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1. Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case-control matched analysis from a large multicenter study

Author

Cortellini, A, De Giglio, A, Cannita, K, Cortinovis, D, Cornelissen, R, Baldessari, C, Giusti, R, D'Argento, E, Grossi, F, Santoni, M, Catino, A, Berardi, R, Sforza, V, Rossi, G, Antonuzzo, L, Di Noia, V, Signorelli, D, Gelibter, A, Occhipinti, M, Follador, A, Rastelli, F, Chiari, R, Gravara, L, Inno, A, De Tursi, M, Di Marino, P, Mansueto, G, Zoratto, F, Filetti, M, Montrone, M, Citarella, F, Pensieri, M, Russano, M, Cantini, L, Nigro, O, Leonetti, A, Bordi, P, Minuti, G, Landi, L, De Toma, A, Donisi, C, Ricciardi, S, Migliorino, M, Napoli, V, Leone, G, Metro, G, Banna, G, Friedlaender, A, Addeo, A, Ficorella, C, Porzio, G, Cortellini A, De Giglio A, Cannita K, Cortinovis D, Cornelissen R, Baldessari C, Giusti R, D'Argento E, Grossi F, Santoni M, Catino A, Berardi R, Sforza V, Rossi G, Antonuzzo L, Di Noia V, Signorelli D, Gelibter A, Occhipinti MA, Follador A, Rastelli F, Chiari R, Gravara LD, Inno A, De Tursi M, Di Marino P, Mansueto G, Zoratto F, Filetti M, Montrone M, Citarella F, Pensieri MV, Russano M, Cantini L, Nigro O, Leonetti A, Bordi P, Minuti G, Landi L, De Toma A, Donisi C, Ricciardi S, Migliorino MR, Napoli VM, Leone G, Metro G, Banna GL, Friedlaender A, Addeo A, Ficorella C, Porzio G, Cortellini, A, De Giglio, A, Cannita, K, Cortinovis, D, Cornelissen, R, Baldessari, C, Giusti, R, D'Argento, E, Grossi, F, Santoni, M, Catino, A, Berardi, R, Sforza, V, Rossi, G, Antonuzzo, L, Di Noia, V, Signorelli, D, Gelibter, A, Occhipinti, M, Follador, A, Rastelli, F, Chiari, R, Gravara, L, Inno, A, De Tursi, M, Di Marino, P, Mansueto, G, Zoratto, F, Filetti, M, Montrone, M, Citarella, F, Pensieri, M, Russano, M, Cantini, L, Nigro, O, Leonetti, A, Bordi, P, Minuti, G, Landi, L, De Toma, A, Donisi, C, Ricciardi, S, Migliorino, M, Napoli, V, Leone, G, Metro, G, Banna, G, Friedlaender, A, Addeo, A, Ficorella, C, Porzio, G, Cortellini A, De Giglio A, Cannita K, Cortinovis D, Cornelissen R, Baldessari C, Giusti R, D'Argento E, Grossi F, Santoni M, Catino A, Berardi R, Sforza V, Rossi G, Antonuzzo L, Di Noia V, Signorelli D, Gelibter A, Occhipinti MA, Follador A, Rastelli F, Chiari R, Gravara LD, Inno A, De Tursi M, Di Marino P, Mansueto G, Zoratto F, Filetti M, Montrone M, Citarella F, Pensieri MV, Russano M, Cantini L, Nigro O, Leonetti A, Bordi P, Minuti G, Landi L, De Toma A, Donisi C, Ricciardi S, Migliorino MR, Napoli VM, Leone G, Metro G, Banna GL, Friedlaender A, Addeo A, Ficorella C, and Porzio G

Abstract

Background: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy. Results: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking stat

