Ipilimumab

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Omid Hamid - One of the best experts on this subject based on the ideXlab platform.

  • randomized open label phase ii study evaluating the efficacy and safety of talimogene laherparepvec in combination with Ipilimumab versus Ipilimumab alone in patients with advanced unresectable melanoma
    Journal of Clinical Oncology, 2017
    Co-Authors: Jason Chesney, Omid Hamid, Igor Puzanov, Frances A Collichio, Parminder Singh, Mohammed M Milhem, John A Glaspy, Merrick I Ross, Philip Friedlander, Claus Garbe
    Abstract:

    Purpose We evaluated the combination of talimogene laherparepvec plus Ipilimumab versus Ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus Ipilimumab or Ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the Ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus Ipilimumab (n = 98), or Ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the Ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the Ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; Ipilimumab alone, 42%), chills (combination, 53%; Ipilimumab alone, 3%), and diarrhea (combination, 42%; Ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus Ipilimumab versus Ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus Ipilimumab.

  • Ipilimumab 10 mg kg versus Ipilimumab 3 mg kg in patients with unresectable or metastatic melanoma a randomised double blind multicentre phase 3 trial
    Lancet Oncology, 2017
    Co-Authors: Paolo A Ascierto, Caroline Robert, Celeste Lebbe, Omid Hamid, Vanna Chiarionsileni, Michele Del Vecchio, Andrzej Mackiewicz, Ana Arance, Lars Bastholt, Piotr Rutkowski
    Abstract:

    Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with Ipilimumab 10 mg/kg compared with Ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of Ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to Ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to Ipilimumab 10 mg/kg (365 patients; 364 treated) or Ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the Ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the Ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for Ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for Ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two ( Interpretation In patients with advanced melanoma, Ipilimumab 10 mg/kg resulted in significantly longer overall survival than did Ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of Ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.

  • adjuvant Ipilimumab versus placebo after complete resection of high risk stage iii melanoma eortc 18071 a randomised double blind phase 3 trial
    Lancet Oncology, 2015
    Co-Authors: Alexander M M Eggermont, Caroline Robert, Omid Hamid, Jedd D Wolchok, Paolo A Ascierto, Vanna Chiarionsileni, Jean Jacques Grob, Reinhard Dummer, Henrik Schmidt, Jon M Richards
    Abstract:

    Summary Background Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess Ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. Methods We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg Ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Findings Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to Ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28–3·22), there were 528 recurrence-free survival events (234 in the Ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3–39·3) in the Ipilimumab group versus 17·1 months (95% CI 13·4–21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64–0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5–51·3) in the Ipilimumab group versus 34·8% (30·1–39·5) in the placebo group. The most common grade 3–4 immune-related adverse events in the Ipilimumab group were gastrointestinal (75 [16%] vs four [ vs one [ vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started Ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the Ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barre syndrome. Interpretation Adjuvant Ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk–benefit ratio of adjuvant Ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Funding Bristol-Myers Squibb.

  • Ipilimumab alone or in combination with radiotherapy in metastatic castration resistant prostate cancer results from an open label multicenter phase i ii study
    Annals of Oncology, 2013
    Co-Authors: Susan F Slovin, Omid Hamid, Kevin M Chin, Celestia S Higano, Sheela Tejwani, Andrea L Harzstark, Joshi J Alumkal, Howard I Scher, Paul Gagnier, M B Mchenry
    Abstract:

    BACKGROUND: This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored Ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. PATIENTS AND METHODS: In dose escalation, 33 patients (≥6/cohort) received Ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (Ipilimumab monotherapy, 16; Ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. RESULTS: Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). CONCLUSIONS: In mCRPC patients, Ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating Ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882.

