Olga Nigro1, Graziella Pinotti2, Federica De Galitiis3, Francesca Romana Di Pietro4, Raffaele Giusti5, Marco Filetti5, Melissa Bersanelli6, Alessandro Lazzarin6, Paola Bordi6, Annamaria Catino7, Pamela Pizzutilo7, Domenico Galetta7, Paolo Marchetti8, Andrea Botticelli9, Simone Scagnoli9, Marco Russano10, Daniele Santini10, Mariangela Torniai11, Rossana Berardi11, Biagio Ricciuti12, Andrea De Giglio12, Rita Chiari13, Alessandro Russo14, Vincenzo Adamo14, Marianna Tudini15, Rosa Rita Silva15, Elena Bolzacchini16, Monica Giordano16, Pietro Di Marino17, Michele De Tursi18, Erika Rijavec19, Michele Ghidini19, Ilaria Vallini2, Luigia Stefania Stucci20, Marco Tucci21, Laura Pala22, Fabio Conforti22, Paola Queirolo22, Enrica Tanda23, Francesco Spagnolo23, Federica Cecchi23, Sergio Bracarda24, Serena Macrini24, Matteo Santoni25, Nicola Battelli25, Maria Concetta Fargnoli26, Giampiero Porzio27, Alessandro Tuzi2, Matteo Basilio Suter2, Corrado Ficorella27, Alessio Cortellini27. 1. Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy. Electronic address: nigro.olga3@gmail.com. 2. Medical Oncology, ASST Sette Laghi, Ospedale di Circolo e Fondazione Macchi, Varese, Italy. 3. Oncologia Ed Oncologia Dermatologica, IDI-IRCCS, Roma, Italy. 4. Oncologia Ed Oncologia Dermatologica, IDI-IRCCS, Roma, Italy; Medical Oncology, Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Italy. 5. Medical Oncology, Azienda Ospedaliero-Universitaria Sant'Andrea, Roma, Italy. 6. Medical Oncology, Azienda Ospedaliero-Universitaria di Parma, Italy. 7. Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy. 8. Oncologia Ed Oncologia Dermatologica, IDI-IRCCS, Roma, Italy; Dipartimento di Scienze Medico-Chirurgiche e Medicina Traslazionale Università "La Sapienza" Roma, Italy. 9. Dipartimento di Scienze Medico-Chirurgiche e Medicina Traslazionale Università "La Sapienza" Roma, Italy. 10. Medical Oncology, Campus Bio-Medico, Roma, Italy. 11. Clinica Oncologica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, GM Lancisi, G Salesi, Ancona, Italy. 12. Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy. 13. Medical Oncology, Ospedali Riuniti Padova Sud "Madre Teresa Di Calcutta", Monselice, Italy. 14. Medical Oncology, A.O. Papardo & Department of Human Pathology, University of Messina, Italy. 15. Medical Oncology, ASUR Marche, Area Vasta 2, Fabriano, Italy. 16. Medical Oncology, ASST Lariana, Ospedale Sant'Anna, Como, Italy. 17. Clinical Oncology Unit, S.S. Annunziata Hospital, Chieti, Italy. 18. Department of Medical, Oral and Biotechnological Sciences, University G. D'Annunzio, Chieti-Pescara, Italy. 19. Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 20. Medical Oncology Unit, University of Bari, Department of Biomedical Sciences and Human Oncology, Bari, Italy. 21. Medical Oncology Unit, University of Bari, Department of Biomedical Sciences and Human Oncology, Bari, Italy; National Cancer Research Center, Tumori Institute Giovanni Paolo II, Bari, Italy. 22. Division of Medical Oncology for Melanoma, Sarcoma, and Rare Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy. 23. IRCCS Ospedale Policlinico San Martino, Genova, Italy. 24. Department of Medical Oncology, "Santa Maria" Hospital, Terni, Italy. 25. Department of Oncology, Macerata Hospital, Macerata, Italy. 26. Department of Dermatology, St. Salvatore Hospital, L'Aquila, Italy; Department of Biotechnology and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. 27. Department of Dermatology, St. Salvatore Hospital, L'Aquila, Italy; Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy.
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.
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.
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