Published
2021

2. Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes

Author

Cortellini, A, Friedlaender, A, Banna, G, Porzio, G, Bersanelli, M, Cappuzzo, F, Aerts, J, Giusti, R, Bria, E, Cortinovis, D, Grossi, F, Migliorino, M, Galetta, D, Passiglia, F, Berardi, R, Mazzoni, F, Di Noia, V, Signorelli, D, Tuzi, A, Gelibter, A, Marchetti, P, Macerelli, M, Rastelli, F, Chiari, R, Rocco, D, Inno, A, Di Marino, P, Mansueto, G, Zoratto, F, Santoni, M, Tudini, M, Ghidini, M, Filetti, M, Catino, A, Pizzutilo, P, Sala, L, Occhipinti, M, Citarella, F, Marco, R, Torniai, M, Cantini, L, Follador, A, Sforza, V, Nigro, O, Ferrara, M, D'Argento, E, Leonetti, A, Pettoruti, L, Antonuzzo, L, Scodes, S, Landi, L, Guaitoli, G, Baldessari, C, Bertolini, F, Della Gravara, L, Dal Bello, M, Belderbos, R, De Filippis, M, Cecchi, C, Ricciardi, S, Donisi, C, De Toma, A, Proto, C, Addeo, A, Cantale, O, Ricciuti, B, Genova, C, Morabito, A, Santini, D, Ficorella, C, Cannita, K, Cortellini A, Friedlaender A, Banna GL, Porzio G, Bersanelli M, Cappuzzo F, Aerts JGJV, Giusti R, Bria E, Cortinovis D, Grossi F, Migliorino MR, Galetta D, Passiglia F, Berardi R, Mazzoni F, Di Noia V, Signorelli D, Tuzi A, Gelibter A, Marchetti P, Macerelli M, Rastelli F, Chiari R, Rocco D, Inno A, Di Marino P, Mansueto G, Zoratto F, Santoni M, Tudini M, Ghidini M, Filetti M, Catino A, Pizzutilo P, Sala L, Occhipinti MA, Citarella F, Marco R, Torniai M, Cantini L, Follador A, Sforza V, Nigro O, Ferrara MG, D'Argento E, Leonetti A, Pettoruti L, Antonuzzo L, Scodes S, Landi L, Guaitoli G, Baldessari C, Bertolini F, Della Gravara L, Dal Bello MG, Belderbos RA, De Filippis M, Cecchi C, Ricciardi S, Donisi C, De Toma A, Proto C, Addeo A, Cantale O, Ricciuti B, Genova C, Morabito A, Santini D, Ficorella C, Cannita K., Cortellini, A, Friedlaender, A, Banna, G, Porzio, G, Bersanelli, M, Cappuzzo, F, Aerts, J, Giusti, R, Bria, E, Cortinovis, D, Grossi, F, Migliorino, M, Galetta, D, Passiglia, F, Berardi, R, Mazzoni, F, Di Noia, V, Signorelli, D, Tuzi, A, Gelibter, A, Marchetti, P, Macerelli, M, Rastelli, F, Chiari, R, Rocco, D, Inno, A, Di Marino, P, Mansueto, G, Zoratto, F, Santoni, M, Tudini, M, Ghidini, M, Filetti, M, Catino, A, Pizzutilo, P, Sala, L, Occhipinti, M, Citarella, F, Marco, R, Torniai, M, Cantini, L, Follador, A, Sforza, V, Nigro, O, Ferrara, M, D'Argento, E, Leonetti, A, Pettoruti, L, Antonuzzo, L, Scodes, S, Landi, L, Guaitoli, G, Baldessari, C, Bertolini, F, Della Gravara, L, Dal Bello, M, Belderbos, R, De Filippis, M, Cecchi, C, Ricciardi, S, Donisi, C, De Toma, A, Proto, C, Addeo, A, Cantale, O, Ricciuti, B, Genova, C, Morabito, A, Santini, D, Ficorella, C, Cannita, K, Cortellini A, Friedlaender A, Banna GL, Porzio G, Bersanelli M, Cappuzzo F, Aerts JGJV, Giusti R, Bria E, Cortinovis D, Grossi F, Migliorino MR, Galetta D, Passiglia F, Berardi R, Mazzoni F, Di Noia V, Signorelli D, Tuzi A, Gelibter A, Marchetti P, Macerelli M, Rastelli F, Chiari R, Rocco D, Inno A, Di Marino P, Mansueto G, Zoratto F, Santoni M, Tudini M, Ghidini M, Filetti M, Catino A, Pizzutilo P, Sala L, Occhipinti MA, Citarella F, Marco R, Torniai M, Cantini L, Follador A, Sforza V, Nigro O, Ferrara MG, D'Argento E, Leonetti A, Pettoruti L, Antonuzzo L, Scodes S, Landi L, Guaitoli G, Baldessari C, Bertolini F, Della Gravara L, Dal Bello MG, Belderbos RA, De Filippis M, Cecchi C, Ricciardi S, Donisi C, De Toma A, Proto C, Addeo A, Cantale O, Ricciuti B, Genova C, Morabito A, Santini D, Ficorella C, and Cannita K.

Abstract

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%. Patients and methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes. Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival. Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.

