizumab with stable disease or better after receiving at least 24 months of Pembrolizumab or discontinued with complete response after at least 6 months of Pembrolizumab and then progressed could receive an additional 17 cycles of Pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive Pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7–59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5–41·6) in the combined Pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6–11·3) in the combined Pembrolizumab groups versus 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p Interpretation Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of Pembrolizumab in patients with advanced melanoma. Funding Merck Sharp & Dohme.
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final analysis of a randomised trial comparing Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory advanced melanoma
European Journal of Cancer, 2017Co-Authors: Omid Hamid, Caroline Robert, Reinhard Dummer, Jacob Schachter, Adil Daud, Igor Puzanov, Dirk Schadendorf, Christian U Blank, Lee D Cranmer, Anna C PavlickAbstract:Abstract Aim To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study ( NCT01704287 ) of Pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. Methods In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to Pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p Results A total of 180 patients were randomised to Pembrolizumab 2 mg/kg, 181 to Pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5), 368 patients died and 98 (55%) crossed over to Pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus 11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with Pembrolizumab versus chemotherapy, regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. Conclusion Improvement in OS with Pembrolizumab was not statistically significant at either dose versus chemotherapy.
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Pembrolizumab versus ipilimumab for advanced melanoma final overall survival results of a multicentre randomised open label phase 3 study keynote 006
The Lancet, 2017Co-Authors: Jacob Schachter, Georgina V Long, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of Pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. Methods In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of Pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous Pembrolizumab every 2 weeks (n=279), intravenous Pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the Pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either Pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53–0·87 for Pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53–0·86 for Pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. Interpretation Substantiating the results of the interim analyses of KEYNOTE-006, Pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between Pembrolizumab dosing schedules. These conclusions further support the use of Pembrolizumab as a standard of care for advanced melanoma. Funding Merck & Co.
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Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory melanoma keynote 002 a randomised controlled phase 2 trial
Lancet Oncology, 2015Co-Authors: Antoni Ribas, Stephen F Hodi, Caroline Robert, Reinhard Dummer, Omid Hamid, Jacob Schachter, Igor Puzanov, Dirk Schadendorf, Anna C Pavlick, Karl D LewisAbstract:Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 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 BRAF V600 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 BRAF V600 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 Interpretation These findings establish Pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
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Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory melanoma keynote 002 a randomised controlled phase 2 trial
Lancet Oncology, 2015Co-Authors: Antoni Ribas, Stephen F Hodi, Caroline Robert, Reinhard Dummer, Omid Hamid, Jacob Schachter, Igor Puzanov, Dirk Schadendorf, Anna C Pavlick, Karl D LewisAbstract:Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 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 BRAF V600 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 BRAF V600 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 Interpretation These findings establish Pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
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epacadostat plus Pembrolizumab versus placebo plus Pembrolizumab in patients with unresectable or metastatic melanoma echo 301 keynote 252 a phase 3 randomised double blind study
