33 results on '"Federica De Galitiis"'
Search Results
2. Adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma: Health-related quality of life from the randomized phase 3 KEYNOTE-716 study
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Muhammad A. Khattak, Jason J. Luke, Georgina V. Long, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Caroline Robert, Jean-Jacques Grob, Luis de la Cruz Merino, Michele Del Vecchio, Francesco Spagnolo, Jacek Mackiewicz, Vanna Chiarion-Sileni, Matteo S. Carlino, Peter Mohr, Federica De Galitiis, Merrick I. Ross, Zeynep Eroglu, Ke Chen, Ruixuan Jiang, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M.M. Eggermont, and John M. Kirkwood
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Cancer Research ,Patient-reported outcomes ,Adjuvants, Immunologic ,Oncology ,Quality of Life ,Medizin ,Humans ,Immunotherapy ,Neoplasm Recurrence, Local ,Melanoma ,Pembrolizumab ,Adjuvant - Abstract
Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported.Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment.The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms.HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.
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- 2022
3. Pituitary Enlargement and Hypopituitarism in Patients Treated with Immune Checkpoint Inhibitors: Two Sides of the Same Coin?
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Sabrina Chiloiro, Antonella Giampietro, Antonio Bianchi, Sara Menotti, Flavia Angelini, Tommaso Tartaglione, Gian Carlo Antonini Cappellini, Federica De Galitiis, Ernesto Rossi, Giovanni Schinzari, Alessandro Scoppola, Alfredo Pontecorvi, Laura De Marinis, and Maria Fleseriu
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melanoma ,Medicine (miscellaneous) ,Settore MED/13 - ENDOCRINOLOGIA ,autoimmune disease ,chemotherapy ,hypophysitis - Abstract
Background: Immune checkpoint inhibitor hypophysitis (IIHs) is an emerging problem in cancer patients treated with immune checkpoint inhibitors (ICIs). We aimed to describe the clinical and molecular features of a multicenter series of IIHs. Methods: Demographic and clinical features were retrospectively collected for all cases. Anti-pituitary and anti-hypothalamus autoantibodies were also measured. Results: Nine patients were included. Six patients were treated with nivolumab and three with ipilimumab. Secondary hypoadrenalism was diagnosed in all patients. Pituitary MRI showed pituitary enlargement in two cases and no abnormalities in the other seven. Anti-pituitary antibodies were positive in 57.1% of cases and anti-hypothalamus antibodies in 85.7% of cases. Multidisciplinary treatments were established by a neuroendocrinologist and oncologists: all patients were treated with hydrocortisone replacement; ICI was withdrawn in two cases. At follow-up, hypoadrenalism persisted in all cases. Pituitary enlargement on MRI spontaneously recovered in the two affected patients. We found that the typical features of hypophysitis involved more frequently females and patients treated with ipilimumab. Conclusions: Although this study did not clarify if autoimmune secondary hypoadrenalism and ICI hypophysitis on brain imaging are two sides of the same disease, our preliminary data underline the need for molecular studies of IIHs and of autoimmune ICIs-related hypopituitarism.
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- 2023
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4. Clinicians’ Attitude to Doublet Plus Anti-EGFR Versus Triplet Plus Bevacizumab as First-line Treatment in Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Patients: A Multicenter, 'Real-Life', Case-Control Study
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N. Zanaletti, Susana Roselló Keränen, Debora Ierinò, Riccardo Giampieri, Michele De Tursi, Fabio Gelsomino, Ingrid Garajová, Alessio Cortellini, P. Vitale, Pasquale Lombardi, Emanuela Dell'Aquila, Teresa Troiani, Silvana Leo, Andrea Spallanzani, Giampiero Porzio, Ilaria Depetris, Federica De Galitiis, Olga Venditti, Angelica Petrillo, Michela Roberto, Francesca Di Pietro, Corrado Ficorella, Olga Nigro, Michele Ghidini, Roberto Filippi, Giampaolo Tortora, Antonio Avallone, Katia Cannita, Nicola Tinari, Gian Paolo Spinelli, Cristina Morelli, Lisa Salvatore, Giacomo Aimar, Fulgenzi Claudia, Alessandro Parisi, M. Ribelli, Valeria Zurlo, Federica Zoratto, and Carla D'Orazio
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Proto-Oncogene Proteins B-raf ,Oncology ,medicine.medical_specialty ,Bevacizumab ,Population ,Neutropenia ,FOLFOX ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,education ,Retrospective Studies ,education.field_of_study ,FOLFOXIRI ,business.industry ,Gastroenterology ,Retrospective cohort study ,medicine.disease ,Regimen ,Case-Control Studies ,FOLFIRI ,Fluorouracil ,sense organs ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
BACKGROUND: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. METHODS: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. RESULTS: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). CONCLUSION: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.
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- 2021
5. Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy
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Lauretta Levati, Cristian Bassi, Simona Mastroeni, Laura Lupini, Gian Carlo Antonini Cappellini, Laura Bonmassar, Ester Alvino, Simona Caporali, Pedro Miguel Lacal, Maria Grazia Narducci, Ivan Molineris, Federica De Galitiis, Massimo Negrini, Giandomenico Russo, and Stefania D’Atri
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resistance ,Cancer Research ,Oncology ,BRAF inhibitors ,MEK inhibitors ,circulating miRNAs ,melanoma - Abstract
Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients treated with targeted therapy. Using next-generation sequencing, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR. Receiver Operating Characteristics (ROC), Kaplan–Meier and univariate and multivariate Cox regression analyses were performed on the validated miR-1246 and miR-485-3p baseline levels. The median baseline levels of miR-1246 and miR-485-3p were significantly higher and lower, respectively, in the group of patients not responding to therapy (NRs) as compared with the group of responding patients (Rs). In Rs, a trend toward an increase in miR-1246 and a decrease in miR-485-3p was observed at progression. Baseline miR-1246 level and the miR-1246/miR-485-3p ratio showed a good ability to discriminate between Rs and NRs. Poorer PFS and OS were observed in patients with unfavorable levels of at least one miRNA. In multivariate analysis, a low level of miR-485-3p and a high miR-1246/miR-485-3p ratio remained independent negative prognostic factors for PFS, while a high miR-1246/miR-485-3p ratio was associated with an increased risk of mortality, although statistical significance was not reached. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify melanoma patients most likely to be unresponsive to targeted therapy or at higher risk for short-term PFS and mortality, thus improving their management.
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- 2022
6. Vitiligo-specific soluble biomarkers as early indicators of response to immune checkpoint inhibitors in metastatic melanoma patients
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Maria Luigia Carbone, Gabriele Madonna, Alessia Capone, Marianna Bove, Simona Mastroeni, Lauretta Levati, Mariaelena Capone, Paolo Antonio Ascierto, Federica De Galitiis, Stefania D’Atri, Cristina Fortes, Elisabetta Volpe, and Cristina Maria Failla
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Hypopigmentation ,Multidisciplinary ,Vitiligo ,Humans ,Immune Checkpoint Inhibitors ,Melanoma ,Biomarkers - Abstract
Immunotherapy with checkpoint inhibitors (CPIs) strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select responding patients is currently of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of CPIs and a favorable prognostic factor, we analyzed soluble biomarkers of vitiligo to validate them as early indicators of response to CPIs. Fifty-seven metastatic melanoma patients receiving CPIs were enrolled and divided according to the best overall response to treatment. Patient sera were evaluated at pre-treatment and after 1 and 3 months of therapy. We found that basal CD25 serum levels were higher in stable and responding patients and remained higher during the first 3 months of CPI therapy compared to non-responders. CXCL9 was absent in non-responding patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responding compared to non-responding patients. Variations in circulating immune cell subsets was also analyzed, revealing a reduced number of regulatory T lymphocytes in responding patients. Altogether, our data indicate that a pre-existing and maintained activation of the immune system could be an indication of response to CPI treatment in melanoma patients.