Published
2020

3. Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation

Author

Cortellini, A, Ricciuti, B, Tiseo, M, Bria, E, Banna, G, Aerts, J, Barbieri, F, Giusti, R, Cortinovis, D, Migliorino, M, Catino, A, Passiglia, F, Torniai, M, Morabito, A, Genova, C, Mazzoni, F, Di Noia, V, Signorelli, D, Gelibter, A, Occhipinti, M, Rastelli, F, Chiari, R, Rocco, D, Inno, A, De Tursi, M, Di Marino, P, Mansueto, G, Zoratto, F, Grossi, F, Filetti, M, Pizzutilo, P, Russano, M, Citarella, F, Cantini, L, Targato, G, Nigro, O, Ferrara, M, Buti, S, Scodes, S, Landi, L, Guaitoli, G, Della Gravara, L, Tabbò, F, Ricciardi, S, De Toma, A, Friedlaender, A, Petrelli, F, Addeo, A, Porzio, G, Ficorella, C, Cortellini A, Ricciuti B, Tiseo M, Bria E, Banna GL, Aerts JG, Barbieri F, Giusti R, Cortinovis D, Migliorino MR, Catino A, Passiglia F, Torniai M, Morabito A, Genova C, Mazzoni F, Di Noia V, Signorelli D, Gelibter A, Occhipinti MA, Rastelli F, Chiari R, Rocco D, Inno A, De Tursi M, Di Marino P, Mansueto G, Zoratto F, Grossi F, Filetti M, Pizzutilo P, Russano M, Citarella F, Cantini L, Targato G, Nigro O, Ferrara MG, Buti S, Scodes S, Landi L, Guaitoli G, Della Gravara L, Tabbò F, Ricciardi S, De Toma A, Friedlaender A, Petrelli F, Addeo A, Porzio G, Ficorella C., Cortellini, A, Ricciuti, B, Tiseo, M, Bria, E, Banna, G, Aerts, J, Barbieri, F, Giusti, R, Cortinovis, D, Migliorino, M, Catino, A, Passiglia, F, Torniai, M, Morabito, A, Genova, C, Mazzoni, F, Di Noia, V, Signorelli, D, Gelibter, A, Occhipinti, M, Rastelli, F, Chiari, R, Rocco, D, Inno, A, De Tursi, M, Di Marino, P, Mansueto, G, Zoratto, F, Grossi, F, Filetti, M, Pizzutilo, P, Russano, M, Citarella, F, Cantini, L, Targato, G, Nigro, O, Ferrara, M, Buti, S, Scodes, S, Landi, L, Guaitoli, G, Della Gravara, L, Tabbò, F, Ricciardi, S, De Toma, A, Friedlaender, A, Petrelli, F, Addeo, A, Porzio, G, Ficorella, C, Cortellini A, Ricciuti B, Tiseo M, Bria E, Banna GL, Aerts JG, Barbieri F, Giusti R, Cortinovis D, Migliorino MR, Catino A, Passiglia F, Torniai M, Morabito A, Genova C, Mazzoni F, Di Noia V, Signorelli D, Gelibter A, Occhipinti MA, Rastelli F, Chiari R, Rocco D, Inno A, De Tursi M, Di Marino P, Mansueto G, Zoratto F, Grossi F, Filetti M, Pizzutilo P, Russano M, Citarella F, Cantini L, Targato G, Nigro O, Ferrara MG, Buti S, Scodes S, Landi L, Guaitoli G, Della Gravara L, Tabbò F, Ricciardi S, De Toma A, Friedlaender A, Petrelli F, Addeo A, Porzio G, and Ficorella C.

Abstract

Background The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression. Methods We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group. Results 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts. Conclusions Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes.

Published
2020

4. Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression >= 50%: a multicenter study with external validation

Author

Cortellini, A, Ricciuti, B, Tiseo, M, Bria, E, Banna, GL, Aerts, Joachim, Barbieri, F, Giusti, R, Cortinovis, DL, Migliorino, MR, Catino, A, Passiglia, F, Torniai, M, Morabito, A, Genova, C, Mazzoni, F, Di Noia, V, Signorelli, D, Gelibter, A, Occhipinti, MA, Rastelli, F, Chiari, R, De Rocco, D, Inno, A, De Tursi, M, Di Marino, P, Mansueto, G, Zoratto, F, Grossi, F, Filetti, M, Pizzutilo, P, Russano, M, Citarella, F, Cantini, Luca, Targato, G, Nigro, O, Ferrara, MG, Buti, S, Scodes, S, Landi, L, Guaitoli, G, Della Gravara, L, Tabbo, F, Ricciardi, S, De Toma, A, Friedlaender, A, Petrelli, F, Addeo, A, Porzio, G, Ficorella, C, Cortellini, A, Ricciuti, B, Tiseo, M, Bria, E, Banna, GL, Aerts, Joachim, Barbieri, F, Giusti, R, Cortinovis, DL, Migliorino, MR, Catino, A, Passiglia, F, Torniai, M, Morabito, A, Genova, C, Mazzoni, F, Di Noia, V, Signorelli, D, Gelibter, A, Occhipinti, MA, Rastelli, F, Chiari, R, De Rocco, D, Inno, A, De Tursi, M, Di Marino, P, Mansueto, G, Zoratto, F, Grossi, F, Filetti, M, Pizzutilo, P, Russano, M, Citarella, F, Cantini, Luca, Targato, G, Nigro, O, Ferrara, MG, Buti, S, Scodes, S, Landi, L, Guaitoli, G, Della Gravara, L, Tabbo, F, Ricciardi, S, De Toma, A, Friedlaender, A, Petrelli, F, Addeo, A, Porzio, G, and Ficorella, C

Published
2020

5. Clinical outcomes of NSCLC patients experiencing early immune-related adverse events to PD-1/PD-L1 checkpoint inhibitors leading to treatment discontinuation.