Lancet Oncology, 2019Co-Authors: Georgina V Long, Reinhard Dummer, Omid Hamid, Thomas F Gajewski, Christian Caglevic, S Dalle, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Tae Min KimAbstract:Summary Background Immunotherapy combination treatments can improve patient outcomes. Epacadostat, an IDO1 selective inhibitor, and Pembrolizumab, a PD-1 inhibitor, showed promising antitumour activity in the phase 1–2 ECHO-202/KEYNOTE-037 study in advanced melanoma. In this trial, we aimed to compare progression-free survival and overall survival in patients with unresectable stage III or IV melanoma receiving epacadostat plus Pembrolizumab versus placebo plus Pembrolizumab. Methods In this international, randomised, placebo-controlled, double-blind, parallel-group, phase 3 trial, eligible participants were aged 18 years or older, with unresectable stage III or IV melanoma previously untreated with PD-1 or PD-L1 checkpoint inhibitors, an ECOG performance status of 0 or 1, and had a known BRAFV600 mutant status or consented to BRAFV600 mutation testing during screening. Patients were stratified by PD-L1 expression and BRAFV600 mutation status and randomly assigned (1:1) through a central interactive voice and integrated web response system to receive epacadostat 100 mg orally twice daily plus Pembrolizumab 200 mg intravenously every 3 weeks or placebo plus Pembrolizumab for up to 2 years. We used block randomisation with a block size of four in each stratum. Primary endpoints were progression-free survival and overall survival in the intention-to-treat population. The safety analysis population included randomly assigned patients who received at least one dose of study treatment. The study was stopped after the second interim analysis; follow-up for safety is ongoing. This study is registered with ClinicalTrials.gov , number NCT02752074 . Findings Between June 21, 2016, and Aug 7, 2017, 928 patients were screened and 706 patients were randomly assigned to receive epacadostat plus Pembrolizumab (n=354) or placebo plus Pembrolizumab (n=352). Median follow-up was 12·4 months (IQR 10·3–14·5). No significant differences were found between the treatment groups for progression-free survival (median 4·7 months, 95% CI 2·9–6·8, for epacadostat plus Pembrolizumab vs 4·9 months, 2·9–6·8, for placebo plus Pembrolizumab; hazard ratio [HR] 1·00, 95% CI 0·83–1·21; one-sided p=0·52) or overall survival (median not reached in either group; epacadostat plus Pembrolizumab vs placebo plus Pembrolizumab: HR 1·13, 0·86–1·49; one-sided p=0·81). The most common grade 3 or worse treatment-related adverse event was lipase increase, which occurred in 14 (4%) of 353 patients receiving epacadostat plus Pembrolizumab and 11 (3%) of 352 patients receiving placebo plus Pembrolizumab. Treatment-related serious adverse events were reported in 37 (10%) of 353 patients receiving epacadostat plus Pembrolizumab and 32 (9%) of 352 patients receiving placebo plus Pembrolizumab. There were no treatment-related deaths in either treatment group. Interpretation Epacadostat 100 mg twice daily plus Pembrolizumab did not improve progression-free survival or overall survival compared with placebo plus Pembrolizumab in patients with unresectable or metastatic melanoma. The usefulness of IDO1 inhibition as a strategy to enhance anti-PD-1 therapy activity in cancer remains uncertain. Funding Incyte Corporation, in collaboration with Merck Sharp & Dohme.
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durable complete response after discontinuation of Pembrolizumab in patients with metastatic melanoma
Journal of Clinical Oncology, 2017Co-Authors: Wenjen Hwu, Caroline Robert, Omid Hamid, Adil Daud, Antoni Ribas, Jedd D Wolchok, Anthony M Joshua, Jeffrey S Weber, Tara C GangadharAbstract:Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after Pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with Pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of Pembrolizumab. Eligible patients who received Pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued Pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of Pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
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final analysis of a randomised trial comparing Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory advanced melanoma
European Journal of Cancer, 2017Co-Authors: Omid Hamid, Caroline Robert, Reinhard Dummer, Jacob Schachter, Adil Daud, Igor Puzanov, Dirk Schadendorf, Christian U Blank, Lee D Cranmer, Anna C PavlickAbstract:Abstract Aim To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study ( NCT01704287 ) of Pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. Methods In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to Pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p Results A total of 180 patients were randomised to Pembrolizumab 2 mg/kg, 181 to Pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5), 368 patients died and 98 (55%) crossed over to Pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus 11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with Pembrolizumab versus chemotherapy, regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. Conclusion Improvement in OS with Pembrolizumab was not statistically significant at either dose versus chemotherapy.