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- 2022
7. Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study
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Alessandro Lazzarin, Rossana Berardi, Simone Scagnoli, Federica Cecchi, Sergio Bracarda, Luigia Stefania Stucci, Giampiero Porzio, Marco Russano, Pietro Di Marino, Marco Tucci, Francesco Spagnolo, Ilaria Vallini, V. Adamo, Biagio Ricciuti, Graziella Pinotti, Rita Chiari, Laura Pala, Melissa Bersanelli, Nicola Battelli, Alessandro Russo, Paolo Marchetti, Domenico Galetta, Olga Nigro, Fabio Conforti, Mariangela Torniai, Monica Giordano, Matteo B. Suter, Michele Ghidini, Corrado Ficorella, Erika Rijavec, Annamaria Catino, Alessio Cortellini, Michele De Tursi, Raffaele Giusti, Paola Bordi, Marco Filetti, Federica De Galitiis, Andrea De Giglio, Paola Queirolo, Alessandro Tuzi, Serena Macrini, Maria Concetta Fargnoli, Andrea Botticelli, Daniele Santini, Enrica Teresa Tanda, Pamela Pizzutilo, Elena Bolzacchini, Matteo Santoni, Rosa Rita Silva, Francesca Di Pietro, and Marianna Tudini
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Male ,Oncology ,0301 basic medicine ,Cancer Research ,Immune checkpoint inhibitors ,Pembrolizumab ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Immune-related adverse events ,Neoplasms ,Atezolizumab ,Aged, 80 and over ,biology ,Middle Aged ,Prognosis ,Treatment period ,Survival Rate ,Nivolumab ,030220 oncology & carcinogenesis ,Female ,Immune checkpoint ,Immunotherapy ,Adult ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Side effect ,03 medical and health sciences ,Immune system ,PD-L1 ,Internal medicine ,medicine ,Humans ,In patient ,Adverse effect ,Survival rate ,Aged ,Retrospective Studies ,business.industry ,Disease progression ,Retrospective cohort study ,medicine.disease ,030104 developmental biology ,Multicenter study ,biology.protein ,business ,Adverse drug reaction ,Follow-Up Studies - Abstract
Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICI) are lacking.We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in advanced cancer patients. IrAEs were categorized into “early” (≤12 months) and “late” (>12 months).From September 2013 to October 2019, 436 consecutive patients were evaluated. 223 experienced any grade early-irAEs (51.1%), while 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, while 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced G3/G4 irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95%CI: 2.8-4.2), while the median time to onset of late-irAEs was 16.6 months (95%CI: 15.8-17.6). Cumulative time-adjusted risk of disease progression according to both the early-irAEs (HR = 0.63 [95%CI: 0.30-1.29], p = 0.204) and late-irAEs occurrence revealed no statistically significant differences (HR = 0.75 [95%CI: 0.37-1.56], p = 0.452). Also the time-adjusted cumulative risk of death according to both early-irAEs (HR = 0.79 [95%CI: 0.34-1.86], p = 0.598) and late-irAEs (HR = 0.92 [95%CI: 0.49-1.74], p = 0.811) did not show statistically significant differences.Although less frequent than early-irAEs, late-irAEs are quite common in long responders to PD-(L)1 ICIs, and are different in terms of spectrum and grade. Time-adjusted analysis revealed that the cumulative risk of disease progression and death were not significantly reduced in patients who experienced late-irAEs.
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- 2020
8. Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/ Programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: A multicentre analysis of immune-related adverse events
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Giampiero Porzio, Michele De Tursi, Paolo A. Ascierto, Tea Zeppola, Marcello Tiseo, Daniele Santini, Sebastiano Buti, Francesca Rastelli, Sergio Bracarda, Rossana Berardi, Riccardo Marconcini, Clara Natoli, Andrea De Giglio, Rita Chiari, Cecilia Anesi, Marco Filetti, Federica Zoratto, Rosa Rita Silva, Melissa Bersanelli, Alessio Cortellini, Paolo Marchetti, Raffaele Giusti, Andrea Botticelli, Federica De Galitiis, Alain Gelibter, Corrado Ficorella, Claudia Mosillo, Vito Vanella, Maria Rita Migliorino, Marianna Tudini, Fabiana Perrone, Francesco Atzori, Marco Russano, Biagio Ricciuti, Katia Cannita, Silvia Rinaldi, Domenico Mallardo, and Maria Giuseppa Vitale
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,Programmed Cell Death 1 Receptor ,Overweight ,Severity of Illness Index ,B7-H1 Antigen ,Body Mass Index ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Risk Factors ,Immune-related adverse events ,Renal cell carcinoma ,Neoplasms ,80 and over ,Cancer ,Aged, 80 and over ,Incidence ,Middle Aged ,Immunological ,BMI ,Checkpoint inhibitors ,Immunotherapy ,Obesity ,PD-1/PD-L1 ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Underweight ,Adult ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Aged ,Humans ,Retrospective Studies ,Young Adult ,Antineoplastic Agents ,03 medical and health sciences ,Internal medicine ,medicine ,Carcinoma ,Adverse effect ,business.industry ,Retrospective cohort study ,medicine.disease ,030104 developmental biology ,business ,Body mass index - Abstract
Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p 0.0001), G3/G4 irAEs (p 0.0001) and irAEs leading to discontinuation (LTD) (p 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.
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- 2020
9. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716) : distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial
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Georgina V Long, Jason J Luke, Muhammad A Khattak, Luis de la Cruz Merino, Michele Del Vecchio, Piotr Rutkowski, Francesco Spagnolo, Jacek Mackiewicz, Vanna Chiarion-Sileni, John M Kirkwood, Caroline Robert, Jean-Jacques Grob, Federica de Galitiis, Dirk Schadendorf, Matteo S Carlino, Peter Mohr, Reinhard Dummer, Jeffrey E Gershenwald, Charles H Yoon, Xi Lawrence Wu, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M M Eggermont, and Paolo A Ascierto
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Male ,Skin Neoplasms ,Oncology ,Double-Blind Method ,Testicular Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Medizin ,Humans ,Neoplasm Recurrence, Local ,Child ,Antibodies, Monoclonal, Humanized ,Melanoma - Abstract
Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up.KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment.Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [lt;1%]), rash (seven [1%] vs two [lt;1%]), autoimmune hepatitis (seven [1%] vs two [lt;1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported.Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting.Merck Sharpamp; Dohme, a subsidiary of Merckamp; Co.
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- 2022
10. Early fatigue in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: an insight from clinical practice
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Cecilia Anesi, Paolo Marchetti, Alessio Cortellini, Rossana Berardi, Mario Occhipinti, Marianna Tudini, Francesca Rastelli, Alain Gelibter, Andrea Botticelli, Rosa Rita Silva, Francesca Di Pietro, Paolo A. Ascierto, Giampiero Porzio, Mariangela Torniai, Daniele Santini, Federica De Galitiis, Corrado Ficorella, Federica Pergolesi, Pietro Di Marino, Maria Grazia Vitale, Vito Vanella, Domenico Mallardo, Michele De Tursi, Antonino Grassadonia, and Tea Zeppola
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Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,Programmed Cell Death 1 Receptor ,lcsh:Medicine ,Kaplan-Meier Estimate ,General Biochemistry, Genetics and Molecular Biology ,B7-H1 Antigen ,Disease-Free Survival ,Young Adult ,Renal cell carcinoma ,Immune-related adverse events ,Internal medicine ,Medicine ,Humans ,Practice Patterns, Physicians' ,Adverse effect ,Fatigue ,Aged ,Cancer ,Aged, 80 and over ,IL-6 ,Performance status ,business.industry ,Melanoma ,Research ,lcsh:R ,PD-1/PD-L1 inhibitors ,General Medicine ,Middle Aged ,medicine.disease ,Clinical trial ,IL-6, PD-1/PD-L1 inhibitors ,Immunotherapy ,Multivariate Analysis ,Population study ,Female ,business - Abstract
Background Fatigue was reported as the most common any-grade adverse event (18.3%), and the most common grade 3 or higher immune-related adverse event (irAE) (0.89%) in patients receiving PD-1/PD-L1 checkpoint inhibitors in clinical trial. Methods The aim of this retrospective multicenter study was to evaluate the correlations between “early ir-fatigue”, “delayed ir-fatigue”, and clinical outcomes in cancer patients receiving PD-1/PD-L1 inhibitors in clinical practice. Results 517 patients were evaluated. After the 12-weeks landmark selection, 386 (74.7%) patients were eligible for the clinical outcomes analysis. 40.4% were NSCLC, 42.2% were melanoma, 15.3% renal cell carcinoma and 2.1% other malignancies. 76 patients (19.7%) experienced early ir-fatigue (within 1 month from treatment commencement), while 150 patients (38.9%) experienced delayed ir-fatigue. Early ir-fatigue was significantly related to shortened PFS (HR = 2.29 [95% CI 1.62–3.22], p Conclusions Early ir-fatigue seems to be negative prognostic parameter, but to proper weight its role we must to consider the predominant role of performance status, which was related to early ir-fatigue in the study population.