Author

Russano M, Cortellini A, Giusti R, Russo A, Zoratto F, Rastelli F, Gelibter A, Chiari R, Nigro O, De Tursi M, Bracarda S, Gori S, Grossi F, Bersanelli M, Calvetti L, Di Noia V, Scartozzi M, Di Maio M, Bossi P, Falcone A, Citarella F, Pantano F, Ficorella C, Filetti M, Adamo V, Veltri E, Pergolesi F, Occhipinti MA, Nicolardi L, Tuzi A, Di Marino P, Macrini S, Inno A, Ghidini M, Buti S, Aprile G, Lai E, Audisio M, Intagliata S, Marconcini R, Brocco D, Porzio G, Piras M, Rijavec E, Simionato F, Natoli C, Tiseo M, Vincenzi B, Tonini G, and Santini D

Subjects
B7-H1 Antigen, Humans, Immune Checkpoint Inhibitors adverse effects, Programmed Cell Death 1 Receptor, Retrospective Studies, Antineoplastic Agents, Immunological adverse effects, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
Abstract

Background: The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood., Methods: The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point., Results: Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2-78.8) in the LTD cohort and 32.7% (95% CI 27.8-38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10-5.78], P = .0288)., Conclusions: We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2022
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6. Smoking status during first-line immunotherapy and chemotherapy in NSCLC patients: A case-control matched analysis from a large multicenter study.

Author

Cortellini A, De Giglio A, Cannita K, Cortinovis DL, Cornelissen R, Baldessari C, Giusti R, D'Argento E, Grossi F, Santoni M, Catino A, Berardi R, Sforza V, Rossi G, Antonuzzo L, Di Noia V, Signorelli D, Gelibter A, Occhipinti MA, Follador A, Rastelli F, Chiari R, Gravara LD, Inno A, De Tursi M, Di Marino P, Mansueto G, Zoratto F, Filetti M, Montrone M, Citarella F, Pensieri MV, Russano M, Cantini L, Nigro O, Leonetti A, Bordi P, Minuti G, Landi L, De Toma A, Donisi C, Ricciardi S, Migliorino MR, Napoli VM, Leone G, Metro G, Banna GL, Friedlaender A, Addeo A, Ficorella C, and Porzio G

Subjects
Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Case-Control Studies, Female, Humans, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Survival Analysis, Carcinoma, Non-Small-Cell Lung drug therapy, Immunotherapy methods, Lung Neoplasms drug therapy, Smoking trends
Abstract

Background: Improved outcome in tobacco smoking patients with non-small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first-line immunotherapy in patients with high PD-L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts., Methods: We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first-line pembrolizumab and platinum-based chemotherapy., Results: A total of 962 NSCLC patients with PD-L1 expression ≥50% who received first-line pembrolizumab and 462 NSCLC patients who received first-line platinum-based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15-1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02-1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52-1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45-1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case-control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression-free survival (PFS) (HR = 1.68 [95% CI: 1.17-2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84-2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49-0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45-0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts., Conclusions: Among metastatic NSCLC patients with PD-L1 expression ≥50% receiving first-line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first-line chemotherapy., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Published
2021
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7. Effect of concomitant medications with immune-modulatory properties on the outcomes of patients with advanced cancer treated with immune checkpoint inhibitors: development and validation of a novel prognostic index.

Author

Buti S, Bersanelli M, Perrone F, Tiseo M, Tucci M, Adamo V, Stucci LS, Russo A, Tanda ET, Spagnolo F, Rastelli F, Pergolesi F, Santini D, Russano M, Anesi C, Giusti R, Filetti M, Marchetti P, Botticelli A, Gelibter A, Occhipinti MA, Ferrari M, Vitale MG, Nicolardi L, Chiari R, Rijavec E, Nigro O, Tuzi A, De Tursi M, Di Marino P, Conforti F, Queirolo P, Bracarda S, Macrini S, Gori S, Zoratto F, Veltri E, Di Cocco B, Mallardo D, Vitale MG, Santoni M, Patruno L, Porzio G, Ficorella C, Pinato DJ, Ascierto PA, and Cortellini A

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Prognosis, Reproducibility of Results, Treatment Outcome, Carcinoma, Non-Small-Cell Lung drug therapy, Immune Checkpoint Inhibitors therapeutic use, Immunotherapy methods, Lung Neoplasms drug therapy
Abstract