  • randomized phase i pharmacokinetic study of Ipilimumab with or without one of two different chemotherapy regimens in patients with untreated advanced melanoma
    Cancer Immunity Archive, 2013
    Co-Authors: Jeffrey S. Weber, Steven J Oday, Susan M Parker, Scott D Chasalow, Omid Hamid, Asim Amin, Eric Masson, Stacie M Goldberg, Daphne Williams, Suresh Alaparthy
    Abstract:

    We describe a randomized three-arm phase I study of Ipilimumab administered alone (I group) or in combination with dacarbazine (D group) or carboplatin/paclitaxel (CP group) in patients with previously untreated advanced melanoma. The primary objective was to estimate the effect of Ipilimumab on the pharmacokinetics (PK) of dacarbazine and paclitaxel and, conversely, to estimate the effects of dacarbazine and carboplatin/paclitaxel on the PK of Ipilimumab. Secondary objectives included evaluation of the safety and anti-tumor activity of Ipilimumab when administered alone or with either dacarbazine or carboplatin/paclitaxel, and assessment of pharmacodynamic (PD) effects of Ipilimumab on the immune system when administered alone or with either of the two chemotherapies. Ipilimumab was administered at a dose of 10 mg/kg intravenously (IV) every 3 weeks for up to 4 doses. Patients in the D group received dacarbazine 850 mg/m 2 IV every

Caroline Robert - One of the best experts on this subject based on the ideXlab platform.

  • patient reported outcomes in keynote 006 a randomised study of pembrolizumab versus Ipilimumab in patients with advanced melanoma
    European Journal of Cancer, 2017
    Co-Authors: Teresa M Petrella, Caroline Robert, Celeste Lebbe, Erika Richtig, Wilson H Miller, Giuseppe Masucci, Euan Walpole, Neil Steven, Mark R Middleton, Darcy A Hille
    Abstract:

    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.

  • Ipilimumab 10 mg kg versus Ipilimumab 3 mg kg in patients with unresectable or metastatic melanoma a randomised double blind multicentre phase 3 trial
    Lancet Oncology, 2017
    Co-Authors: Paolo A Ascierto, Caroline Robert, Celeste Lebbe, Omid Hamid, Vanna Chiarionsileni, Michele Del Vecchio, Andrzej Mackiewicz, Ana Arance, Lars Bastholt, Piotr Rutkowski
    Abstract:

    Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with Ipilimumab 10 mg/kg compared with Ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of Ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to Ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to Ipilimumab 10 mg/kg (365 patients; 364 treated) or Ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the Ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the Ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for Ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for Ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two ( Interpretation In patients with advanced melanoma, Ipilimumab 10 mg/kg resulted in significantly longer overall survival than did Ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of Ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.

  • combined nivolumab and Ipilimumab versus Ipilimumab alone in patients with advanced melanoma 2 year overall survival outcomes in a multicentre randomised controlled phase 2 trial
    Lancet Oncology, 2016
    Co-Authors: Stephen F Hodi, Caroline Robert, David F. Mcdermott, Jason Chesney, Anna C Pavlick, Kenneth F Grossmann, Gerald P Linette, Nicolas Meyer, Jeffrey K Giguere, Sanjiv S Agarwala
    Abstract:

    Summary Background Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus Ipilimumab (an anti-CTLA-4 antibody) compared with Ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. Methods In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus Ipilimumab 3 mg/kg or Ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus Ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to Ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF V600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. Findings Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus Ipilimumab and 47 to Ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus Ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to Ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus Ipilimumab compared with nine (20%) of 46 patients who received Ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the Ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus Ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received Ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Interpretation Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus Ipilimumab might lead to improved outcomes compared with first-line Ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Funding Bristol-Myers Squibb.

  • adjuvant Ipilimumab versus placebo after complete resection of high risk stage iii melanoma eortc 18071 a randomised double blind phase 3 trial
    Lancet Oncology, 2015
    Co-Authors: Alexander M M Eggermont, Caroline Robert, Omid Hamid, Jedd D Wolchok, Paolo A Ascierto, Vanna Chiarionsileni, Jean Jacques Grob, Reinhard Dummer, Henrik Schmidt, Jon M Richards
    Abstract:

    Summary Background Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess Ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. Methods We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg Ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Findings Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to Ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28–3·22), there were 528 recurrence-free survival events (234 in the Ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3–39·3) in the Ipilimumab group versus 17·1 months (95% CI 13·4–21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64–0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5–51·3) in the Ipilimumab group versus 34·8% (30·1–39·5) in the placebo group. The most common grade 3–4 immune-related adverse events in the Ipilimumab group were gastrointestinal (75 [16%] vs four [ vs one [ vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started Ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the Ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barre syndrome. Interpretation Adjuvant Ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk–benefit ratio of adjuvant Ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Funding Bristol-Myers Squibb.