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- 2019
11. Vitiligo-like Leukoderma as an Indicator of Clinical Response to Immune Checkpoint Inhibitors in Late-stage Melanoma Patients
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Sofia Verkhovskaia, Francesca Romana Di Pietro, Simona Mastroeni, Maria Luigia Carbone, Damiano Abeni, Roberto Morese, Francesca Maria Morelli, Stefania D’Atri, Paolo Marchetti, Federica De Galitiis, Cristina M. Failla, and Cristina Fortes
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Purpose. Although development of immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma, more than a half of treated patients experience disease progression during therapy. Cases of spontaneous vitiligo-like leukoderma have been described in melanoma patients and have been associated with a favorable outcome. This vitiligo-like leukoderma can also appear in melanoma patients undergoing immune therapies such as immune checkpoint inhibitors. However, no consensus exists about the relationship between vitiligo-like leukoderma onset and improved overall survival. Our study investigates the possible association between the onset of vitiligo-like leukoderma during immune checkpoint inhibitor treatment and a better prognosis.Methods. A non-concurrent cohort study was conducted by identifying retrospectively 280 patients who had inoperable or metastatic melanoma and had undergone immune therapy with checkpoint inhibitors in any line of treatment. Toxicities developed during therapy were evaluated. Results. Among the 280 study participants, 50% developed at least one type of toxicity, and vitiligo-like leukoderma was observed in 43 patients (15.4%). In the multivariate Cox model, a protective effect for mortality was observed for patients with vitiligo-like leukoderma development (HR = 0.23; 95% CI = 0.11-0.44, p Conclusion. Our findings indicate that onset of vitiligo-like leukoderma during melanoma treatment could be a marker of favorable outcome in patients treated with immune checkpoint inhibitors.
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- 2021
12. Vitiligo-Specific Soluble Biomarkers as Early Indicators of Response to Immune Checkpoint Inhibitors in Metastatic Melanoma Patients
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Simona Mastroeni, Lauretta Levati, Stefania D'Atri, Cristina Fortes, Gabriele Madonna, Mariaelena Capone, Cristina Maria Failla, Paolo A. Ascierto, Marianna Bove, Maria Luigia Carbone, and Federica De Galitiis
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Metastatic melanoma ,business.industry ,Immune checkpoint inhibitors ,Cancer research ,Medicine ,Vitiligo ,business ,medicine.disease - Abstract
Background: Immunotherapy with checkpoint inhibitors strongly improved the outcome of metastatic melanoma patients. However, not all the patients respond to treatment and identification of prognostic biomarkers able to select patients who would respond to this therapy is of outmost importance. Considering that development of vitiligo-like depigmentation in melanoma patients represents both an adverse event of immunotherapy and a favorable prognostic factor for overall survival, we analyzed known soluble biomarkers of vitiligo to validate them as early indicators of response to checkpoint inhibitors in metastatic melanoma.Methods: Fifty-seven patients with metastatic melanoma receiving anti-PD-1 checkpoint inhibitor immunotherapy were enrolled. Patient sera and plasma were evaluated for vitiligo biomarkers at pre-treatment and after 1 and 3 months of therapy. Patients were divided and analyzed according to the best overall response to treatment. Characteristic vitiligo proteins were analyzed by ELISA, while expression of circulating microRNAs, distinctive of vitiligo, was determined using real-time RT-PCR.Results: Basal serum CD25 levels were higher in stable and responder melanoma patients and remained higher during the first 3 months of anti-PD-1 therapy compared to non-responder patients. The chemokine CXCL9 was absent in non-responder patients before therapy beginning. Moreover, an increase of CXCL9 levels was observed at 1 and 3 months of therapy for all patients, although higher CXCL9 amounts were present in stable and responder compared to non-responder patients. Finally, higher levels of miR-19b, miR-25 and miR-16 were observed after 1 month of therapy in plasma of stable and responder compared to non-responder patients.Conclusions: Serum levels of CD25 and CXCL9 before and during the first months of treatment could represent biomarkers of response to anti-PD-1 immunotherapy in metastatic melanoma patients. Plasmatic miR-19b, miR-25 and miR-16 could also represent possible early biomarkers of response to anti-PD-1 treatment, but they must be validated in a higher number of patients.
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- 2021
13. integrated care pathway for melanoma: the Istituto Dermopatico dell’Immacolata experience in Rome
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Maurizio Nudo, Cristina Fortes, Giandomenico Russo, Giovanni Di Lella, Alessio Caggiati, Francesca Passarelli, Annarita Panebianco, Federica De Galitiis, Cristina Maria Failla, Francesco Ricci, Cinzia Mazzanti, Sabatino Pallotta, Paolo Marchetti, Giorgio Annessi, Tommaso Tartaglione, Stefania D'Atri, Vincenzo Ziparo, Damiano Abeni, Maurizio Elia, and Marie Perez
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Nursing ,Multidisciplinary approach ,Current practice ,business.industry ,Care plan ,Facilitator ,Medicine ,Continuity of care ,General Medicine ,Process map ,business ,Patient care ,Integrated care - Abstract
Introduction: The Integrated Care Pathway (ICP) represents a multidisciplinary outline of anticipated care, placed in an appropriate timeframe, to support patients with specific conditions or symptoms. The aim of this paper is to define the ICP for patients with melanoma referring to the “Istituto Dermopatico dell’Immacolata-IRCCS di Roma e Villa Paola” (“Center”). Methods and results: A multidisciplinary group (oncologists, dermatologists, surgeons, pathologists etc.) was defined as well as a facilitator to act as a link between all experts. The first step of ICP development was a review of current practice for patients with melanoma referring to the Center. This first step had the scope to define the multidisciplinary process map (a “picture” of the care plan) for patients with melanoma. The process map defined: i) the activities performed during delivery of care to the patients, ii) the responsibilities for these activities and iii) potential problem areas or opportunities for improvements. The process map formed the basis of the final ICP document. Conclusion: The adoption of melanoma ICP will allow the multidisciplinary group to ensure that clinical guidelines and available evidence are incorporated into everyday practice. (Oncology, HTA & Market Access)
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- 2019
14. Distant metastasis-free survival with pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: The phase 3 KEYNOTE-716 study
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Georgina V. Long, Jason J. Luke, Muhammad Khattak, Luis de la Cruz Merino, Michele Del Vecchio, Piotr Rutkowski, Francesco Spagnolo, Jacek Mackiewicz, Vanna Chiarion-Sileni, John M. Kirkwood, Caroline Robert, Jean-Jacques Grob, Federica de Galitiis, Dirk Schadendorf, Matteo S. Carlino, Larry Wu, Mizuho Fukunaga-Kalabis, Clemens Krepler, Alexander M. Eggermont, and Paolo Antonio Ascierto
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Cancer Research ,Oncology - Abstract
LBA9500 Background: In previous analyses of the phase 3, double-blind KEYNOTE-716 study, adjuvant pembrolizumab (pembro) significantly improved recurrence-free survival compared with placebo in patients (pts) with resected AJCC-8 stage IIB or IIC melanoma. We present new data from the analysis of distant metastasis-free survival (DMFS), and recurrence-free survival (RFS) with longer follow up. Methods: A total of 976 pts aged ≥12 years with complete resection of cutaneous stage IIB or IIC melanoma and negative sentinel lymph node biopsy were randomized 1:1 to pembro 200 mg (2 mg/kg for pediatric pts) or placebo Q3W for 17 cycles (approximately 1 year) in Part 1 of the study. Randomization was stratified by T category 3b, 4a, 4b (adults) with a separate stratum for pediatric pts. Treatment continued until disease recurrence or unacceptable toxicity. Pts who received placebo in Part 1, or who did not experience disease progression within 6 months of completing Part 1 were eligible for additional cycles of pembro Q3W at recurrence (Part 2). The primary endpoint was RFS per investigator. DMFS by investigator is a secondary endpoint. The data cut-off date for this interim analysis was Jan 4th, 2022. Results: At median follow-up of 26.9 mo (range, 4.6-39.2), adjuvant pembro significantly improved DMFS (HR 0.64, 95% CI, 0.47-0.88; P=0.0029; median not reached [NR] for both) vs placebo. The 24-mo DMFS rate was 88.1% vs 82.2%. There was consistent reduction in the risk of recurrence with pembro vs placebo (HR 0.64, 95% CI, 0.50-0.84) with further follow-up. The 24-mo RFS rate was 81.2% vs 72.8%. Grade ≥ 3 any-cause AEs occurred in 137 (28.4%) vs 97 (20.0%) pts in the pembro vs placebo arms. Grade ≥ 3 drug-related AEs occurred in 83 (17.2%) vs 24 (4.9%) pts. One pt in the pembro arm and 5 pts in the placebo arm died due to an any-cause AE. No deaths were drug-related. Immune-mediated AEs occurred in 182 (37.7%) vs 45 (9.3%) pts, most commonly hypothyroidism (17.2% vs 3.7%). Conclusions: Adjuvant pembrolizumab vs placebo for resected stage IIB and IIC melanoma significantly improved DMFS, with continued reduction in the risk of recurrence, and a favorable benefit-risk profile. Clinical trial information: NCT03553836.