Background: Concomitant medications are known to impact on clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs). We aimed weighing the role of different concomitant baseline medications to create a drug-based prognostic score., Methods: We evaluated concomitant baseline medications at immunotherapy initiation for their impact on objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) in a single-institution cohort of patients with advanced cancer treated with ICIs (training cohort, N = 217), and a drug-based prognostic score with the drugs resulting significantly impacting the OS was computed. Secondly, we externally validated the score in a large multicenter external cohort (n = 1012)., Results: In the training cohort (n = 217), the median age was 69 years (range: 32-89), and the primary tumours were non-small-cell lung cancer (70%), melanoma (14.7%), renal cell carcinoma (9.2%) and others (6%). Among baseline medications, corticosteroids (hazard ratio [HR] = 2.3; 95% confidence interval [CI]: 1.60-3.30), systemic antibiotics (HR = 2.07; 95% CI: 1.31-3.25) and proton-pump inhibitors (PPIs) (HR = 1.57; 95% CI: 1.13-2.18) were significantly associated with OS. The prognostic score was calculated using these three drug classes, defining good, intermediate and poor prognosis patients. Within the training cohort, OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0297) were significantly distinguished by the score stratification. The prognostic value of the score was also demonstrated in terms of OS (p < 0.0001), PFS (p < 0.0001) and ORR (p = 0.0006) within the external cohort., Conclusion: Cumulative exposure to corticosteroids, antibiotics and PPIs (three likely microbiota-modulating drugs) leads to progressively worse outcomes after ICI therapy. We propose a simple score that can help stratifying patients in routine practice and clinical trials of ICIs., Competing Interests: Conflict of interest statement M.B. reports receiving research funding by Roche, Seqirus, Pfizer and Novartis and personal fees as a speaker/consultant from AstraZeneca, Novartis, Pfizer and BMS. M.T. reports receiving speaker fees and grant consultancies from AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. A.C. reports receiving speaker fees and grant consultancies from Roche, MSD, BMS, AstraZeneca, Novartis and Astellas. R.G. reports receiving speaker fees and grant consultancies from AstraZeneca and Roche. M.G.V. reports receiving speaker fees, grant consultancies and travel support from BMS, Ipsen, Novartis, Pfizer, Astellas, Jansen and Pierre-Fabre. A.R. reports receiving grant consultancies from AstraZeneca and MSD. F.S. reports receiving speaker fees and grant consultancies from Roche, Novartis, BMS, MSD, Pierre-Fabre, Sanofi, Merck and Sunpharma. D.J.P. reports receiving lecture fees from ViiV Healthcare and Bayer Healthcare; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche and AstraZeneca and research funding (to institution) from MSD and BMS. P.A.A. reports receiving speaker fees and grant consultancies from BMS, Roche-Genentech, MSD, Dohme, Array, Novartis, Merck-Serono, Pierre-Fabre, Incyte, New Link Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar and Boehringer-Ingelheim and research funds from BMS, Roche-Genentech and Array. All other authors declared no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Published
2021
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8. Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice.

Author

Cortellini A, Tucci M, Adamo V, Stucci LS, Russo A, Tanda ET, Spagnolo F, Rastelli F, Bisonni R, Santini D, Russano M, Anesi C, Giusti R, Filetti M, Marchetti P, Botticelli A, Gelibter A, Occhipinti MA, Marconcini R, Vitale MG, Nicolardi L, Chiari R, Bareggi C, Nigro O, Tuzi A, De Tursi M, Petragnani N, Pala L, Bracarda S, Macrini S, Inno A, Zoratto F, Veltri E, Di Cocco B, Mallardo D, Vitale MG, Pinato DJ, Porzio G, Ficorella C, and Ascierto PA

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Immune Checkpoint Inhibitors pharmacology, Male, Middle Aged, Retrospective Studies, Young Adult, Immune Checkpoint Inhibitors therapeutic use
Abstract

Background: Concomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors., Methods: We conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids., Results: From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death., Conclusion: We confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects., Competing Interests: Competing interests: AC received speaker fees and grant consultancies from Roche, MSD, BMS, AstraZeneca, Novartis, Astellas. RG received speaker fees and grant consultancies from AstraZeneca and Roche. MGV received speaker fees, grant consultancies and travel support from BMS, Ipsen, Novartis, Pfizer, Astellas, Jansen and Pierre-Fabre. AR received grant consultancies from AstraZeneca and MSD. RM received grant consultancies from Pierre-Fabre, MSD, Incyte, BMS, and Roche. FS received speaker fees and grant consultancies from Roche, Novartis, BMS, MSD, Pierre-Fabre, Sanofi, Merck and Sunpharma. DP received lecture fees from ViiV Healthcare, Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, Astra Zeneca; received research funding (to institution) from MSD, BMS. PAA received speaker fees and grant consultancies from BMS, Roche-Genentech, MSD, Dohme, Array, Novartis, Merck-Serono, Pierre-Fabre, Incyte, New Link Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim; he also received research funds from BMS, Roche-Genentech, Array., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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9. Immune-related Adverse Events of Pembrolizumab in a Large Real-world Cohort of Patients With NSCLC With a PD-L1 Expression ≥ 50% and Their Relationship With Clinical Outcomes.

Author

Cortellini A, Friedlaender A, Banna GL, Porzio G, Bersanelli M, Cappuzzo F, Aerts JGJV, Giusti R, Bria E, Cortinovis D, Grossi F, Migliorino MR, Galetta D, Passiglia F, Berardi R, Mazzoni F, Di Noia V, Signorelli D, Tuzi A, Gelibter A, Marchetti P, Macerelli M, Rastelli F, Chiari R, Rocco D, Inno A, Di Marino P, Mansueto G, Zoratto F, Santoni M, Tudini M, Ghidini M, Filetti M, Catino A, Pizzutilo P, Sala L, Occhipinti MA, Citarella F, Russano M, Torniai M, Cantini L, Follador A, Sforza V, Nigro O, Ferrara MG, D'Argento E, Leonetti A, Pettoruti L, Antonuzzo L, Scodes S, Landi L, Guaitoli G, Baldessari C, Bertolini F, Della Gravara L, Dal Bello MG, Belderbos RA, De Filippis M, Cecchi C, Ricciardi S, Donisi C, De Toma A, Proto C, Addeo A, Cantale O, Ricciuti B, Genova C, Morabito A, Santini D, Ficorella C, and Cannita K

