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.
Late immune-related adverse events in long-term responders to PD-1/PD-L1 checkpoint inhibitors: A multicentre study / Nigro, O.; Pinotti, G.; De Galitiis, F.; Di Pietro, F. R.; Giusti, R.; Filetti, M.; Bersanelli, M.; Lazzarin, A.; Bordi, P.; Catino, A.; Pizzutilo, P.; Galetta, D.; Marchetti, P.; Botticelli, A.; Scagnoli, S.; Russano, M.; Santini, D.; Torniai, M.; Berardi, R.; Ricciuti, B.; De Giglio, A.; Chiari, R.; Russo, A.; Adamo, V.; Tudini, M.; Silva, R. R.; Bolzacchini, E.; Giordano, M.; Di Marino, P.; De Tursi, M.; Rijavec, E.; Ghidini, M.; Vallini, I.; Stucci, L. S.; Tucci, M.; Pala, L.; Conforti, F.; Queirolo, P.; Tanda, E.; Spagnolo, F.; Cecchi, F.; Bracarda, S.; Macrini, S.; Santoni, M.; Battelli, N.; Fargnoli, M. C.; Porzio, G.; Tuzi, A.; Suter, M. B.; Ficorella, C.; Cortellini, A.. - In: EUROPEAN JOURNAL OF CANCER. - ISSN 0959-8049. - 134:(2020), pp. 19-28. [10.1016/j.ejca.2020.04.025]