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- 2022
15. The role of opioids in cancer response to immunotherapy
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Francesca Di Pietro, Federica De Galitiis, Enrico Cortesi, Giulia Mammone, Simone Scagnoli, Giulia Pomati, Michela Roberto, Silvia Mezi, Gaetano Lanzetta, Edoardo Cerbelli, Alessio Cirillo, Paolo Marchetti, Bruna Cerbelli, Alain Gelibter, Andrea Botticelli, and Maria Letizia Calandrella
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,early progression ,Lung Neoplasms ,medicine.medical_treatment ,lcsh:Medicine ,opioid receptors ,General Biochemistry, Genetics and Molecular Biology ,predictive factor ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,prognostic factor ,Retrospective Studies ,business.industry ,lcsh:R ,Cancer ,opioids ,Retrospective cohort study ,General Medicine ,Immunotherapy ,Drug interaction ,immunotherapy ,medicine.disease ,Primary tumor ,Analgesics, Opioid ,030104 developmental biology ,Opioid ,030220 oncology & carcinogenesis ,Concomitant ,business ,medicine.drug - Abstract
Background The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. Methods This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p p Discussion Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. Conclusions A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.
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- 2021
16. Real world data of cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma
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Maria Concetta Potenza, Luca Bianchi, Paolo A. Ascierto, Michele Guida, Paola Queirolo, Corrado Ficorella, Teresa Troiani, Paolo Bossi, Salvatore Alfieri, Luca Tondulli, Maria Concetta Fargnoli, Alessio Cortellini, Marco Rubatto, K. Peris, Vito Barbieri, Maristella Saponara, Roberta Depenni, Andrea Botticelli, Lisa Licitra, Ilaria Proietti, Alice Baggi, Pietro Quaglino, Riccardo Marconcini, Federica De Galitiis, Francesco Spagnolo, and Claudia Trojaniello
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Drug-Related Side Effects and Adverse Reactions ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Antibodies, Monoclonal, Humanized ,Antibodies ,Cemiplimab ,Cutaneous squamous cell carcinoma ,Immunotherapy ,Real world ,Aged ,Aged, 80 and over ,Carcinoma, Squamous Cell ,Female ,Humans ,Immune Checkpoint Inhibitors ,Italy ,Middle Aged ,Response Evaluation Criteria in Solid Tumors ,Retrospective Studies ,Young Adult ,Settore MED/35 ,Internal medicine ,Monoclonal ,medicine ,80 and over ,Adverse effect ,Humanized ,cutaneous squamous cell carcinoma ,immunotherapy ,cemiplimab ,real world ,Autoimmune disease ,Chemotherapy ,Performance status ,business.industry ,Carcinoma ,Common Terminology Criteria for Adverse Events ,medicine.disease ,Radiation therapy ,Clinical trial ,Oncology ,Squamous Cell ,Concomitant ,business ,Settore MED/35 - MALATTIE CUTANEE E VENEREE - Abstract
Background Cutaneous squamous cell carcinoma (cSCC) has an overall favourable outcome, except for patients with an advanced stage disease. The programmed death protein-1 (PD-1) inhibitor cemiplimab has been approved for use in advanced cSCC. We report clinical outcomes from the named patient programme-compassionate use of cemiplimab for patients with advanced cSCC in Italy. Methods This is a retrospective, observational, multicentre study. We analysed medical records of patients with advanced cSCC treated with cemiplimab between May 2019 and February 2020 in 17 referral Italian centres. We assessed the safety profile according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), the clinical activity in terms of response rate, clinical benefit and duration of response and baseline clinical-pathologic characteristics associated with response. Results 131 patients were included, with a median age of 79 years. Of them, 9.2% had a concurrent chronic lymphoproliferative disease and 8.5% a concomitant autoimmune disease. Some 42.7% of the total patients had at least one treatment-related adverse events (AEs); out of above, 9.2% had grade 3–4 adverse events, and there were two fatal adverse events. The overall response rate (ORR) was 58%, and the disease control rate (DCR) was 71.7%. Cutaneous squamous cell carcinomas (cSCCs) arising on the head and neck area (p = 0.007) and haemoglobin values in normal range (p = 0.034) were significantly associated with a better response, while cSCCs on the genitalia (p = 0.041), treatment with any systemic antibiotic within 1 month of cemiplimab initiation (p = 0.012), performance status ≥1 (p = 0.012), chronic corticosteroids therapy (p = 0.038), previous radiation therapy to lymph nodes (p = 0.052) and previous chemotherapy (p = 0.0020) were significantly associated with a worse response. Conclusions Our real-world study showed safety and effectiveness results comparable to those obtained in clinical trials. We identified some clinical and biochemical factors potentially associated with response to cemiplimab.
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- 2021
17. [The integrated care pathway for non melanoma skin cancer: the Istituto Dermopatico dell'Immacolata - IRCCS experience in Rome.]
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Luca, Fania, Roberto, Morese, Giovanni, Di Lella, Enzo, Palese, Cinzia, Mazzanti, Sabatino, Pallotta, Annarita, Panebianco, Rosaria, Laporta, Alessio, Caggiati, Francesca, Passarelli, Vincenzo, Ziparo, Tommaso, Tartaglione, Eleonora, Candi, Elena, Dellambra, Francesca Romana, Di Pietro, Federica, De Galitiis, Paolo, Marchetti, and Damiano, Abeni
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Skin Neoplasms ,Delivery of Health Care, Integrated ,Incidence ,Rome ,Critical Pathways ,Humans - Abstract
The incidence of non-melanoma skin cancers (NMSC) is increasing worldwide and these skin cancers have become an important health issue. An integrated care pathway (ICP) is a multidisciplinary outline of anticipated care, placed in an appropriate timeframe, to help a patient with a specific condition. The aim of this paper is to define the ICP for patients affected by NMSC referring to the Istituto Dermopatico dell'Immacolata - IRCCS of Rome and Villa Paola, Italy. This ICP is multidisciplinary and included various specialists like dermatologist, oncologist, general surgeon, plastic surgeon, anatomopathologist, molecular biologist and epidemiologist. This ICP is based on the most recent acquisitions in the literature, referring in particular to the national (EADO and SIDEMAST) and international guidelines (EDF and NCCN). We firstly valued the current practice for patients affected by NMSC referring to our Institute to define the multidisciplinary process map. This process delineated the activities and the responsibilities performed during delivery of care to the patients and the potential problem areas or opportunities for improvements. Subsequently, we defined the final ICP process. This ICP of NMSC represents an innovative strategy to provide high quality healthcare. This allows to ensure all the necessary procedures for the patient, optimizing the "continuum" of care and the use of health services, and improving the organization of the Institute regarding an important health issue.