Subjects
Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Drug-Related Side Effects and Adverse Reactions etiology, Female, Follow-Up Studies, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents, Immunological adverse effects, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Squamous Cell drug therapy, Drug-Related Side Effects and Adverse Reactions pathology, Lung Neoplasms drug therapy
Abstract

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Published
2020
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10. Baseline BMI and BMI variation during first line pembrolizumab in NSCLC patients with a PD-L1 expression ≥ 50%: a multicenter study with external validation.

Author

Cortellini A, Ricciuti B, Tiseo M, Bria E, Banna GL, Aerts JG, Barbieri F, Giusti R, Cortinovis DL, Migliorino MR, Catino A, Passiglia F, Torniai M, Morabito A, Genova C, Mazzoni F, Di Noia V, Signorelli D, Gelibter A, Occhipinti MA, Rastelli F, Chiari R, Rocco D, Inno A, De Tursi M, Di Marino P, Mansueto G, Zoratto F, Grossi F, Filetti M, Pizzutilo P, Russano M, Citarella F, Cantini L, Targato G, Nigro O, Ferrara MG, Buti S, Scodes S, Landi L, Guaitoli G, Della Gravara L, Tabbò F, Ricciardi S, De Toma A, Friedlaender A, Petrelli F, Addeo A, Porzio G, and Ficorella C

Subjects
Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized pharmacology, Female, Humans, Male, Middle Aged, Antibodies, Monoclonal, Humanized therapeutic use, B7-H1 Antigen metabolism, Body Mass Index, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Obesity physiopathology
Abstract

Background: The association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression., Methods: We present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group., Results: 962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04-2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37-0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45-0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01-1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49-0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts., Conclusions: Baseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes., Competing Interests: Competing interests: AC received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis and Astellas. JA reports receiving commercial research grants from Amphera and Roche, holds ownership interest (including patents) in Amphera BV, and is a consultant/advisory board member for Amphera, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, MSD and Roche. EB received speakers’ and travels’ fee from MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis and Roche. EB received consultant’s fee from Roche, Pfizer. EB received institutional research grants from Astra-Zeneca, Roche. MT received speaker fees and grant consultancies by Astrazeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda and Pierre Fabre. AM received speaker fees by Astra, Roche, BMS, MSD, Boehringer, Pfizer, Takeda. FM received grant consultancies by MSD and Takeda. RG received speaker fees and grant consultancies by Astrazeneca and Roche. FP received grant consultancies by MSD and Astrazeneca. AF received grant consultancies by Roche, Pfizer, Astellas and BMS. AA received grant consultancies by Takeda, MSD, BMJ, Astrazeneca, Roche and Pfizer. RC received speaker fees by BMS, MSD, Takeda, Pfizer, Roche and Astrazeneca. CG received speaker fees/grant consultancies by Astrazeneca, BMS, Boehringer-Ingelheim, Roche and MSD. MR received honoraria for scientific events by Roche, Astrazeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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11. Evaluation of Second-line Anti-VEGF after First-line Anti-EGFR Based Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Multicenter "SLAVE" Study.

Author

Parisi A, Cortellini A, Cannita K, Venditti O, Camarda F, Calegari MA, Salvatore L, Tortora G, Rossini D, Germani MM, Boccaccino A, Dell'Aquila E, Fulgenzi C, Santini D, Tursi M, Tinari N, Marino PD, Lombardi P, Keränen SR, Álvaro MH, Zurlo IV, Corsi DC, Emiliani A, Zanaletti N, Troiani T, Vitale P, Giampieri R, Merloni F, Occhipinti MA, Marchetti P, Roberto M, Mazzuca F, Ghidini M, Indini A, Garajova I, Zoratto F, Monache SD, Porzio G, and Ficorella C

Abstract

: Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated., Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles., Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7-34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95-1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3-18.1) and 12.7 (95%CI: 8.8-17.5) months, respectively (HR= 1.31 (95%CI: 0.89-1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02-2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99-2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively ( p = 0.0001)., Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed., Competing Interests: Alessio Cortellini received grants as a speaker by MSD and Astra-Zeneca, grant consultancies by BMS, Roche, Novartis and Astellas. Dr. Daniele Rossini received personal fees from Takeda. Dr. Ingrid Garajova received grants as a speaker by Amgen and Takeda. The other authors declare no conflict of interest.

Published
2020
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12. Prognostic clinical factors in patients affected by non-small-cell lung cancer receiving Nivolumab.