  • five year survival rates for treatment naive patients with advanced melanoma who received Ipilimumab plus dacarbazine in a phase iii trial
    Journal of Clinical Oncology, 2015
    Co-Authors: Michele Maio, Caroline Robert, Alessandro Testori, Vanna Chiarionsileni, Jean Jacques Grob, Luc Thomas, Igor Bondarenko, Claus Garbe, Steinar Aamdal, Taitsang Chen
    Abstract:

    Purpose There is evidence from nonrandomized studies that a proportion of Ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with Ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. Patients and Methods A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received Ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive Ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance Ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive Ipilimumab as maintenance therapy. Results The 5-year survival rate was 18.2% ...

David Berman - One of the best experts on this subject based on the ideXlab platform.

  • development of Ipilimumab a novel immunotherapeutic approach for the treatment of advanced melanoma
    Annals of the New York Academy of Sciences, 2013
    Co-Authors: Jedd D Wolchok, Steven J Oday, Jeffrey S. Weber, Caroline Robert, Stephen F Hodi, Axel Hoos, Rachel Humphrey, James P Allison, Walter J Urba, David Berman
    Abstract:

    The immunotherapeutic agent Ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, Ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of Ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received Ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with Ipilimumab therapy are inflammatory in nature. These immune-related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long-term follow-up of patients who received Ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of Ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

  • an immune active tumor microenvironment favors clinical response to Ipilimumab
    Cancer Immunology Immunotherapy, 2012
    Co-Authors: Scott D Chasalow, David Berman, Omid Hamid, Suresh Alaparthy, Lisu Wang, Henrik Schmidt, John Cogswell, Maria Jurekunkel, Nathan O Siemers, Jeffrey R Jackson
    Abstract:

    Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, Ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of Ipilimumab treatment, gene expression profiles of tumors from patients treated with Ipilimumab were characterized. Gene expression profiling was performed on tumor biopsies collected from 45 melanoma patients before and 3 weeks after the start of treatment in a phase II clinical trial. Analysis of pre-treatment tumors indicated that patients with high baseline expression levels of immune-related genes were more likely to respond favorably to Ipilimumab. Furthermore, Ipilimumab appeared to induce two major changes in tumors from patients who exhibited clinical activity: genes involved in immune response showed increased expression, whereas expression of genes for melanoma-specific antigens and genes involved in cell proliferation decreased. These changes were associated with the total lymphocyte infiltrate in tumors, and there was a suggestion of association with prolonged overall survival in these patients. Many IFN-γ-inducible genes and Th1-associated markers showed increased expression after Ipilimumab treatment, suggesting an accumulation of this particular type of T cell at the tumor sites, which might play an important role in mediating the antitumor activity of Ipilimumab. These results support the proposed mechanism of action of Ipilimumab, suggesting that cell-mediated immune responses play an important role in the antitumor activity of Ipilimumab.

  • an immune active tumor microenvironment favors clinical response to Ipilimumab
    Cancer Immunology Immunotherapy, 2012
    Co-Authors: Ruiru Ji, David Berman, Scott D Chasalow, Omid Hamid, Suresh Alaparthy, Lisu Wang, Henrik Schmidt, John Cogswell, Maria Jurekunkel, Nathan O Siemers
    Abstract:

    Purpose Ipilimumab, a fully human monoclonal antibody specific to CTLA-4, has been shown to improve overall survival in metastatic melanoma patients. As a consequence of CTLA-4 blockade, Ipilimumab treatment is associated with proliferation and activation of peripheral T cells. To better understand various tumor-associated components that may influence the clinical outcome of Ipilimumab treatment, gene expression profiles of tumors from patients treated with Ipilimumab were characterized.

