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Elizabeth R Plimack - One of the best experts on this subject based on the ideXlab platform.
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Nivolumab versus everolimus in patients with advanced renal cell carcinoma updated results with long term follow up of the randomized open label phase 3 checkmate 025 trial
Cancer, 2020Co-Authors: Robert J Motzer, Bernard Escudier, Saby George, Hansjoerg Hammers, Sandhya Srinivas, Scott S Tykodi, Jeffrey A Sosman, Elizabeth R Plimack, Giuseppe Procopio, David F McdermottAbstract:BACKGROUND CheckMate 025 has shown superior efficacy for Nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of Nivolumab versus everolimus. METHODS The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to Nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). RESULTS Eight hundred twenty-one patients were randomized to Nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with Nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), Nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with Nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored Nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with Nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with Nivolumab but remained the same or deteriorated with everolimus. CONCLUSIONS The superior efficacy of Nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of Nivolumab monotherapy in patients with previously treated aRCC. LAY SUMMARY CheckMate 025 compared the effects of Nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, Nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of Nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.
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Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma
The New England Journal of Medicine, 2018Co-Authors: Robert J Motzer, Elizabeth R Plimack, David F Mcdermott, Nizar M Tannir, Osvaldo Aren Frontera, Bohuslav Melichar, Toni K Choueiri, Philippe Barthelemy, Camillo Porta, Saby GeorgeAbstract:Abstract Background Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared Nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. Methods We randomly assigned adults in a 1:1 ratio to receive either Nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by Nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. Results A total of 1096 patients were assigned to receive Nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follo...
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checkmate 025 randomized phase 3 study outcomes by key baseline factors and prior therapy for Nivolumab versus everolimus in advanced renal cell carcinoma
European Urology, 2017Co-Authors: Bernard Escudier, Saby George, Hansjoerg Hammers, Sandhya Srinivas, Scott S Tykodi, Jeffrey A Sosman, Giuseppe Procopio, David F Mcdermott, Padmanee Sharma, Elizabeth R PlimackAbstract:Abstract Background The randomized, phase 3 CheckMate 025 study of Nivolumab ( n =410) versus everolimus ( n =411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). Objective To investigate which baseline factors were associated with OS and ORR benefit with Nivolumab versus everolimus. Design, setting, and participants Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Intervention Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. Results and limitations The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between Nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age Conclusion The trend for OS and ORR benefit with Nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports Nivolumab as the standard of care in previously treated patients with aRCC. Patient summary We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with Nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of Nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.
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safety and efficacy of Nivolumab in combination with ipilimumab in metastatic renal cell carcinoma the checkmate 016 study
Journal of Clinical Oncology, 2017Co-Authors: Hans J Hammers, Elizabeth R Plimack, David F Mcdermott, Padmanee Sharma, Jeffrey R Infante, Brian I Rini, Lionel D Lewis, Martin H Voss, Sumanta K Pal, Albiruni R A RazakAbstract:Purpose Combination treatment with immune checkpoint inhibitors has shown enhanced antitumor activity compared with monotherapy in tumor types such as melanoma. The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of Nivolumab plus ipilimumab in combination, and Nivolumab plus a tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). Safety and efficacy results from the Nivolumab plus ipilimumab arms of the study are presented. Patients and Methods Patients with mRCC received intravenous Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or Nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by Nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. End points included safety (primary), objective response rate, and overall survival (OS). Results All patients in the N3I3 arm (n = 6) were censored at the time of analysis as a result of dose-limiting toxicity or other reasons. Forty-seven patients were treated in both the N3I1 and the N1I3 arm, and baseline patient characteristics were balanced between arms. Grade 3 to 4 treatment-related adverse events were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 arms, respectively. At a median follow-up of 22.3 months, the confirmed objective response rate was 40.4% in both arms, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively. Conclusion Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising OS in patients with mRCC.