Author

Pantano F, Russano M, Berruti A, Mansueto G, Migliorino MR, Adamo V, Aprile G, Gelibter A, Ficorella C, Falcone A, Russo A, Aieta M, Maio M, Martelli O, Barni S, Napolitano A, Roca E, Quadrini S, Iacono D, Russo A, Calvetti L, Occhipinti MA, Cortellini A, Vasile E, Passiglia F, Imperatori M, Calabrò L, Di Giacomo AM, Petrelli F, Pasquini G, Franchina T, Venditti O, Intagliata S, Galvano A, Fioroni I, Vincenzi B, Tonini G, and Santini D

Subjects
Adult, Brain Neoplasms pathology, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Kaplan-Meier Estimate, Liver Neoplasms pathology, Liver Neoplasms secondary, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Pleural Effusion, Malignant complications, Prognosis, Retrospective Studies, Treatment Outcome, Carcinoma, Non-Small-Cell Lung drug therapy, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms drug therapy, Nivolumab therapeutic use
Abstract

Background : Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab. Methods : This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC. Results : Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study. Conclusions : This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.

Published
2020
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13. 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.

Author

Cortellini A, Buti S, Bersanelli M, Giusti R, Perrone F, Di Marino P, Tinari N, De Tursi M, Grassadonia A, Cannita K, Tessitore A, Zoratto F, Veltri E, Malorgio F, Russano M, Anesi C, Zeppola T, Filetti M, Marchetti P, Botticelli A, Cappellini GCA, De Galitiis F, Vitale MG, Rastelli F, Pergolesi F, Berardi R, Rinaldi S, Tudini M, Silva RR, Pireddu A, Atzori F, Iacono D, Migliorino MR, Gelibter A, Occhipinti MA, Martella F, Inno A, Gori S, Bracarda S, Zannori C, Mosillo C, Parisi A, Porzio G, Mallardo D, Fargnoli MC, Tiseo M, Santini D, Ascierto PA, and Ficorella C

Subjects
B7-H1 Antigen genetics, Humans, Immune Checkpoint Inhibitors, Programmed Cell Death 1 Receptor therapeutic use, Retrospective Studies, Antineoplastic Agents, Immunological adverse effects, Neoplasms diagnosis
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., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Published
2020
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14. Early fatigue in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: an insight from clinical practice.

Author

Cortellini A, Vitale MG, De Galitiis F, Di Pietro FR, Berardi R, Torniai M, De Tursi M, Grassadonia A, Di Marino P, Santini D, Zeppola T, Anesi C, Gelibter A, Occhipinti MA, Botticelli A, Marchetti P, Rastelli F, Pergolesi F, Tudini M, Silva RR, Mallardo D, Vanella V, Ficorella C, Porzio G, and Ascierto PA

Subjects
Adult, Aged, Aged, 80 and over, B7-H1 Antigen metabolism, Disease-Free Survival, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Multivariate Analysis, Programmed Cell Death 1 Receptor metabolism, Young Adult, B7-H1 Antigen antagonists & inhibitors, Fatigue etiology, Immunotherapy adverse effects, Practice Patterns, Physicians', Programmed Cell Death 1 Receptor antagonists & inhibitors
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 < 0.0001) and OS (HR = 2.32 [95% CI 1.59-3.38], p < 0.0001) at the multivariate analysis. On the other hand, we found a significant association between the occurrence of early ir-fatigue, ECOG-PS ≥ 2 (p < 0.0001), and disease burden (p = 0.0003). Delayed ir-fatigue was not significantly related to PFS nor OS., 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.

Published
2019
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15. Weight loss and body mass index in advanced gastric cancer patients treated with second-line ramucirumab: a real-life multicentre study.

Author

Parisi A, Cortellini A, Roberto M, Venditti O, Santini D, Dell'Aquila E, Stellato M, Marchetti P, Occhipinti MA, Zoratto F, Mazzuca F, Tinari N, De Tursi M, Iezzi L, Natoli C, Ratti M, Pizzo C, Ghidini M, Porzio G, Ficorella C, and Cannita K

Subjects
Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Chemotherapy, Adjuvant, Disease Progression, Female, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Stomach Neoplasms diagnosis, Stomach Neoplasms mortality, Stomach Neoplasms pathology, Survival Analysis, Treatment Outcome, Weight Loss physiology, Ramucirumab, Antibodies, Monoclonal administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Body Mass Index, Stomach Neoplasms drug therapy, Weight Loss drug effects
Abstract

