Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

Rik J. Verheijden, Anne M. May, Christian U. Blank, Astrid A. M. van der Veldt, Marye J. Boers-Sonderen, Maureen J. B. Aarts, Franchette W. P. J. van den Berkmortel, Alfonsus J. M. van den Eertwegh, Jan Willem B. de Groot, Jacobus J. M. van der Hoeven, Geke A. P. Hospers, Djura Piersma, Rozemarijn S. van Rijn, Albert J. ten Tije, Gerard Vreugdenhil, Michiel C. T. van Zeijl, Michel W. J. M. Wouters, John B. A. G. Haanen, Ellen Kapiteijn, Karijn P. M. Suijkerbuijk

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Background Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now. Methods Risk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry. Results 111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RR adj) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RR adj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs. Conclusion In patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found.
Original languageEnglish
Article number000945
JournalESMO open
Issue number6
Publication statusPublished - 16 Nov 2020


  • DMTR
  • anti-PD1
  • checkpoint inhibition
  • immune-related adverse event (irAE)
  • melanoma

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