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correlation of response with overall survival os for Nivolumab vs everolimus in advanced renal cell carcinoma arcc results from the phase iii checkmate 025 study
Journal of Clinical Oncology, 2016Co-Authors: Robert J Motzer, Bernard Escudier, Saby George, Scott S Tykodi, Jeffrey A Sosman, Elizabeth R Plimack, David F Mcdermott, Padmanee Sharma, Sandy Srinivas, Paul NathanAbstract:4552Background: In CheckMate 025 (NCT01668784), Nivolumab demonstrated superior OS (25.0 mo; 95% CI, 21.8–not estimable [NE]) vs everolimus (19.6 mo; 95% CI, 17.6–23.1) and a higher objective response rate (25% vs 5%, P< 0.001) in previously treated patients with aRCC (N Engl J Med 2015;373:1803–13). Here, we investigated OS benefit with Nivolumab vs everolimus by tumor response. Methods: Patients were randomized 1:1 to Nivolumab 3 mg/kg intravenously every 2 wk or everolimus 10 mg orally once daily. We conducted a landmark analysis of OS by best response (complete/partial response; responders), stable disease [SD], and progressive disease [PD]) within 4 mo of randomization. OS was assessed using the Kaplan–Meier method. Results: For the 410 and 411 patients randomized to Nivolumab and everolimus, median time to response was 3.5 mo (range: 1.4–24.8) and 3.7 mo (1.5–11.2), respectively. By mo 4 with Nivolumab, 19% of patients were responders, 30% had SD, and 40% had PD; with everolimus, 3% of patients were...
David F Mcdermott - One of the best experts on this subject based on the ideXlab platform.
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Nivolumab versus everolimus in patients with advanced renal cell carcinoma updated results with long term follow up of the randomized open label phase 3 checkmate 025 trial
Cancer, 2020Co-Authors: Robert J Motzer, Bernard Escudier, Saby George, Hansjoerg Hammers, Sandhya Srinivas, Scott S Tykodi, Jeffrey A Sosman, Elizabeth R Plimack, Giuseppe Procopio, David F McdermottAbstract:BACKGROUND CheckMate 025 has shown superior efficacy for Nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of Nivolumab versus everolimus. METHODS The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to Nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). RESULTS Eight hundred twenty-one patients were randomized to Nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with Nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), Nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with Nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored Nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with Nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with Nivolumab but remained the same or deteriorated with everolimus. CONCLUSIONS The superior efficacy of Nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of Nivolumab monotherapy in patients with previously treated aRCC. LAY SUMMARY CheckMate 025 compared the effects of Nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, Nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of Nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.
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Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma
The New England Journal of Medicine, 2018Co-Authors: Robert J Motzer, Elizabeth R Plimack, David F Mcdermott, Nizar M Tannir, Osvaldo Aren Frontera, Bohuslav Melichar, Toni K Choueiri, Philippe Barthelemy, Camillo Porta, Saby GeorgeAbstract:Abstract Background Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared Nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. Methods We randomly assigned adults in a 1:1 ratio to receive either Nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by Nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. Results A total of 1096 patients were assigned to receive Nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follo...
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checkmate 025 randomized phase 3 study outcomes by key baseline factors and prior therapy for Nivolumab versus everolimus in advanced renal cell carcinoma
European Urology, 2017Co-Authors: Bernard Escudier, Saby George, Hansjoerg Hammers, Sandhya Srinivas, Scott S Tykodi, Jeffrey A Sosman, Giuseppe Procopio, David F Mcdermott, Padmanee Sharma, Elizabeth R PlimackAbstract:Abstract Background The randomized, phase 3 CheckMate 025 study of Nivolumab ( n =410) versus everolimus ( n =411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). Objective To investigate which baseline factors were associated with OS and ORR benefit with Nivolumab versus everolimus. Design, setting, and participants Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Intervention Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. Results and limitations The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between Nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age Conclusion The trend for OS and ORR benefit with Nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports Nivolumab as the standard of care in previously treated patients with aRCC. Patient summary We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with Nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of Nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.