Aims and Methods: This multicenter retrospective study aims to evaluate the correlations between Body Weight Loss (BWL), Body Mass Index (BMI) and clinical outcomes (ORR, PFS, and OS) of advanced gastric cancer (aGC) patients treated with second-line ramucirumab-based therapy in a "real-life" setting., Results: From December 2014 to October 2018, 101 consecutive aGC patients progressed to a first-line chemotherapy were treated with ramucirumab alone (10.9%) or in combination with paclitaxel (89.1%). Median BMI was 21.2 kg/m 2 and mBWL since first-line treatment commencement was 4.5%. Among 53 patients who underwent primary tumor resection (PTR), 73.6% experienced BWL, while 26.4% did not experience BWL (p = 0.0429). Patients who underwent PTR had a significantly higher probability of experiencing BWL (yes vs no) [OR = 2.35 (95% CI 1.02-5.42), p = 0.0439]. Among the 89 evaluable patients, ORR was 26.9% (95% CI 17.2-40.1). At a median follow-up of 17.3 months, mPFS was 5.4 months (95% CI 3.6-6.8) and mOS was 8.7 months (95% CI 7.3-11.9). In the multivariate analysis, only ECOG-PS and BMI were confirmed independent predictors for shorter PFS [HR = 1.69 (95% CI 1.01-2.82), p = 0.04] [HR = 1.97 (95% CI 1.12-3.46), p = 0.01] and OS [HR = 1.69 (95% CI 1.01-2.83), p = 0.04] [HR = 2.08 (95% CI 1.17-3.70), p = 0.01]., Conclusion: Efficacy of ramucirumab is confirmed in this "real-life" analysis. BWL seems not to have correlations with clinical outcomes in these patients, while BMI and ECOG-PS remain major prognostic factors. A possible explanation for the lack of prognostic effect of BWL might be the proportion of patients subjected to PTR in this series (52.5%).

Published
2019
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16. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable.

Author

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 GC, De Galitiis F, Vitale MG, Rastelli F, Pergolesi F, Berardi R, Rinaldi S, Tudini M, Silva RR, Pireddu A, Atzori F, Chiari R, Ricciuti B, De Giglio A, Iacono D, Gelibter A, Occhipinti MA, Parisi A, Porzio G, Fargnoli MC, Ascierto PA, Ficorella C, and Natoli C

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological pharmacology, Antineoplastic Agents, Immunological therapeutic use, B7-H1 Antigen antagonists & inhibitors, Biomarkers, Tumor, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Molecular Targeted Therapy, Neoplasm Staging, Neoplasms drug therapy, Neoplasms pathology, Obesity epidemiology, Overweight epidemiology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Proportional Hazards Models, Treatment Outcome, Young Adult, Body Mass Index, Neoplasms epidemiology
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 (< 25). A gender analysis was also performed, using the same binomial cut-off. Further subgroup analyses were performed categorizing patients into underweight, normal weight, overweight and obese., Results: Between September 2013 and May 2018, 976 patients were evaluated. The median age was 68 years, male/female ratio was 663/313. Primary tumors were: NSCLC (65.1%), melanoma (18.7%), renal cell carcinoma (13.8%) and others (2.4%). ECOG-PS was ≥2 in 145 patients (14.9%). PD-1/PD-L1 inhibitors were administered as first-line treatment in 26.6% of cases. Median BMI was 24.9: 492 patients (50.6%) were non-overweight, 480 patients (50.4%) were overweight/obese. 25.2% of non-overweight patients experienced irAEs of any grade, while 55.6% of overweight/obese patients (p < 0.0001). ORR was significantly higher in overweight/obese patients compared to non-overweight (p < 0.0001). Median follow-up was 17.2 months. Median TTF, PFS and OS were significantly longer for overweight/obese patients in univariate (p < 0.0001, for all the survival intervals) and multivariate models (p = 0.0009, p < 0.0001 and p < 0.0001 respectively). The significance was confirmed in both sex, except for PFS in male patients (p = 0.0668)., Conclusions: Overweight could be considered a tumorigenic immune-dysfunction that could be effectively reversed by ICIs. BMI could be a useful predictive tool in clinical practice and a stratification factor in prospective clinical trials with ICIs.

Published
2019
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17. Unexpected long survival of brain oligometastatic non-small cell lung cancer (NSCLC) treated with multimodal treatment: a single-center experience and review of the literature.

Author

Onesti CE, Iacono D, Angelini S, Lauro S, Mazzotta M, Occhipinti MA, Giusti R, and Marchetti P

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Fifty percent of the cases are metastatic at diagnosis and about 20% develop brain metastasis. The brain involvement represents a negative prognostic factor. However, some patients could benefit from locoregional treatments of metastatic foci and experience an unexpected long survival or healing. In the previous years some classifications were proposed to identify patients' prognostic category, according to stage of the primary tumor, the timing of metastases occurrence (synchronous or metachronous) and the number of metastatic sites. Several data show a benefit in patients receiving resection of both the primary tumor and brain metastases. Whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) are the selected options in most cases. Overall, literature data showed highly variable outcome, with an overall survival (OS) ranging from 5.9 to 68 months. No data from randomized and homogeneous trials are currently available. Therefore, a growing interest in this field is observed. Different trials investigating the effectiveness of local treatments and studies analyzing biological mechanisms are ongoing. In this report we analyze literature data and we explore the current field of study. Furthermore, we show a single institutional experience of multimodal management of stage IV NSCLC with brain metastases, experiencing an unexpected long survival. We conclude that a better knowledge of this subpopulation of patients and new studies in this field can lead to distinguish the patients who can benefit from local treatment from those with poor prognosis., Competing Interests: The authors have no conflicts of interest to declare.

Published
2016
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