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Observational Study
. 2020 Jul:134:19-28.
doi: 10.1016/j.ejca.2020.04.025. Epub 2020 May 23.

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

Olga Nigro  1 , Graziella Pinotti  2 , Federica De Galitiis  3 , Francesca Romana Di Pietro  4 , Raffaele Giusti  5 , Marco Filetti  5 , Melissa Bersanelli  6 , Alessandro Lazzarin  6 , Paola Bordi  6 , Annamaria Catino  7 , Pamela Pizzutilo  7 , Domenico Galetta  7 , Paolo Marchetti  8 , Andrea Botticelli  9 , Simone Scagnoli  9 , Marco Russano  10 , Daniele Santini  10 , Mariangela Torniai  11 , Rossana Berardi  11 , Biagio Ricciuti  12 , Andrea De Giglio  12 , Rita Chiari  13 , Alessandro Russo  14 , Vincenzo Adamo  14 , Marianna Tudini  15 , Rosa Rita Silva  15 , Elena Bolzacchini  16 , Monica Giordano  16 , Pietro Di Marino  17 , Michele De Tursi  18 , Erika Rijavec  19 , Michele Ghidini  19 , Ilaria Vallini  2 , Luigia Stefania Stucci  20 , Marco Tucci  21 , Laura Pala  22 , Fabio Conforti  22 , Paola Queirolo  22 , Enrica Tanda  23 , Francesco Spagnolo  23 , Federica Cecchi  23 , Sergio Bracarda  24 , Serena Macrini  24 , Matteo Santoni  25 , Nicola Battelli  25 , Maria Concetta Fargnoli  26 , Giampiero Porzio  27 , Alessandro Tuzi  2 , Matteo Basilio Suter  2 , Corrado Ficorella  27 , Alessio Cortellini  27
Affiliations
Observational Study

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

Olga Nigro et al. Eur J Cancer. 2020 Jul.

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.

Keywords: Atezolizumab; Immune checkpoint; Immune-related adverse events; Immunotherapy; Nivolumab; Pembrolizumab.

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Conflict of interest statement

Conflict of interest statement A.C. reports having received grants as speaker by MSD and Astra-Zeneca; grant consultancies by BMS, Roche, Novartis, Istituto Gentili and Ipsen. M.B. reports having received research funding by Roche, Pfizer, Seqirus, AstraZeneca, Bristol-Myers Squibb, Novartis and Sanofi; she also received honoraria for advisory role and as speaker at scientific events by Bristol-Myers Squibb, Novartis and Pfizer. M.R. reports having received honoraria for scientific events by Roche, Astrazeneca, Bristol-Myers Squibb, Merck Sharp & Dohme and Boehringer Ingelheim. R.G. reports to be a part of the advisory boards/Honoraria/Speakers’ fee/Consultant for: Astra Zeneca, Roche. All remaining authors declare no conflict of interest.

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