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safety and efficacy of Nivolumab in combination with ipilimumab in metastatic renal cell carcinoma the checkmate 016 study
Journal of Clinical Oncology, 2017Co-Authors: Hans J Hammers, Elizabeth R Plimack, David F Mcdermott, Padmanee Sharma, Jeffrey R Infante, Brian I Rini, Lionel D Lewis, Martin H Voss, Sumanta K Pal, Albiruni R A RazakAbstract:Purpose Combination treatment with immune checkpoint inhibitors has shown enhanced antitumor activity compared with monotherapy in tumor types such as melanoma. The open-label, parallel-cohort, dose-escalation, phase I CheckMate 016 study evaluated the efficacy and safety of Nivolumab plus ipilimumab in combination, and Nivolumab plus a tyrosine kinase inhibitor in metastatic renal cell carcinoma (mRCC). Safety and efficacy results from the Nivolumab plus ipilimumab arms of the study are presented. Patients and Methods Patients with mRCC received intravenous Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3), or Nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by Nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity. End points included safety (primary), objective response rate, and overall survival (OS). Results All patients in the N3I3 arm (n = 6) were censored at the time of analysis as a result of dose-limiting toxicity or other reasons. Forty-seven patients were treated in both the N3I1 and the N1I3 arm, and baseline patient characteristics were balanced between arms. Grade 3 to 4 treatment-related adverse events were reported in 38.3% and 61.7% of the patients in the N3I1 and N1I3 arms, respectively. At a median follow-up of 22.3 months, the confirmed objective response rate was 40.4% in both arms, with ongoing responses in 42.1% and 36.8% of patients in the N3I1 and N1I3 arms, respectively. The 2-year OS was 67.3% and 69.6% in the N3I1 and N1I3 arms, respectively. Conclusion Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising OS in patients with mRCC.
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correlation of response with overall survival os for Nivolumab vs everolimus in advanced renal cell carcinoma arcc results from the phase iii checkmate 025 study
Journal of Clinical Oncology, 2016Co-Authors: Robert J Motzer, Bernard Escudier, Saby George, Scott S Tykodi, Jeffrey A Sosman, Elizabeth R Plimack, David F Mcdermott, Padmanee Sharma, Sandy Srinivas, Paul NathanAbstract:4552Background: In CheckMate 025 (NCT01668784), Nivolumab demonstrated superior OS (25.0 mo; 95% CI, 21.8–not estimable [NE]) vs everolimus (19.6 mo; 95% CI, 17.6–23.1) and a higher objective response rate (25% vs 5%, P< 0.001) in previously treated patients with aRCC (N Engl J Med 2015;373:1803–13). Here, we investigated OS benefit with Nivolumab vs everolimus by tumor response. Methods: Patients were randomized 1:1 to Nivolumab 3 mg/kg intravenously every 2 wk or everolimus 10 mg orally once daily. We conducted a landmark analysis of OS by best response (complete/partial response; responders), stable disease [SD], and progressive disease [PD]) within 4 mo of randomization. OS was assessed using the Kaplan–Meier method. Results: For the 410 and 411 patients randomized to Nivolumab and everolimus, median time to response was 3.5 mo (range: 1.4–24.8) and 3.7 mo (1.5–11.2), respectively. By mo 4 with Nivolumab, 19% of patients were responders, 30% had SD, and 40% had PD; with everolimus, 3% of patients were...
Sandra P Dangelo - One of the best experts on this subject based on the ideXlab platform.
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Nivolumab with or without ipilimumab treatment for metastatic sarcoma alliance a091401 two open label non comparative randomised phase 2 trials
Lancet Oncology, 2018Co-Authors: Sandra P Dangelo, Michelle R Mahoney, Brian A Van Tine, James N Atkins, Mohammed M Milhem, Balkrishna N Jahagirdar, Cristina R Antonescu, Elise HorvathAbstract:Summary Background Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of Nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma. Methods We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0–1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous Nivolumab 3 mg/kg every 2 weeks, or Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received Nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797. Findings Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either Nivolumab monotherapy (43 patients) or Nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1–16] of 38 patients) in the Nivolumab group and six (16% [7–30] of 38 patients) in the Nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the Nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the Nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths. Interpretation Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of Nivolumab plus ipilimumab in a randomised study is warranted. Funding Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.