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Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory melanoma keynote 002 a randomised controlled phase 2 trial
Lancet Oncology, 2015Co-Authors: Antoni Ribas, Stephen F Hodi, Caroline Robert, Reinhard Dummer, Omid Hamid, Jacob Schachter, Igor Puzanov, Dirk Schadendorf, Anna C Pavlick, Karl D LewisAbstract:Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 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 BRAF V600 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 BRAF V600 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 Interpretation These findings establish Pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
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Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory melanoma keynote 002 a randomised controlled phase 2 trial
Lancet Oncology, 2015Co-Authors: Antoni Ribas, Stephen F Hodi, Caroline Robert, Reinhard Dummer, Omid Hamid, Jacob Schachter, Igor Puzanov, Dirk Schadendorf, Anna C Pavlick, Karl D LewisAbstract:Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 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 BRAF V600 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 BRAF V600 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 Interpretation These findings establish Pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
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Pembrolizumab versus ipilimumab in advanced melanoma keynote 006 post hoc 5 year results from an open label multicentre randomised controlled phase 3 study
Lancet Oncology, 2019Co-Authors: Caroline Robert, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Jacob Schachter, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Pembrolizumab improved progression-free survival and overall survival versus ipilimumab in patients with advanced melanoma and is now a standard of care in the first-line setting. However, the optimal duration of anti-PD-1 administration is unknown. We present results from 5 years of follow-up of patients in KEYNOTE-006. Methods KEYNOTE-006 was an open-label, multicentre, randomised, controlled, phase 3 study done at 87 academic institutions, hospitals, and cancer centres in 16 countries. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0 or 1, ipilimumab-naive histologically confirmed advanced melanoma with known BRAFV600 status and up to one previous systemic therapy were randomly assigned (1:1:1) to intravenous Pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks or four doses of intravenous ipilimumab 3 mg/kg every 3 weeks. Treatments were assigned using a centralised, computer-generated allocation schedule with blocked randomisation within strata. Exploratory combination of data from the two Pembrolizumab dosing regimen groups was not protocol-specified. Pembrolizumab treatment continued for up to 24 months. Eligible patients who discontinued Pembrolizumab with stable disease or better after receiving at least 24 months of Pembrolizumab or discontinued with complete response after at least 6 months of Pembrolizumab and then progressed could receive an additional 17 cycles of Pembrolizumab. Co-primary endpoints were overall survival and progression-free survival. Efficacy was analysed in all randomly assigned patients, and safety was analysed in all randomly assigned patients who received at least one dose of study treatment. Exploratory assessment of efficacy and safety at 5 years' follow-up was not specified in the protocol. Data cutoff for this analysis was Dec 3, 2018. Recruitment is closed; the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients were enrolled and randomly assigned to receive Pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up of 57·7 months (IQR 56·7–59·2) in surviving patients, median overall survival was 32·7 months (95% CI 24·5–41·6) in the combined Pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median progression-free survival was 8·4 months (95% CI 6·6–11·3) in the combined Pembrolizumab groups versus 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p Interpretation Pembrolizumab continued to show superiority over ipilimumab after almost 5 years of follow-up. These results provide further support for use of Pembrolizumab in patients with advanced melanoma. Funding Merck Sharp & Dohme.
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durable complete response after discontinuation of Pembrolizumab in patients with metastatic melanoma
Journal of Clinical Oncology, 2017Co-Authors: Wenjen Hwu, Caroline Robert, Omid Hamid, Adil Daud, Antoni Ribas, Jedd D Wolchok, Anthony M Joshua, Jeffrey S Weber, Tara C GangadharAbstract:Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after Pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with Pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of Pembrolizumab. Eligible patients who received Pembrolizumab for ≥ 6 months and at least two treatments beyond confirmed CR could discontinue therapy. Response was assessed every 12 weeks by central Response Evaluation Criteria in Solid Tumors version 1.1. For this analysis, CR was defined per investigator assessment, immune-related response criteria, and potential predictors of CR were evaluated using univariate and multivariate analyses. Results Of 655 treated patients, 105 (16.0%) achieved CR after median follow-up of 43 months. At data cutoff, 92 patients (87.6%) had CR, with median follow-up of 30 months from first CR. Fourteen (13.3%) patients continued to receive treatment for a median of ≥ 40 months. Pembrolizumab was discontinued by 91 patients (86.7%), including 67 (63.8%) who proceeded to observation without additional anticancer therapy. The 24-month disease-free survival rate from time of CR was 90.9% in all 105 patients with CR and 89.9% in the 67 patients who discontinued Pembrolizumab after CR for observation. Tumor size and programmed death-ligand 1 status were among the baseline factors independently associated with CR by univariate analysis. Conclusion Patients with metastatic melanoma can have durable complete remission after discontinuation of Pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable CR require further investigation.
