Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study: European Journal of Cancer

O. Nigro, G. Pinotti, F. De Galitiis, F.R. Di Pietro, R. Giusti, M. Filetti, M. Bersanelli, A. Lazzarin, P. Bordi, A. Catino, P. Pizzutilo, D. Galetta, P. Marchetti, A. Botticelli, S. Scagnoli, M. Russano, D. Santini, M. Torniai, R. Berardi, B. RicciutiA. De Giglio, R. Chiari, A. Russo, V. Adamo, M. Tudini, R.R. Silva, E. Bolzacchini, M. Giordano, P. Di Marino, M. De Tursi, E. Rijavec, M. Ghidini, I. Vallini, L.S. Stucci, M. Tucci, L. Pala, F. Conforti, P. Queirolo, E. Tanda, F. Spagnolo, F. Cecchi, S. Bracarda, S. Macrini, M. Santoni, N. Battelli, M.C. Fargnoli, G. Porzio, A. Tuzi, M.B. Suter, C. Ficorella, A. Cortellini

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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. © 2020 Elsevier Ltd
Original languageEnglish
Pages (from-to)19-28
Number of pages10
JournalEur. J. Cancer
Publication statusPublished - 2020


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