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- 2020
18. The Agnostic Role of Site of Metastasis in Predicting Outcomes in Cancer Patients Treated with Immunotherapy
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Raffaele Giusti, Federica De Galitiis, Silvia Mezi, Paolo Marchetti, Andrea Botticelli, Enrico Cortesi, Francesca Di Pietro, Patrizia Vici, Alessio Cirillo, Giulia d'Amati, L. Pizzuti, Carlo Della Rocca, Lidia Strigari, Bruna Cerbelli, Edoardo Cerbelli, Simone Scagnoli, Marianna Nuti, Alessio Cortellini, Alain Gelibter, Paolo A. Ascierto, and Michele Ghidini
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,predictive factors ,Colorectal cancer ,Immunology ,lcsh:Medicine ,Context (language use) ,NSCLC ,agnostic biomarkers ,Article ,Metastasis ,Agnostic biomarkers ,Immunotherapy ,Melanoma ,Metastatic sites ,Predictive factors ,Prognostic factors ,RCC ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,Drug Discovery ,Carcinoma ,medicine ,melanoma ,Pharmacology (medical) ,metastatic sites ,Progression-free survival ,Pharmacology ,business.industry ,lcsh:R ,Cancer ,prognostic factors ,medicine.disease ,030104 developmental biology ,Infectious Diseases ,030220 oncology & carcinogenesis ,immunotherapy ,business - Abstract
Immune checkpoint inhibitors have revolutionized treatment and outcome of melanoma and many other solid malignancies including non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Unfortunately, only a minority of patients have a long-term benefit, while the remaining demonstrate primary or acquired resistance. Recently, it has been demonstrated that the prevalence of programmed death-ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) varies based on the anatomical site of metastases. In particular, liver seems to have more immunosuppressive microenvironment while both the presence of lymph nodal disease and lung metastases seem to have the highest prevalence of PD-L1 and TILs. The aim of the present study is to investigate the possible role of site of metastases as a predictive factor for response or resistance to immunotherapy in several types of cancer. In this multicenter retrospective study, we enrolled patients with metastatic NSCLC, melanoma, RCC, urothelial, merkel carcinoma, and colon cancer who received immunotherapy from April 2015 to August 2019. Major clinicopathological parameters were retrieved and correlated with patients&rsquo, survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision-making process. A total of 291 patients were included in this study. One hundred eighty-seven (64%) patients were male and 104 (36%) female. The tumor histology was squamous NSCLC in 56 (19%) patients, non-squamous NSCLC in 99 (34%) patients, melanoma in 101 (35%) patients, RCC in 28 (10%) patients, and other tumors in the remaining 7 (2%) patients. The number of metastatic sites was 1 in 103 patients (35%), 2 in 104 patients (36%) and 3 in 84 patients (29%). Out of 183 valuable patients, the entity of response was complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD) in 15, 53, 31, and 79 patients, respectively. Using an univariate analysis (UVA), tumor burden (p = 0.0004), the presence of liver (p = 0.0009), bone (p = 0.0016), brain metastases (p <, 0.0001), the other metastatic sites (p = 0.0375), the number of metastatic sites (p = 0.0039), the histology (p = 0.0034), the upfront use of immunotherapy (p = 0.0032), and Eastern Cooperative Oncology Group (ECOG) Perfomance status (PS) &ge, 1 (p <, 0.0001) were significantly associated with poor overall survival (OS). Using a multivariate analysis (MVA) the presence of liver (p = 0.0105) and brain (p = 0.0026) metastases, the NSCLC diagnosis (p <, 0.0001) and the ECOG PS (p <, 0.0001) resulted as significant prognostic factors of survival. Regarding the progression free survival (PFS), using a UVA of the tumor burden (p = 0.0004), bone (p = 0.0098) and brain (p = 0.0038) metastases, the presence of other metastatic sites (p = 0.0063), the number of metastatic sites (p = 0.0007), the histology (p = 0.0007), the use of immunotherapy as first line (p = 0.0031), and the ECOG PS &ge, 1 (p &le, 0.0001) were associated with a lower PFS rate. Using an MVA, the presence of brain (p = 0.0088) and liver metastases (p = 0.024) and the ECOG PS (p <, 0.0001) resulted as predictors of poor PFS. Our study suggests that the site of metastases could have a role as prognostic and predictive factor in patients treated with immunotherapy. Indeed, regardless of the histology, the presence of liver and brain metastases was associated with a shorter PFS and OS, but these results must be confirmed in further studies. In this context, a deep characterization of microenvironment could be crucial to prepare patients through novel strategies with combination or sequential immunotherapy in order to improve treatment response.
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- 2020
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19. Evaluating the role of FAMIly history of cancer and diagnosis of multiple neoplasms in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors. the multicenter FAMI-L1 study
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Fabiana Perrone, Rosa Rita Silva, Cristina Zannori, Paolo Marchetti, Francesco Atzori, Giampiero Porzio, Raffaele Giusti, Domenico Mallardo, Nicola Tinari, Enzo Veltri, Tea Zeppola, Federica De Galitiis, Marcello Tiseo, Alessio Cortellini, Cecilia Anesi, Claudia Mosillo, Alessandro Inno, Marianna Tudini, Stefania Gori, Alain Gelibter, Marco Filetti, Corrado Ficorella, Alessandra Tessitore, Melissa Bersanelli, Andrea Botticelli, Mario Occhipinti, Antonino Grassadonia, Marco Russano, Maria Giuseppa Vitale, Annagrazia Pireddu, Maria Concetta Fargnoli, Francesco Malorgio, Katia Cannita, Federica Pergolesi, Silvia Rinaldi, Michele De Tursi, Maria Rita Migliorino, Francesca Rastelli, Daniela Iacono, Gian Carlo Antonini Cappellini, Rossana Berardi, Pietro Di Marino, Alessandro Parisi, Sergio Bracarda, Paolo A. Ascierto, Daniele Santini, Sebastiano Buti, Federica Zoratto, and Francesco Martella
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0301 basic medicine ,Oncology ,multiple neoplasms ,medicine.medical_specialty ,Multivariate analysis ,medicine.medical_treatment ,Immunology ,Programmed Cell Death 1 Receptor ,ddr genes ,B7-H1 Antigen ,family history of cancer ,immune checkpoint inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Internal medicine ,Neoplasms ,medicine ,Immunology and Allergy ,Humans ,cardiovascular diseases ,Family history ,Adverse effect ,RC254-282 ,Retrospective Studies ,Original Research ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,pd-1 ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Retrospective cohort study ,Immunotherapy ,RC581-607 ,medicine.disease ,immunotherapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunologic diseases. Allergy ,business - Abstract
Background: We investigate the role of family history of cancer (FHC) and diagnosis of metachronous and/or synchronous multiple neoplasms (MN), during anti-PD-1/PD-L1 immunotherapy. Design: This was a multicenter retrospective study of advanced cancer patients treated with anti-PD-1/PD-L1 immunotherapy. FHC was collected in lineal and collateral lines, and patients were categorized as follows: FHC-high (in case of cancer diagnoses in both the lineal and collateral family lines), FHC-low (in case of cancer diagnoses in only one family line), and FHC-negative. Patients were also categorized according to the diagnosis of MN as follows: MN-high (>2 malignancies), MN-low (two malignancies), and MN-negative. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and incidence of immune-related adverse events (irAEs) of any grade were evaluated. Results: 822 consecutive patients were evaluated. 458 patients (55.7%) were FHC-negative, 289 (35.2%) were FHC-low, and 75 (9.1%) FHC-high, respectively. 29 (3.5%) had a diagnosis of synchronous MN and 94 (11.4%) of metachronous MN. 108 (13.2%) and 15 (1.8%) patients were MN-low and MN-high, respectively. The median follow-up was 15.6 months. No significant differences were found regarding ORR among subgroups. FHC-high patients had a significantly longer PFS (hazard ratio [HR] = 0.69 [95% CI: 0.48–0.97], p = .0379) and OS (HR = 0.61 [95% CI: 0.39–0.93], p = .0210), when compared to FHC-negative patients. FHC-high was confirmed as an independent predictor for PFS and OS at multivariate analysis. No significant differences were found according to MN categories. FHC-high patients had a significantly higher incidence of irAEs of any grade, compared to FHC-negative patients (p = .0012). Conclusions: FHC-high patients seem to benefit more than FHC-negative patients from anti-PD-1/PD-L1 checkpoint inhibitors.