  • development of Ipilimumab contribution to a new paradigm for cancer immunotherapy
    Seminars in Oncology, 2010
    Co-Authors: Axel Hoos, David Berman, Ramy Ibrahim, Alan J Korman, Kald Abdallah, Vafa Shahabi, Kevin M Chin, Renzo Canetta, Rachel Humphrey
    Abstract:

    Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody Ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined Ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of Ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, Ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with Ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with Ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of Ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium.

  • blockade of cytotoxic t lymphocyte antigen 4 by Ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma
    Cancer Immunity Archive, 2010
    Co-Authors: David Berman, Jeffrey S. Weber, Susan M Parker, Jonathan Siegel, Scott D Chasalow, Susan Galbraith, Stephan R Targan, Hanlin L Wang
    Abstract:

    Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by Ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of Ipilimumab-induced gastrointestinal irAEs. Treatment-naive or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label Ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of Ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent Ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and Ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests Ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.

Jeffrey S. Weber - One of the best experts on this subject based on the ideXlab platform.

  • sequential administration of nivolumab and Ipilimumab with a planned switch in patients with advanced melanoma checkmate 064 an open label randomised phase 2 trial
    Lancet Oncology, 2016
    Co-Authors: Jeffrey S. Weber, Jeffrey A Sosman, Donald P Lawrence, Ryan J Sullivan, Geoff Gibney, Craig L Slingluff, Theodore F Logan, Lynn M Schuchter, Suresh G Nair, Leslie A Fecher
    Abstract:

    Summary Background Concurrent administration of the immune checkpoint inhibitors nivolumab and Ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by Ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous Ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by Ipilimumab (n=70) or to the reverse sequence of Ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by Ipilimumab group (34 [50%; 95% CI 37·6–62·4] of 68 patients) and in the Ipilimumab followed by nivolumab group (30 [43%; 31·1–55·3] of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by Ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by Ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4–53·8] vs 14 [20%; 11·4–31·3]). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by Ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8–25·7), median overall survival was not reached in the nivolumab followed by Ipilimumab group (95% CI 23·7–not reached), whereas over a median follow-up of 14·7 months (IQR 5·6–23·9) in the Ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2–26·5; HR 0·48 [95% CI 0·29–0·80]). A higher proportion of patients in the nivolumab followed by Ipilimumab group achieved 12-month overall survival than in the Ipilimumab followed by nivolumab group (76%; 95% CI 64–85 vs 54%; 42–65). Interpretation Nivolumab followed by Ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. Funding Bristol-Myers Squibb.

  • phase i ii study of metastatic melanoma patients treated with nivolumab who had progressed after Ipilimumab
    Cancer immunology research, 2016
    Co-Authors: Jeffrey S. Weber, Ragini R Kudchadkar, Geoffrey T Gibney, Alberto J Martinez, Pingyan Cheng, Jodie Kroeger, Allison Richards, Lori Mccormick, Valerie Moberg, Heather Cronin
    Abstract:

    The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed Ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 Ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to Ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for Ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naive and Ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to Ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in Ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from Ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.

  • development of Ipilimumab a novel immunotherapeutic approach for the treatment of advanced melanoma
    Annals of the New York Academy of Sciences, 2013
    Co-Authors: Jedd D Wolchok, Steven J Oday, Jeffrey S. Weber, Caroline Robert, Stephen F Hodi, Axel Hoos, Rachel Humphrey, James P Allison, Walter J Urba, David Berman
    Abstract:

    The immunotherapeutic agent Ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, Ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of Ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received Ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with Ipilimumab therapy are inflammatory in nature. These immune-related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long-term follow-up of patients who received Ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of Ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.