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overall survival in patients with advanced melanoma who received Nivolumab versus investigator s choice chemotherapy in checkmate 037 a randomized controlled open label phase iii trial
Journal of Clinical Oncology, 2017Co-Authors: James Larkin, Ralf Gutzmer, Michael Smylie, David R Minor, Sandra P Dangelo, Bart Neyns, Wilson H Miller, Gerald P Linette, Bartosz Chmielowski, Christopher D LaoAbstract:Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that Nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to Nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m2 every 3 weeks or carboplatin area under the curve 6 plus paclitaxel 175 mg/m2 every 3 weeks). Patients were treated until they experienced progression or unacceptable toxicity, with follow-up of approximately 2 years. Results Two hundred seventy-two patients were randomly assigned to Nivolumab (99% treated) and 133 to ICC (77% treated). More Nivolumab-treated patients had brain metastases (20% v 14%) and increased lactate dehydrogenase levels (52% v 38%) at baseline; 41% of patients treated with ICC versus 11% of patients treated with Nivolumab received anti-programmed death 1 agents after randomly assigned therapy. Median OS was 16 months for Nivolumab versus 14 months for ICC (hazard ratio, 0.95; 95.54% CI, 0.73 to 1.24); median progression-free survival was 3.1 months versus 3.7 months, respectively (hazard ratio, 1.0; 95.1% CI, 0.78 to 1.436). Overall response rate (27% v 10%) and median duration of response (32 months v 13 months) were notably higher for Nivolumab versus ICC. Fewer grade 3 and 4 treatment-related adverse events were observed in patients on Nivolumab (14% v 34%). Conclusion Nivolumab demonstrated higher, more durable responses but no difference in survival compared with ICC. OS should be interpreted with caution as it was likely impacted by an increased dropout rate before treatment, which led to crossover therapy in the ICC group, and by an increased proportion of patients in the Nivolumab group with poor prognostic factors.
Saby George - One of the best experts on this subject based on the ideXlab platform.
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Nivolumab versus everolimus in patients with advanced renal cell carcinoma updated results with long term follow up of the randomized open label phase 3 checkmate 025 trial
Cancer, 2020Co-Authors: Robert J Motzer, Bernard Escudier, Saby George, Hansjoerg Hammers, Sandhya Srinivas, Scott S Tykodi, Jeffrey A Sosman, Elizabeth R Plimack, Giuseppe Procopio, David F McdermottAbstract:BACKGROUND CheckMate 025 has shown superior efficacy for Nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of Nivolumab versus everolimus. METHODS The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to Nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). RESULTS Eight hundred twenty-one patients were randomized to Nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with Nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), Nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with Nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P < .001). PFS also favored Nivolumab (HR, 0.84; 95% CI, 0.72-0.99; P = .0331). The most common treatment-related adverse events of any grade were fatigue (34.7%) and pruritus (15.5%) with Nivolumab and fatigue (34.5%) and stomatitis (29.5%) with everolimus. HRQOL improved from baseline with Nivolumab but remained the same or deteriorated with everolimus. CONCLUSIONS The superior efficacy of Nivolumab over everolimus is maintained after extended follow-up with no new safety signals, and this supports the long-term benefits of Nivolumab monotherapy in patients with previously treated aRCC. LAY SUMMARY CheckMate 025 compared the effects of Nivolumab (a novel immunotherapy) with those of everolimus (an older standard-of-care therapy) for the treatment of advanced kidney cancer in patients who had progressed on antiangiogenic therapy. After 5 years of study, Nivolumab continues to be better than everolimus in extending the lives of patients, providing a long-lasting response to treatment, and improving quality of life with a manageable safety profile. The results demonstrate that the clinical benefits of Nivolumab versus everolimus in previously treated patients with advanced kidney cancer continue in the long term.