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- 2020
20. Insulin Resistance as a Risk Factor for Cutaneous Melanoma. A Case Control Study and Risk-Assessment Nomograms
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Alessandro Scoppola, Lidia Strigari, Agnese Barnabei, Pierpaolo Petasecca, Federica De Galitiis, Claudia Angela Maria Fulgenzi, Mario Roselli, Antonino De Lorenzo, Laura Di Renzo, Paolo Marchetti, and Francesco Torino
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Settore MED/06 - Oncologia Medica ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,body mass index ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,HOMA-IR ,Settore MED/13 - Endocrinologia ,03 medical and health sciences ,cutaneous melanoma ,0302 clinical medicine ,Insulin resistance ,Endocrinology ,Internal medicine ,insulin resistance ,medicine ,Settore MED/49 - Scienze Tecniche Dietetiche Applicate ,Risk factor ,Original Research ,QUICKI ,lcsh:RC648-665 ,business.industry ,Melanoma ,Quantitative insulin sensitivity check index ,Case-control study ,medicine.disease ,Obesity ,030104 developmental biology ,Cutaneous melanoma ,business ,Body mass index - Abstract
Insulin resistance and obesity are suggested to have a key role in the molecular pathogenesis of various disorders, including several malignancies. Moreover, insulin resistance has recently been found to be associated with cutaneous and uveal melanoma, while a variable positive correlation between obesity and the risk of cutaneous melanoma was also found at least in men. The present trial aims at confirming whether insulin resistance, assessed with the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI), is a risk factor for cutaneous melanoma. One hundred and thirty patients diagnosed with cutaneous melanoma and 130 age-, sex-, and skin phototype-matched controls were evaluated. At the univariate and multivariate analysis, the diagnosis of cutaneous melanoma was inversely related with insulin resistance (HOMA-IR) and positively with BMI (p = 0.0014 and p = 0.008, respectively). Consistently, insulin sensitivity (QUICKI) and BMI resulted positively associated with the diagnosis of cutaneous melanoma (p = 0.0001 and p = 0.0026, respectively). The results obtained are partially in agreement with those reported in the literature. By comparing our data with those generated by other studies, inconsistencies in key features among subgroups of different trials have emerged, possibly affecting final correlations. Based on insulin resistance/sensitivity, fasting insulinemia/glycemia, and BMI values collected from patients who participated in the present trial, two nomograms potentially assessing the risk of cutaneous melanoma have been generated. Molecular aspects sustain a role for insulin resistance in the carcinogenesis of cutaneous melanoma, but clinical data remain uncertain. Larger, well-balanced, correlative trials are still needed to define the potential role of insulin resistance in the carcinogenesis of cutaneous melanoma.
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- 2019
21. CTLA-4 gene variant -1661A>G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab
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Stefania Tommasi, Maria Pia Pistillo, Beatrice Dozin, Vincenzo Fontana, Paolo Fava, Massimo Guidoboni, Massimo Romani, Barbara Banelli, Italian Melanoma Intergroup, Pier Francesco Ferrucci, Gabriele Madonna, Michele Guida, Francesco Spagnolo, Chiara Martinoli, Federica De Galitiis, Laura Ghilardi, Barbara Merelli, Paolo Marchetti, Diego Ferone, Roberta Carosio, Emilia Cocorocchio, Paola Queirolo, Anna Morabito, Ester Simeone, Paolo A. Ascierto, Gian Carlo Antonini Cappellini, and Simona Osella-Abate
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Hypophysitis ,medicine.medical_treatment ,Ipilimumab ,Endocrine System Diseases ,Thyroiditis ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Internal medicine ,Genetic model ,Biomarkers, Tumor ,medicine ,Humans ,Endocrine system ,CTLA-4 Antigen ,Adverse effect ,Melanoma ,Polymorphism, Genetic ,Endocrine disease ,business.industry ,Prognosis ,medicine.disease ,030104 developmental biology ,Oncology, Cancer Research ,business ,030215 immunology ,medicine.drug - Published
- 2018
22. Clinical Outcomes of Patients with Advanced Cancer and Pre-Existing Autoimmune Diseases Treated with Anti-Programmed Death-1 Immunotherapy: A Real-World Transverse Study
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Carlo Garufi, Antonino Grassadonia, Maria Giuseppa Vitale, Sergio Bracarda, Roberto Sabbatini, Tea Zeppola, Paolo A. Ascierto, Riccardo Marconcini, Andrea Botticelli, Marcello Tiseo, Cecilia Anesi, Giampiero Porzio, Raffaele Giusti, Gian Carlo Antonini Cappellini, Fabiana Perrone, Valeria Ciciarelli, Maria Concetta Fargnoli, Francesco Atzori, Sebastiano Buti, Enzo Veltri, Marco Filetti, Alessio Cortellini, Paolo Marchetti, Daniela Iacono, Michele De Tursi, Federica De Galitiis, Rossana Berardi, Annagrazia Pireddu, Davide Brocco, Melissa Bersanelli, Marianna Tudini, Rosa Rita Silva, Silvia Rinaldi, Federica Zoratto, Maria Rita Migliorino, Marco Russano, Antonio Rossi, Biagio Ricciuti, Katia Cannita, Francesco Malorgio, Maria Michiara, Rita Chiari, Daniele Santini, Nicola Tinari, and Corrado Ficorella
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Adult ,Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Severity of Illness Index ,Autoimmune Diseases ,Young Adult ,03 medical and health sciences ,Immune checkpoint inhibitors ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Acquired immunodeficiency syndrome (AIDS) ,Neoplasms ,Internal medicine ,Autoimmune disease ,medicine ,Humans ,Anti-programmed death-1 ,Immunotherapy ,Performance status ,Sex ,Oncology ,Adverse effect ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Incidence ,Incidence (epidemiology) ,Middle Aged ,medicine.disease ,Immuno‐Oncology ,Progression-Free Survival ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,Kidney cancer - Abstract
BACKGROUND. Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors. MATERIALS AND METHODS. Consecutive patients with advanced cancer, treated with anti‐programmed death‐1 (PD‐1) agents, were evaluated according to the presence of pre‐existing AIDs. The incidence of immune‐related adverse events (irAEs) and clinical outcomes were compared among subgroups. RESULTS. A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non‐small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%); kidney cancer, 94 (12.5%); and others, 6 (0.8%). Male/female ratio was 499/252. Eighty‐five patients (11.3%) had pre‐existing AIDs, further differentiated in clinically active (17.6%) and inactive (82.4%). Among patients with pre‐existing AIDs, incidence of irAEs of any grade was significantly higher when compared with patients without AIDs (65.9% vs. 39.9%). At multivariate analysis, both inactive (p = .0005) and active pre‐existing AIDs (p = .0162), female sex (p = .0004), and Eastern Cooperative Oncology Group Performance Status
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- 2019
23. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: When overweight becomes favorable
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Mario Occhipinti, Gian Carlo Antonini Cappellini, Marco Filetti, Giampiero Porzio, Clara Natoli, Andrea De Giglio, Francesca Rastelli, Federica Zoratto, Silvia Rinaldi, Cecilia Anesi, Sebastiano Buti, Rita Chiari, Fabiana Perrone, Francesco Atzori, Pietro Di Marino, Andrea Botticelli, Enzo Veltri, Melissa Bersanelli, Federica Pergolesi, Nicola Tinari, Alessio Cortellini, Paolo A. Ascierto, Corrado Ficorella, Daniele Santini, Alain Gelibter, Marianna Tudini, Rossana Berardi, Maria Concetta Fargnoli, Tea Zeppola, Rosa Rita Silva, Marcello Tiseo, Riccardo Marconcini, Daniela Iacono, Raffaele Giusti, Federica De Galitiis, Annagrazia Pireddu, Paolo Marchetti, Alessandro Parisi, Francesco Malorgio, Maria Giuseppa Vitale, Michele De Tursi, Maria Michiara, Marco Russano, Biagio Ricciuti, Katia Cannita, Cortellini A., Bersanelli M., Buti S., Cannita K., Santini D., Perrone F., Giusti R., Tiseo M., Michiara M., Di Marino P., Tinari N., De Tursi M., Zoratto F., Veltri E., Marconcini R., Malorgio F., Russano M., Anesi C., Zeppola T., Filetti M., Marchetti P., Botticelli A., Antonini Cappellini G.C., De Galitiis F., Vitale M.G., Rastelli F., Pergolesi F., Berardi R., Rinaldi S., Tudini M., Silva R.R., Pireddu A., Atzori F., Chiari R., Ricciuti B., De Giglio A., Iacono D., Gelibter A., Occhipinti M.A., Parisi A., Porzio G., Fargnoli M.C., Ascierto P.A., Ficorella C., and Natoli C.