  • phase i ii trial of pd 1 antibody nivolumab with peptide vaccine in patients naive to or that failed Ipilimumab
    Journal of Clinical Oncology, 2013
    Co-Authors: Jeffrey S. Weber, Ragini R Kudchadkar, Geoffrey T Gibney, Ronald C De Conti, Wenshi Wang, Amod A Sarnaik, Alberto J Martinez, Jodi Kroeger, Cabell Eysmans, Donna Gallenstein
    Abstract:

    9011 Background: Nivolumab, an IgG4 fully human monoclonal antibody against checkpoint protein PD-1, is active in metastatic melanoma, renal cell and non-small cell lung cancer. It was administered with a multi-peptide vaccine to patients (pts) with unresectable melanoma who failed at least one regimen for metastatic disease and were Ipilimumab naive, or failed Ipilimumab, to assess the toxicity and tolerability of the combination and perform correlative immune assays. Methods: Three cohorts of 10 HLA A0201 positive Ipilimumab-naive pts received nivolumab at 1, 3 or 10 mg/kg, then three additional cohorts of pts who had failed prior Ipilimumab received nivolumab at 3 mg/kg: two cohorts of 10 pts each who were A0201 positive and had either grade 2 or less Ipilimumab toxicity, or grade 3 dose limiting Ipilimumab toxicity; finally 40 pts were treated with antibody who had grade 2 or less Ipilimumab toxicity and were not HLA restricted. Pre-treatment archived tumor tissue as well as pre- and post-treatment pe...

  • patterns of onset and resolution of immune related adverse events of special interest with Ipilimumab detailed safety analysis from a phase 3 trial in patients with advanced melanoma
    Cancer, 2013
    Co-Authors: Jeffrey S. Weber, Reinhard Dummer, Veerle De Pril, Stephen F Hodi
    Abstract:

    BACKGROUND: Ipilimumab 3 mg/kg was the first agent to demonstrate improved survival in previously treated patients with metastatic melanoma in a phase 3 trial (MDX010-20). Ipilimumab produced a characteristic spectrum of immune-related adverse events (irAEs) of special interest, consistent with its immune-based mechanism of action. METHODS: In MDX010-20, 676 previously treated patients were randomized 3:1:1 to receive Ipilimumab 3 mg/kg plus the glycoprotein 100 melanoma antigen vaccine (gp100), Ipilimumab 3 mg/kg + placebo, or gp100 vaccine + placebo. For the current report, the authors conducted a detailed analysis of the time to onset and resolution of irAEs associated with Ipilimumab therapy. RESULTS: Grade 2 through 5 irAEs generally developed during the induction phase of treatment (0-12 weeks). Most, including grade 3/4 irAEs, were reversible when managed with treatment guidelines using vigilant monitoring and corticosteroids. The median time to resolution (to grade 1 or 0 or to the grade at baseline) of irAEs that had an onset during the induction phase was approximately 6 weeks for grade 2 through 4 irAEs and 8 weeks for grade 3 and 4 irAEs. Across the entire study duration, most grade 2 through 4 irAEs resolved within 12 weeks. CONCLUSIONS: Most Ipilimumab-associated irAEs, including grade 3/4 symptoms, developed within 12 weeks of initial dosing and resolved within 12 weeks of onset. IrAEs were well characterized in their evolution and could be managed using published algorithms. Cancer 2013. © 2013 American Cancer Society.

Vanna Chiarionsileni - One of the best experts on this subject based on the ideXlab platform.

  • nivolumab plus Ipilimumab or nivolumab alone versus Ipilimumab alone in advanced melanoma checkmate 067 4 year outcomes of a multicentre randomised phase 3 trial
    Lancet Oncology, 2018
    Co-Authors: F S Hodi, Vanna Chiarionsileni, Rene Gonzalez, Jean Jacques Grob, Dirk Schadendorf, Reinhard Dummer, Charles Lance Cowey, J Wagstaff, Pier Francesco Ferrucci
    Abstract:

    Summary Background Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus Ipilimumab or nivolumab alone compared with Ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study. Methods In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFV600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus Ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or Ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505. Findings Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus Ipilimumab (n=314), nivolumab (n=316), or Ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9–51·8) in the nivolumab plus Ipilimumab group, 36·0 months (10·5–51·4) in the nivolumab group, and 18·6 months (7·6–49·5) in the Ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2–not reached) in the nivolumab plus Ipilimumab group, 36·9 months (28·3–not reached) in the nivolumab group, and 19·9 months (16·9–24·6) in the Ipilimumab group. The hazard ratio for death for the combination versus Ipilimumab was 0·54 (95% CI 0·44–0·67; p Interpretation The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus Ipilimumab or nivolumab alone in patients with advanced melanoma. Funding Bristol-Myers Squibb.

