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Improved survival with ipilimumab in patients with metastatic melanoma.

ABSTRACT: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

SUBMITTER: Hodi FS

PROVIDER: S-EPMC3549297 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Improved survival with ipilimumab in patients with metastatic melanoma.

Hodi F Stephen FS O'Day Steven J SJ McDermott David F DF Weber Robert W RW Sosman Jeffrey A JA Haanen John B JB Gonzalez Rene R Robert Caroline C Schadendorf Dirk D Hassel Jessica C JC Akerley Wallace W van den Eertwegh Alfons J M AJ Lutzky Jose J Lorigan Paul P Vaubel Julia M JM Linette Gerald P GP Hogg David D Ottensmeier Christian H CH Lebbé Celeste C Peschel Christian C Quirt Ian I Clark Joseph I JI Wolchok Jedd D JD Weber Jeffrey S JS Tian Jason J Yellin Michael J MJ Nichol Geoffrey M GM Hoos Axel A Urba Walter J WJ

The New England journal of medicine 20100605 8

<h4>Background</h4>An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.<h4>Methods</h4>A total of 676 HLA-A*0201-positive patients with unresectable stage II ...[more]

PMID: 20525992

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Project description:IntroductionImmunotherapy has revolutionized metastatic Melanoma therapy. The most active regimen is combination therapy of Ipilimumab-Nivolumab (Ipi-Nivo) with response rates (RR) of ~60% and median overall survival (OS) of ~6 years. Immune-related adverse events (irAE) are common (~60% develop grade 3-4) and pose a challenge when treating frail patients. We sought to examine whether Ipi-Nivo therapy is feasible in elderly metastatic melanoma patients.MethodsElectronic records of patients treated at the Ella Lemelbaum Institute with Ipi-Nivo between the years 2017-2021 were screened for age. Elderly patients were defined as age 75 and older (group A) and were matched with records of patients age <75 (group B). Records were analyzed for baseline parameters, immunotherapy regimen, RR, toxicity and progression-free survival (PFS).ResultsTwenty-six relevant patients age >75 (median 77) were identified and were matched to 34 younger patients (median age 57). No statistically significant differences were noted in terms of baseline parameters except for BRAF mutation status (group A 15%, group B 47%, p=0.008). Response rate in group A was 38% and is consistent with previously published data. Median PFS was the same for both groups (A = 5.5 months, B= 7.5 months, p=NS). Treatment was similarly tolerated: 35% of group A patients completed 4 cycles of therapy compared to 28% for group B (p=NS). Grade 2-4 irAE were the same (A=58%, B=66%, p=NS) and there was no difference in the need for hospitalization for G3-4 events between the groups. (A=63%, B=69%, p=NS). Further division into 4 age groups (>80 vs 75-79 in group A and 65-74 vs <65 in group B) found no difference in terms of response rate or G3-4 toxicity.ConclusionIpilimumab-Nivolumab combination therapy in elderly metastatic Melanoma patients seems to be well tolerated and efficient in selected elderly patients based on performance status and comorbidities, just as in younger patients. This regimen seems to be a feasible treatment option for this age group.

Project description:ImportanceCytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade.ObjectiveTo compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma.Design, setting, and participantsThe Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1.InterventionsPatients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle.Main outcomes and measuresPrimary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability.ResultsMedian follow-up was 13.3 months (range, 0.03-19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O'Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P = .04).Conclusion and relevanceAmong patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up.Trial registrationclinicaltrials.gov Identifier: NCT01134614.

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Improved survival with ipilimumab in patients with metastatic melanoma.

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Improved survival with ipilimumab in patients with metastatic melanoma.

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