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Programmed Cell Death 1 Receptor ,Kaplan-Meier Estimate ,Anti-PD-1/PD-L1 ,Overweight ,Gastroenterology ,B7-H1 Antigen ,Body Mass Index ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,BMI ,Cancer ,Immunotherapy ,Obesity ,Immunology and Allergy ,Immunology ,Molecular Medicine ,Oncology ,Pharmacology ,Renal cell carcinoma ,Neoplasms ,Molecular Targeted Therapy ,Aged, 80 and over ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Underweight ,medicine.symptom ,Research Article ,Adult ,medicine.medical_specialty ,lcsh:RC254-282 ,Young Adult ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Aged ,Neoplasm Staging ,Proportional Hazards Models ,business.industry ,nutritional and metabolic diseases ,Retrospective cohort study ,medicine.disease ,Clinical trial ,030104 developmental biology ,business ,Body mass index - Abstract
Background Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients. Patients and methods We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (
- Published
- 2019
24. Corrigendum: Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study
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Paola Queirolo, Beatrice Dozin, Anna Morabito, Barbara Banelli, Patrizia Piccioli, Cristiana Fava, Claudio Leo, Roberta Carosio, Stefania Laurent, Vincenzo Fontana, Pier Francesco Ferrucci, Chiara Martinoli, Emilia Cocorocchio, Angelo Battaglia, Paolo A. Ascierto, Mariaelena Capone, Ester Simeone, Federica De Galitiis, Elena Pagani, Gian Carlo Antonini Cappellini, Paolo Marchetti, Michele Guida, Stefania Tommasi, Mario Mandalà, Barbara Merelli, Pietro Quaglino, Paolo Fava, Massimo Guidoboni, Massimo Romani, Francesco Spagnolo, and Maria Pia Pistillo
- Subjects
lcsh:Immunologic diseases. Allergy ,best overall response ,overall survival ,Immunology ,melanoma ,predictive/prognostic factor ,Immunology and Allergy ,ipilimumab ,lcsh:RC581-607 ,CTLA-4 variants - Published
- 2018
25. Soluble CTLA-4 as a favorable predictive biomarker in metastatic melanoma patients treated with ipilimumab: an Italian melanoma intergroup study
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Stefania Tommasi, Simona Osella-Abate, Maria Pia Pistillo, Elena Pagani, Vincenzo Fontana, Barbara Banelli, Chiara Martinoli, Enrica Teresa Tanda, Paolo Fava, Emilia Cocorocchio, Anna Morabito, Laura Spano, Massimo Romani, Paola Queirolo, Francesco Spagnolo, Beatrice Dozin, Michele Guida, Francesca Ferrero, Stefania Laurent, Pietro Quaglino, Pier Francesco Ferrucci, Gian Carlo Antonini Cappellini, Paolo Marchetti, Paolo A. Ascierto, Federica De Galitiis, Roberta Carosio, Mariaelena Capone, and Ester Simeone
- Subjects
Male ,Cancer Research ,Kaplan-Meier Estimate ,Gastroenterology ,Best response ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,80 and over ,Immunology and Allergy ,Overall survival ,CTLA-4 Antigen ,Neoplasm Metastasis ,Melanoma ,Aged, 80 and over ,Tumor ,Middle Aged ,Immunological ,Oncology ,Italy ,Predictive value of tests ,Biomarker (medicine) ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adverse events ,Ipilimumab ,Soluble CTLA-4 ,Aged ,Biomarkers, Tumor ,Humans ,Predictive Value of Tests ,Solubility ,Young Adult ,Immunology ,Antineoplastic Agents ,03 medical and health sciences ,Internal medicine ,medicine ,Adverse effect ,Tumor marker ,Proportional hazards model ,business.industry ,medicine.disease ,business ,Progressive disease ,Biomarkers ,030215 immunology - Abstract
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.
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- 2018
26. Association of CTLA-4 Gene Variants with Response to Therapy and Long-term Survival in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study
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Paola Queirolo, Beatrice Dozin, Anna Morabito, Barbara Banelli, Patrizia Piccioli, Cristiana Fava, Claudio Leo, Roberta Carosio, Stefania Laurent, Vincenzo Fontana, Pier Francesco Ferrucci, Chiara Martinoli, Emilia Cocorocchio, Angelo Battaglia, Paolo A. Ascierto, Mariaelena Capone, Ester Simeone, Federica De Galitiis, Elena Pagani, Gian Carlo Antonini Cappellini, Paolo Marchetti, Michele Guida, Stefania Tommasi, Mario Mandalà, Barbara Merelli, Pietro Quaglino, Paolo Fava, Massimo Guidoboni, Massimo Romani, Francesco Spagnolo, and Maria Pia Pistillo
- Subjects
lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Metastatic melanoma ,overall survival ,T cell ,Immunology ,Ipilimumab ,CTLA-4 variants ,03 medical and health sciences ,0302 clinical medicine ,Best overall response ,Melanoma ,Overall survival ,Predictive/prognostic factor ,Immunology and Allergy ,Internal medicine ,Genotype ,melanoma ,medicine ,ipilimumab ,Allele ,Original Research ,business.industry ,predictive/prognostic factor ,Correction ,medicine.disease ,Immune checkpoint ,030104 developmental biology ,medicine.anatomical_structure ,best overall response ,030220 oncology & carcinogenesis ,Cohort ,lcsh:RC581-607 ,business ,medicine.drug - Abstract
Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan–Meier method. Both −1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A “dose” (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, −1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying −1577G/A and CT60G/A, respectively. MM patients carrying −1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.
- Published
- 2017
27. Family history of cancer as surrogate predictor for immunotherapy with anti-PD-1/PD-L1 immune checkpoint inhibitors: The FAMI-L1 study
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Raffaele Giusti, Francesca Rastelli, Marcello Tiseo, Paolo Marchetti, Daniele Santini, Alessandro Inno, Federica De Galitiis, Sebastiano Buti, Melissa Bersanelli, Federica Zoratto, Francesco Atzori, Clara Natoli, Sergio Bracarda, Corrado Ficorella, Alessio Cortellini, Maria Giuseppa Vitale, Rossana Berardi, Marianna Tudini, Paolo A. Ascierto, and Daniela Iacono
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,Immune checkpoint inhibitors ,Anti pd 1 ,Cancer ,Immunotherapy ,medicine.disease ,Preliminary analysis ,Internal medicine ,PD-L1 ,medicine ,biology.protein ,cardiovascular diseases ,Family history ,business - Abstract
2559 Background: In the preliminary analysis of the FAMI-L1 study, we found a significant association between family history of cancer (FHC) and better clinical outcomes with anti-PD1/PD-L1 inhibitors. Methods: We retrospectively evaluated advanced cancer patients treated with single agents PD1/PD-L1 inhibitors. Patients were categorized as follow: FHC-high (in case of at least one cancer diagnoses in both straight and collateral family line), FHC-low (in case of a cancer diagnoses in only one family line) and FHC-negative. FHC was collected till the second degree of relatedness. Results: Between September 2013 and May 2018, 772 consecutive patients were evaluated. Median age was 68 years; male/female ratio was 521/251. Primary tumors were: NSCLC (58.3%), melanoma (22.1%), renal cell carcinoma (16.6%) and others (3%). 114 patients (14.9%) had ECOG-PS ≥ 2. 341 patients (44.3) were FHC-positive: 268 of them (34.75) were FHC-low while 74 (9.6%) were FHC-high. FHC-high patients had a significantly higher incidence of irAEs compared to FHC-negative (55.4% vs 35.6%; p = 0.0012) and to FHC-low (41.4%; p = 0.0323). No significant differences were found in terms of ORR among subgroups (data not shown). At median follow-up of 15.8 months, median PFS was 9.1 months (95%CI: 8.1-10.4; 452 events) and median OS was 19.7 months (95%CI: 15.7-24.4; 436 censored). No significant differences were found regarding PFS (data not shown). Median OS of FHC-high patients was 31.6 months (95%CI: 26.2-31.6; 50 censored patients), which was significantly longer than 18.2 months (95%CI: 14.7-21.3; 229 censored patients) of FHC-negative patients (HR = 0.60 [95%CI: 0.39–0.92), p = 0.0213). No significant differences in terms of OS were found between FHC-high/low patients (data not shown). After adjusting for primary tumor, sex, treatment-line, number of metastatic sites and ECOG-PS, FHC-high was confirmed an independent predictor of longer OS compared to FHC-negative (HR: 0.57 [95%CI: 0.37-0.88], p = 0.0098). Conclusions: FHC-high seems to be an independent predictor for longer OS in cancer patients treated with anti-PD-1/PD-L1. DNA damage and response (DDR) genes alterations may underlie that results.