  • Ipilimumab 10 mg kg versus Ipilimumab 3 mg kg in patients with unresectable or metastatic melanoma a randomised double blind multicentre phase 3 trial
    Lancet Oncology, 2017
    Co-Authors: Paolo A Ascierto, Caroline Robert, Celeste Lebbe, Omid Hamid, Vanna Chiarionsileni, Michele Del Vecchio, Andrzej Mackiewicz, Ana Arance, Lars Bastholt, Piotr Rutkowski
    Abstract:

    Summary Background A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3–4 adverse events with Ipilimumab 10 mg/kg compared with Ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit–risk profile of Ipilimumab 10 mg/kg versus 3 mg/kg. Methods This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to Ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189. Findings Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to Ipilimumab 10 mg/kg (365 patients; 364 treated) or Ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6–42·3) for the Ipilimumab 10 mg/kg group and 11·2 months (4·9–29·4) for the Ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6–17·8) for Ipilimumab 10 mg/kg compared with 11·5 months (9·9–13·3) for Ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70–0·99; p=0·04). The most common grade 3–4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two ( Interpretation In patients with advanced melanoma, Ipilimumab 10 mg/kg resulted in significantly longer overall survival than did Ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of Ipilimumab in refractory patients with unmet medical needs could warrant further assessment. Funding Bristol-Myers Squibb.

  • combined nivolumab and Ipilimumab or monotherapy in untreated melanoma
    The New England Journal of Medicine, 2015
    Co-Authors: James Larkin, Vanna Chiarionsileni, Rene Gonzalez, Jean Jacques Grob, Lance C Cowey, Dirk Schadendorf, Reinhard Dummer, Michael Smylie, Pier Francesco Ferrucci
    Abstract:

    The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus Ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with Ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with Ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-Ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-Ipilimumab group, and 27.3% of those in the Ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with Ipilimumab resulted in significantly longer progression-free survival than Ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)

  • adjuvant Ipilimumab versus placebo after complete resection of high risk stage iii melanoma eortc 18071 a randomised double blind phase 3 trial
    Lancet Oncology, 2015
    Co-Authors: Alexander M M Eggermont, Caroline Robert, Omid Hamid, Jedd D Wolchok, Paolo A Ascierto, Vanna Chiarionsileni, Jean Jacques Grob, Reinhard Dummer, Henrik Schmidt, Jon M Richards
    Abstract:

    Summary Background Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess Ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. Methods We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg Ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. Findings Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to Ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28–3·22), there were 528 recurrence-free survival events (234 in the Ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3–39·3) in the Ipilimumab group versus 17·1 months (95% CI 13·4–21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64–0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5–51·3) in the Ipilimumab group versus 34·8% (30·1–39·5) in the placebo group. The most common grade 3–4 immune-related adverse events in the Ipilimumab group were gastrointestinal (75 [16%] vs four [ vs one [ vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started Ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the Ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barre syndrome. Interpretation Adjuvant Ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk–benefit ratio of adjuvant Ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Funding Bristol-Myers Squibb.

  • five year survival rates for treatment naive patients with advanced melanoma who received Ipilimumab plus dacarbazine in a phase iii trial
    Journal of Clinical Oncology, 2015
    Co-Authors: Michele Maio, Caroline Robert, Alessandro Testori, Vanna Chiarionsileni, Jean Jacques Grob, Luc Thomas, Igor Bondarenko, Claus Garbe, Steinar Aamdal, Taitsang Chen
    Abstract:

    Purpose There is evidence from nonrandomized studies that a proportion of Ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with Ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. Patients and Methods A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received Ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive Ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance Ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive Ipilimumab as maintenance therapy. Results The 5-year survival rate was 18.2% ...