Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study. (July 2020)

• Record Type: Journal Article
• Authors: Nigro, Olga; Pinotti, Graziella; De Galitiis, Federica; Di Pietro, Francesca Romana; Giusti, Raffaele; Filetti, Marco; Bersanelli, Melissa; Lazzarin, Alessandro; Bordi, Paola; Catino, Annamaria; Pizzutilo, Pamela; Galetta, Domenico; Marchetti, Paolo; Botticelli, Andrea; Scagnoli, Simone; Russano, Marco; Santini, Daniele; Torniai, Mariangela; Berardi, Rossana; Ricciuti, Biagio; De Giglio, Andrea; Chiari, Rita; Russo, Alessandro; Adamo, Vincenzo; Tudini, Marianna; Silva, Rosa Rita; Bolzacchini, Elena; Giordano, Monica; Di Marino, Pietro; De Tursi, Michele; Rijavec, Erika; Ghidini, Michele; Vallini, Ilaria; Stucci, Luigia Stefania; Tucci, Marco; Pala, Laura; Conforti, Fabio; Queirolo, Paola; Tanda, Enrica; Spagnolo, Francesco; Cecchi, Federica; Bracarda, Sergio; Macrini, Serena; Santoni, Matteo; Battelli, Nicola; Fargnoli, Maria Concetta; Porzio, Giampiero; Tuzi, Alessandro; Suter, Matteo Basilio; Ficorella, Corrado; Cortellini, Alessio;
• Is Part Of: European journal of cancer. Volume 134(2020)
• Page Start: 19
• Page End: 28
• Publication Date: 2020-07
• Subjects: Immunotherapy -- Immune checkpoint -- Nivolumab -- Pembrolizumab -- Atezolizumab -- Immune-related adverse events; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2020.04.025
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking. Methods: We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months). Results: From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p < 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI]: 2.8–4.2), whereas 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 (hazard ratio [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). In addition, the time-adjusted cumulative risk of death in accordance with 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. Conclusion: 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. Highlights: Clinical trial adverse events methods do not consider the duration of treatment. Study confirms spectrum of immune-related adverse events (irAEs) described in clinical trials and real-life studies. Among late-irAEs, cutaneous, endocrine and gastrointestinal were the most common. Early-irAEs were not related with progression-free survival and overall survival, late-irAEs were associated with them. Time-adjusted progression risk was not reduced in accordance with early- and late-irAEs.