Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''.
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ABSTRACT:
SUBMITTER: Bowyer S
PROVIDER: S-EPMC5396114 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
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Reply to 'Comment on 'Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy''.
Bowyer Samantha S Prithviraj Prashanth P Lorigan Paul P Larkin James J McArthur Grant G Atkinson Victoria V Millward Michael M Khou Muoi M Diem Stefan S Ramanujam Sangeetha S Kong Ben B Liniker Elizabeth E Guminski Alexander A Parente Phillip P Andrews Miles C MC Parakh Sagun S Cebon Jonathan J Long Georgina V GV Carlino Matteo S MS Klein Oliver O
British journal of cancer 20170321 8
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Project description:Ipilimumab (MDX-010, Yervoy; Bristol-Myers Squibb), a fully human monoclonal antibody against CTL antigen 4 (CTLA-4), was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma. In both early- and late-phase trials, ipilimumab has shown consistent activity against melanoma. For example, in a randomized phase III trial that enrolled patients with previously treated metastatic disease, ipilimumab, with or without a peptide vaccine, improved overall survival: Median overall survival was 10.1 and 10.0 months in the ipilimumab and ipilimumab plus vaccine arms, respectively, versus 6.4 months in the vaccine-alone group (hazard ratio, 0.68; P ≤ 0.003). Serious (grade 3-5) immune-related adverse events occurred in 10% to 15% of patients. Thus, although it provides a clear survival benefit, ipilimumab administration requires careful patient monitoring and sometimes necessitates treatment with immune-suppressive therapy. Here, we review the mechanism of action, preclinical data, and multiple clinical trials that led to FDA approval of ipilimumab for metastatic melanoma.
| S-EPMC3575079 | biostudies-literature
Project description:In the last years the onset of new therapies changed the management of malignant melanoma. Anti CTLA-4 antibody ipilimumab was the first drug to achieve a significant improvement in survival of advanced stage melanoma. This new therapeutic agent is characterized by a number of side effects that are totally different from those of traditional chemotherapy, mainly caused by the immune system activation. The purpose of this paper is to underline the central role of ipilimumab in the treatment of metastatic melanoma and to characterize related adverse events in terms of incidence, duration and severity of presentation. The early recognition of these side effects is crucial in order to ensure an appropriate management of the toxicities, thus reducing the long term clinical sequelae and the inappropriate treatment discontinuation.
| S-EPMC4963052 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs), including CTLA-4- and PD-1-blocking antibodies, can have profound effects on tumor immune cell infiltration that have not been consistent in biopsy series reported to date. Here, we analyze seven molecular datasets of samples from patients with advanced melanoma (N = 514) treated with ICI agents to investigate clinical, genomic, and transcriptomic features of anti-PD-1 response in cutaneous melanoma. We find that prior anti-CTLA-4 therapy is associated with differences in genomic, individual gene, and gene signatures in anti-PD-1 responders. Anti-CTLA-4-experienced melanoma tumors that respond to PD-1 blockade exhibit increased tumor mutational burden, inflammatory signatures, and altered cell cycle processes compared with anti-CTLA-4-naive tumors or anti-CTLA-4-experienced, anti-PD-1-nonresponsive melanoma tumors. We report a harmonized, aggregate resource and suggest that prior CTLA-4 blockade therapy is associated with marked differences in the tumor microenvironment that impact the predictive features of PD-1 blockade therapy response.
