Maio M.,Medical Oncology and Immunotherapy |
Ascierto P.,Istituto Nazionale Tumori |
Testori A.,Istituto Europeo di Oncologia |
Ridolfi R.,IRCCS IRST |
And 12 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2012
Background: In recent decades, melanoma incidence has been increasing in European countries; in 2006, there were approximately 60,000 cases leading to 13,000 deaths. Within Europe there is some geographical variation in the incidence of melanoma, with the highest rates reported in Scandinavia (15 cases per 100,000 inhabitants per year) and the lowest in the Mediterranean countries (5 to 7 cases per 100,000 inhabitants per year). Methods. The present article is based on the information collected in the MELODY study (MELanoma treatment patterns and Outcomes among patients with unresectable stage III or stage IV Disease: a retrospective longitudinal survey).In that study, the medical charts of patients were reviewed to document current treatment patterns and to analyse information on patients, disease characteristics and healthcare resource utilization related to the treatment of advanced melanoma regarding patients who presented with a diagnosis of malignant melanoma (stage I to IV) at participating sites between 01 July, 2005 and 30 June, 2006. Results: Summarizing, though the length of the follow-up period varies among sample patients, an amount of the yearly cost per patient can be estimated, dividing the average per patient total cost (€5.040) by the average follow-up duration (17.5 months) and reporting to one year; on these grounds, unresectable stage III or stage IV melanoma in Italy would cost 3,456 per patient per year. © 2012 Maio et al.; licensee BioMed Central Ltd.
Ferrucci P.F.,Italian National Cancer Institute |
Ascierto P.A.,Medical Oncology and Immunotherapy |
Pigozzo J.,Veneto Region Oncology Research Institute |
Del Vecchio M.,Fondazione Istituto Nazionale Tumori |
And 14 more authors.
Annals of Oncology | Year: 2016
Background: Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. Patients and methods: Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. Results: The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. Conclusions: Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials. © The Author 2016.
Maio M.,Medical Oncology and Immunotherapy |
Di Giacomo A.M.,Medical Oncology and Immunotherapy |
Robert C.,French Institute of Health and Medical Research |
Eggermont A.M.M.,French Institute of Health and Medical Research
Current Opinion in Oncology | Year: 2013
Purpose of Review: This article provides an update on the therapeutic role of the monoclonal antibody ipilimumab in melanoma. Recent therapeutic combinations, as well as directions for further investigations, will also be discussed. Recent Findings: By blocking the interaction between CTLA-4 and B7 expressed on activated T lymphocytes and antigen-presenting cells, respectively, ipilimumab inhibits negative signals that physiologically downregulate T-cell activation and exerts its therapeutic activity by upregulating the antitumor activity of T lymphocytes. Ipilimumab has been the first agent to significantly improve the survival of metastatic melanoma patients and to provide long-term benefit to a sizeable proportion of patients treated within phase II/III studies and expanded access programs. On these premises, a number of studies combining ipilimumab with cytotoxic, antiangiogenic, and targeted agents have been most recently conducted. Summary: Ipilimumab is the prototype of a growing family of 'immunomodulating antibodies' and it has demonstrated that immunotherapy will play an increasingly important role in the new treatment approaches for cancer. Combinations of chemotherapy, radiation therapy, and targeted drugs with ipilimumab indicate that additive and synergistic antitumor activity can be achieved. Most importantly, they indicate that involving the immune system is a key strategy to improve the outcome in cancer patients. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Di Giacomo A.M.,Medical Oncology and Immunotherapy |
Ascierto P.A.,Italian National Cancer Institute |
Pilla L.,Melanoma Unit |
Santinami M.,Italian National Cancer Institute |
And 13 more authors.
The Lancet Oncology | Year: 2012
Background: Ipilimumab improves survival of patients with metastatic melanoma, many of whom develop brain metastases. Chemotherapy-induced release of tumour antigens might amplify ipilimumab's antitumour activity. We aimed to investigate the efficacy and safety of ipilimumab plus fotemustine in patients with metastatic melanoma with or without asymptomatic brain metastases. Methods: In our open-label, single-arm phase 2 trial, we enrolled patients 18 years or older with measurable, locally advanced, unresectable stage III or stage IV melanoma between July 6, 2010, and April 14, 2011. Eligible patients had a life expectancy of 16 weeks or more and an Eastern Cooperative Oncology Group performance status of 1 or less, and could have received a maximum of one previous line of chemotherapy. Participants received induction treatment of 10 mg/kg intravenous ipilimumab every 3 weeks to a total of four doses, and 100 mg/m 2 intravenous fotemustine weekly for 3 weeks and then every 3 weeks from week 9 to week 24. Patients with a confirmed clinical response were eligible for maintenance treatment from week 24, with ipilimumab every 12 weeks and fotemustine every 3 weeks. The primary endpoint was the proportion of patients with immune-related disease control as established with immune-related response criteria. Analyses were done per protocol. This trial is registered with EudraCT, number 2010-019356-50, and with ClinicalTrials.gov, number NCT01654692. Findings: 86 patients were eligible for treatment, of whom 20 had asymptomatic brain metastases at baseline. 40 patients in the study population achieved disease control (46·5%, 95% CI 35·7-57·6), as did ten with brain metastases (50·0%, 27·2-72·8). 47 patients (55%) had grade 3 or 4 treatment-related adverse events, of which the most common was myelotoxicity (thrombocytopenia in 21 [24%] patients and neutropenia in 16 [19%]). The most common grade 3 or 4 immune-related adverse events were hepatic: 21 patients (24%) had grade 3 or 4 increases in concentrations of alanine aminotransferase or aspartate aminotransferase. Interpretation: The combination of ipilimumab plus fotemustine has clinical activity in patients with metastatic melanoma, including those with brain metastases. Funding: Bristol-Myers Squibb. © 2012 Elsevier Ltd.
Covre A.,Medical Oncology and Immunotherapy |
Coral S.,Medical Oncology and Immunotherapy |
Nicolay H.,Medical Oncology and Immunotherapy |
Parisi G.,Medical Oncology and Immunotherapy |
And 7 more authors.
OncoImmunology | Year: 2015
The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2′-deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p < 0.01), 54% (p < 0.01) and 33% (p = 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylation-sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3+ lymphocytes, which included both CD8+ and CD4+ T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients. © 2015 Taylor & Francis Group, LLC.