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- 2019
28. Anatomic site of metastases can influence response to nivolumab in NSCLC patients
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Michela Roberto, Giulia d'Amati, Federica Mazzuca, Ilaria Grazia Zizzari, Paolo Sciattella, Paolo Marchetti, V. Picone, Bruna Cerbelli, Federica De Galitiis, Marianna Nuti, Giulia Poti, Massimiliano Salati, and Andrea Botticelli
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immune checkpoint inhibitors ,Internal medicine ,Medicine ,Anatomic Site ,Nivolumab ,business - Abstract
e15021Background: Immune checkpoint inhibitors have revolutionized treatment and outcome of NSCLC. Unfortunately, only 25-30% of patients have a long-term benefit, while the remaining 70-75% demons...
- Published
- 2018
29. P3.02c-094 Italian Nivolumab Advanced Squamous NSCLC Expanded Access Program: Efficacy and Safety in Patients with Brain Metastases
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Claudia Proto, Francesco Grossi, Cristina Noberasco, Lucia Bonomi, Antonio Frassoldati, Davide Tassinari, Annamaria Catino, Giovanni Fadda, Diego Cortinovis, Francesco Cognetti, Angelo Delmonte, Maria Rita Migliorino, Francesco Gelsomino, Rita Chiari, Giovanna Finocchiaro, Federica De Galitiis, Marina Gilli, Hector Soto Parra, and Valeria Albanese
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,business.industry ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Expanded access ,Internal medicine ,medicine ,In patient ,Nivolumab ,business - Published
- 2017
30. Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated, metastatic, mucosal melanoma
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Elena Tornari, Lorenza Di Guardo, Vanna Chiarion Sileni, Riccardo Marconcini, Virginia Ferraresi, Federica De Galitiis, Carmen Nuzzo, Gaetana Rinaldi, Michele Del Vecchio, Paolo A. Ascierto, Luana Calabrò, Paolo Marchetti, Paola Queirolo, Jacopo Pigozzo, Alessandro Testori, Michele Maio, Antonio M. Grimaldi, and Pier Francesco Ferrucci
- Subjects
Adult ,Male ,safety ,Cancer Research ,medicine.medical_specialty ,mucosal ,efficacy ,Ipilimumab ,Malignancy ,Gastroenterology ,Drug Administration Schedule ,NO ,Young Adult ,Internal medicine ,Efficacy, Expanded access programme, Ipilimumab, Metastatic melanoma, Mucosal, Safety ,medicine ,Humans ,Stage (cooking) ,Neoplasm Metastasis ,ipilimumab ,Adverse effect ,Melanoma ,Aged ,Response rate (survey) ,Aged, 80 and over ,Mucous Membrane ,business.industry ,expanded access programme ,Mucosal melanoma ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Surgery ,Clinical trial ,Treatment Outcome ,Oncology ,Expanded access ,Disease Progression ,Female ,metastatic melanoma ,business ,Efficacy ,Expanded access programme ,Metastatic melanoma ,Mucosal ,Safety ,medicine.drug - Abstract
Background Mucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma. Methods Ipilimumab was available upon physician request for patients aged ⩾16 years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each scheduled visit. Results Of 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8 months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4 months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines. Conclusion/interpretation Ipilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials.
- Published
- 2014
31. 'Poker' association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study
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Marianna Tudini, Corrado Ficorella, Paola Lanfiuti Baldi, Adelmo Antonucci, Federica De Galitiis, Katia Cannita, A. Santomaggio, Maria Vincenza Mancini, Paolo Marchetti, Enrico Ricevuto, and Gemma Bruera
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Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Time Factors ,Organoplatinum Compounds ,Bevacizumab ,Colorectal cancer ,Phases of clinical research ,Antibodies, Monoclonal, Humanized ,Irinotecan ,lcsh:RC254-282 ,Disease-Free Survival ,Drug Administration Schedule ,Surgical oncology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,medicine ,Humans ,Neoplasm Metastasis ,Aged ,business.industry ,Antibodies, Monoclonal ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Oxaliplatin ,Treatment Outcome ,Research Design ,Fluorouracil ,Camptothecin ,Colorectal Neoplasms ,business ,Research Article ,medicine.drug - Abstract
Background This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC). Methods Simon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks. Results Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%. Conclusion Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered. Trial registration Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34
- Published
- 2010
32. Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP)
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Paola Savoia, Maria Grazia Bernengo, Paolo A. Ascierto, Michele Del Vecchio, Luca Galli, Massimo Aglietta, Giorgio Parmiani, Ruggero Ridolfi, Anna Maria Di Giacomo, Francesco Cognetti, Francesco Giuseppe De Rosa, Alessandro Testori, Mario Mandalà, Michele Guida, Paola Queirolo, Antonio M. Grimaldi, Vanna Chiarion-Sileni, Federica De Galitiis, Gaetana Rinaldi, and Sabino Strippoli
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Phase iii trials ,Metastatic melanoma ,business.industry ,Ipilimumab ,Surgery ,Expanded access ,Internal medicine ,Cohort ,Toxicity ,medicine ,Overall survival ,business ,Advanced melanoma ,medicine.drug - Abstract
9065 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Early clinical studies explored the potential relationship between immune-related adverse events (irAEs) associated with ipilimumab and antitumor activity but no definitive conclusion has been reached. Here, we evaluated the possible correlation between efficacy of ipilimumab treatment and irAEs in patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Pts were monitored for adverse events (AEs), including immune-related AEs (irAEs), using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to April 2012 across 55 centres. Among 833 evaluable pts, 278 pts (33.4%) reported an irAE and 555 (66.6%) did not. As of December 2012, the disease control rates among pts with or without irAEs were 35.3% and 33.9% respectively. We noted that there was a difference in the distribution of pts with or without irAEs among pts who experienced a fast progression, thus not being able to receive at least 3 cycles, and pts with slow progression. In fact, due to the mechanism of action of the drug and consequent delayed onset of irAEs, pts with irAEs among fast and slow progressors were 22% and 37% respectively. Therefore, median overall survival was evaluated by adjusting the 2 groups for this factor and results showed a comparable survival between pts who reported an irAE and pts who did not (10.0 vs 9.7 months respectively). Conclusions: This exploratory analysis of EAP data suggest that activity and efficacy of ipilimumab is not related with the occurrence of irAEs.
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- 2013
33. Efficacy and safety data from elderly patients with pretreated advanced melanoma in the Italian cohort of ipilimumab expanded access programme (EAP)
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Michele Del Vecchio, Vito Vanella, Virginia Ferraresi, Massimo Aglietta, Paolo A. Ascierto, Riccardo Danielli, Laura Ridolfi, Mario Mandalà, Francesco Cognetti, Maria Grazia Bernengo, Michele Guida, Michele Maio, Federica De Galitiis, Emilia Cocorocchio, Paola Queirolo, Giorgio Parmiani, Vanna Chiarion-Sileni, Alessandro Testori, Andrea Antonuzzo, and Jacopo Pigozzo
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Phase iii trials ,Metastatic melanoma ,business.industry ,Ipilimumab ,Surgery ,Internal medicine ,Expanded access ,Cohort ,medicine ,Overall survival ,business ,medicine.drug ,Advanced melanoma - Abstract
9548 Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Here we evaluate the safety and efficacy of ipilimumab treatment outside of clinical trials in elderly (>70 years old) patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ≥16 years with unresectable stage III/IV melanoma who had either failed systemic therapy or were intolerant to ≥1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Disease evaluation was performed at baseline and after completion of induction therapy using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: Out of 855 Italian pts participating in the EAP from June 2010 to January 2012 across 55 centres, 193 (22.6%) were over 70 years old (median 75; 70-88). Of these, 132 pts (68.4%) received all 4 doses of ipilimumab, 24 (12.4%) 3 doses, 17 (8.8%) 2 doses and 20 pts (10.4%) received 1 dose. With a median follow-up of 7.6 months (range 1-26), the disease control rate among 188 pts evaluable for response was 38.3%, including 4 pts (2.1%) with a complete response, 24 (12.8%) with a partial response and 44 (23.4%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.7 months and 8.9 months respectively, with 1-year survival rate of 38%. In total, 96 pts (49.7%) reported an AE of any grade, which were considered treatment-related in 69 pts (35.7%), with a safety profile comparable to the general population. Grade 3/4 AEs were reported by 19 pts (9.8%) and drug-related in 11 pts (5.7%). AEs were generally reversible with treatment as per protocol-specific guidelines with a median time to resolution of 2.0 weeks. Conclusions: Based on the data from EAP, ipilimumab is a feasible treatment in the elderly population; efficacy and safety results were similar to those observed in the general population.
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