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final analysis of a randomised trial comparing Pembrolizumab versus investigator choice chemotherapy for ipilimumab refractory advanced melanoma
European Journal of Cancer, 2017Co-Authors: Omid Hamid, Caroline Robert, Reinhard Dummer, Jacob Schachter, Adil Daud, Igor Puzanov, Dirk Schadendorf, Christian U Blank, Lee D Cranmer, Anna C PavlickAbstract:Abstract Aim To evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study ( NCT01704287 ) of Pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma. Methods In this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to Pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p Results A total of 180 patients were randomised to Pembrolizumab 2 mg/kg, 181 to Pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5), 368 patients died and 98 (55%) crossed over to Pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus 11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with Pembrolizumab versus chemotherapy, regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively. Conclusion Improvement in OS with Pembrolizumab was not statistically significant at either dose versus chemotherapy.
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Pembrolizumab versus ipilimumab for advanced melanoma final overall survival results of a multicentre randomised open label phase 3 study keynote 006
The Lancet, 2017Co-Authors: Jacob Schachter, Georgina V Long, Ana Arance, Matteo S Carlino, Jeanjacques Grob, Laurent Mortier, Adil Daud, Antoni Ribas, Catriona M Mcneil, Michal LotemAbstract:Summary Background Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of Pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. Methods In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of Pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. Findings Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous Pembrolizumab every 2 weeks (n=279), intravenous Pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the Pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either Pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53–0·87 for Pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53–0·86 for Pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. Interpretation Substantiating the results of the interim analyses of KEYNOTE-006, Pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between Pembrolizumab dosing schedules. These conclusions further support the use of Pembrolizumab as a standard of care for advanced melanoma. Funding Merck & Co.
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Pembrolizumab cutaneous adverse events and their association with disease progression
JAMA Dermatology, 2015Co-Authors: Adil Daud, Martina Sanlorenzo, Igor Vujic, Alain Patrick Algazi, Matthew A Gubens, Sara Alcantara Luna, Kevin Lin, Pietro Quaglino, Klemens RappersbergerAbstract:Importance Immunomodulatory anticancer drugs, such as the anti–programmed death-1 drug Pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response. Objective To describe the frequency and spectrum of cutaneous AEs linked with Pembrolizumab and their possible correlation with treatment response. Design, Setting, and Participants A single-institution, retrospective medical record review was conducted of patients with cancer who were treated with Pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83 consecutive patients who were enrolled in 2 clinical trials, received at least 1 dose of Pembrolizumab, and had at least 1 follow-up visit. Patients were grouped according to the following therapeutic regimen for Pembrolizumab: 43 received 10 mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma. Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted from March 1 to September 30, 2014. Main Outcomes and Measures Occurrence, severity, and type of cutaneous AEs, as well as disease progression and response to Pembrolizumab treatment. Results Thirty-five patients (42%) developed cutaneous AEs attributed to Pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma. Survival analyses showed that patients who developed cutaneous AEs had significantly longer progression-free intervals in all 3 groups (Pembrolizumab, 10 mg/kg, every 3 weeks,P = .001; Pembrolizumab, 10 mg/kg, every 2 weeks,P = .003; Pembrolizumab, 2 mg/kg, every 3 weeks,P = .009) compared with patients who did not develop cutaneous AEs. Conclusions and Relevance Pembrolizumab therapy was associated with cutaneous AEs in 42% of patients. The development of cutaneous AEs, especially of hypopigmentation in patients with melanoma, could point toward better treatment response.