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Nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma
The New England Journal of Medicine, 2018Co-Authors: Robert J Motzer, Elizabeth R Plimack, David F Mcdermott, Nizar M Tannir, Osvaldo Aren Frontera, Bohuslav Melichar, Toni K Choueiri, Philippe Barthelemy, Camillo Porta, Saby GeorgeAbstract:Abstract Background Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared Nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. Methods We randomly assigned adults in a 1:1 ratio to receive either Nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by Nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. Results A total of 1096 patients were assigned to receive Nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follo...
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checkmate 025 randomized phase 3 study outcomes by key baseline factors and prior therapy for Nivolumab versus everolimus in advanced renal cell carcinoma
European Urology, 2017Co-Authors: Bernard Escudier, Saby George, Hansjoerg Hammers, Sandhya Srinivas, Scott S Tykodi, Jeffrey A Sosman, Giuseppe Procopio, David F Mcdermott, Padmanee Sharma, Elizabeth R PlimackAbstract:Abstract Background The randomized, phase 3 CheckMate 025 study of Nivolumab ( n =410) versus everolimus ( n =411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). Objective To investigate which baseline factors were associated with OS and ORR benefit with Nivolumab versus everolimus. Design, setting, and participants Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Intervention Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. Results and limitations The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between Nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age Conclusion The trend for OS and ORR benefit with Nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports Nivolumab as the standard of care in previously treated patients with aRCC. Patient summary We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with Nivolumab versus everolimus in advanced renal cell carcinoma (aRCC). Survival benefit and response were observed for multiple subgroups, supporting the use of Nivolumab as a new standard of care across a broad range of patients with previously treated aRCC. The trial is registered on ClinicalTrials.gov as NCT01668784.
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correlation of response with overall survival os for Nivolumab vs everolimus in advanced renal cell carcinoma arcc results from the phase iii checkmate 025 study
Journal of Clinical Oncology, 2016Co-Authors: Robert J Motzer, Bernard Escudier, Saby George, Scott S Tykodi, Jeffrey A Sosman, Elizabeth R Plimack, David F Mcdermott, Padmanee Sharma, Sandy Srinivas, Paul NathanAbstract:4552Background: In CheckMate 025 (NCT01668784), Nivolumab demonstrated superior OS (25.0 mo; 95% CI, 21.8–not estimable [NE]) vs everolimus (19.6 mo; 95% CI, 17.6–23.1) and a higher objective response rate (25% vs 5%, P< 0.001) in previously treated patients with aRCC (N Engl J Med 2015;373:1803–13). Here, we investigated OS benefit with Nivolumab vs everolimus by tumor response. Methods: Patients were randomized 1:1 to Nivolumab 3 mg/kg intravenously every 2 wk or everolimus 10 mg orally once daily. We conducted a landmark analysis of OS by best response (complete/partial response; responders), stable disease [SD], and progressive disease [PD]) within 4 mo of randomization. OS was assessed using the Kaplan–Meier method. Results: For the 410 and 411 patients randomized to Nivolumab and everolimus, median time to response was 3.5 mo (range: 1.4–24.8) and 3.7 mo (1.5–11.2), respectively. By mo 4 with Nivolumab, 19% of patients were responders, 30% had SD, and 40% had PD; with everolimus, 3% of patients were...
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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, 2018Co-Authors: F S Hodi, Piotr Rutkowski, Vanna Chiarionsileni, Rene Gonzalez, Jean Jacques Grob, Dirk Schadendorf, Reinhard Dummer, Charles Lance Cowey, J Wagstaff, Pier Francesco FerrucciAbstract: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.
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combined Nivolumab and ipilimumab or monotherapy in untreated melanoma
The New England Journal of Medicine, 2015Co-Authors: James Larkin, Piotr Rutkowski, Vanna Chiarionsileni, Rene Gonzalez, Jean Jacques Grob, Lance C Cowey, Dirk Schadendorf, Reinhard Dummer, Michael Smylie, Pier Francesco FerrucciAbstract: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.)