| S-EPMC10187051 | biostudies-literature
Project description:BackgroundSalvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy is frequently used off-label for clear cell metastatic renal cell carcinoma (mRCC). However, limited data are available to guide such therapy. We performed a meta-analysis to characterize further the safety and efficacy of salvage nivolumab and ipilimumab.MethodsWe conducted a systematic review in accordance with PRISMA. Studies of salvage nivolumab and ipilimumab in patients with mRCC published in English before June 1, 2021 were included. We also included patients treated at the Ohio State University from 2012 to 2020 through a retrospective chart review. The included studies were further stratified into adaptive and standard groups based on their designs. We calculated objective response rate (ORR) and adverse events (AEs) via pooled data and quantitative synthesis using the Stata metaprop procedure. A conservative random effect model was used to combine values.ResultsA total of 7 studies and 310 patients were included. Salvage nivolumab and ipilimumab had an ORR of 14% (95% CI, 0.09-0.21) and median progression-free survival ranged between 3.7 and 5.5 months. Four out of the seven studies were standard design, whereas the other three studies were adaptive. The ORR was numerically higher in the standard group compared with the adaptive group (21% and 9-10%, respectively). The responses to salvage nivolumab and ipilimumab did not correlate with the initial anti-PD-1/PD-L1 responses (odds ratio = 1.45; p = 0.5). Grade ≥3 AEs occurred in 26% of the patients (95% CI, 0.19-0.33). There were no new safety signals observed in this study.ConclusionSalvage nivolumab and ipilimumab demonstrated moderate antitumor activity and a manageable safety profile in patients with mRCC who had prior anti-PD-1/PD-L1 therapy.Implication for practicePatients with metastatic renal cell carcinoma have limited treatment options after progressive disease on anti-PD-1/PD-L1 therapy. The role of salvage nivolumab and ipilimumab in this patient population is poorly defined. The studies on this highly important and clinically relevant topic are limited by small sample sizes. The results from our meta-analysis suggest that nivolumab and ipilimumab are feasible in the salvage setting with moderate efficacy and acceptable toxicity profile. The response rates differ with different treatment designs. This information will be beneficial to guide clinical decision-making and accurately estimating toxicity.
| S-EPMC8986145 | biostudies-literature
Project description:BackgroundMetformin is one of the biguanides commonly used in patients with type II Diabetes Mellitus. Apart from its hypoglycemic properties, metformin also inhibits the cell cycle by restricting protein synthesis and cell proliferation via regulating the LKB1/AMPL pathway. Furthermore, it also enhances the PD-1 blockade through a reduction of tumor hypoxia. Metformin has shown a significant favorable impact on treatment-related outcomes in solid tumors, but these outcomes have not been replicated in the limited clinical studies done on malignant melanoma. Moreover, none of these studies have reported on the efficacy of the combined use of metformin and immune checkpoint inhibitors (ICIs).MethodsThis is a retrospective cohort study that includes patients diagnosed with metastatic malignant melanoma and treated with ipilimumab, nivolumab, and/or pembrolizumab (Cohort A); or ipilimumab, nivolumab, and/or pembrolizumab plus metformin (Cohort B) between January 1st 2011 through December 15th 2017. In this study, patients are stratified based on anti-PD-1 only and anti-CTLA4/anti-PD-1 combination therapies in each cohort. Objective response rate (ORR) is the primary endpoint. Disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) are the secondary endpoints.ResultsCohort A had 33 patients (60%), while cohort B had 22 (40%). Overall patient characteristics were similar between both cohorts. ORR was higher in cohort B (68.2% vs. 54.5%, P = 0.31). The DCR was higher in cohort B as well (77.3% vs. 60.6%, P = 0.19). Median OS (46.7 months vs. 28 months), and median PFS (19.8 months vs. 5 months) were longer in cohort B. However, on univariate and multivariate analyses, none of these differences were statistically significant. The mean number of new metastatic sites which appeared during therapy were significantly higher in cohort A (A:1.51 vs. B:0.59, P = 0.009).ConclusionWe have observed favorable treatment-related outcomes (ORR, DCR, median PFS and median OS) in patients who have received metformin in combination with ICIs without reaching significance, probably, due to small sample size. Hence, large prospective clinical trials are required to study the synergistic effect of metformin in combination with ICIs before it can be recommended as routine additive therapy.
| S-EPMC6027578 | biostudies-literature
Project description:BACKGROUND:Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment. CASE PRESENTATION:A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months' post-treatment and continues to do well without any evidence of active disease. CONCLUSION:Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM.
| S-EPMC5809910 | biostudies-literature
Project description:PurposeCombination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy.MethodsPatients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR.ResultsPrior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes.ConclusionTo our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.
| S-EPMC8376314 | biostudies-literature
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.
| S-EPMC9676931 | biostudies-literature
Project description:Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.Patient files (n?=?752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patient? delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
| S-EPMC3544906 | biostudies-literature
Project description:CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.
| S-EPMC11028053 | biostudies-literature