Association of Immune-Related Adverse Event Management With Survival in Patients With Advanced Melanoma

Author:

van Not Olivier J.12,Verheijden Rik J.2,van den Eertwegh Alfonsus J. M.3,Haanen John B. A. G.4,Aarts Maureen J. B.5,van den Berkmortel Franchette W. P. J.6,Blank Christian U.47,Boers-Sonderen Marye J.8,de Groot Jan-Willem B.9,Hospers Geke A. P.10,Kamphuis Anna M.2,Kapiteijn Ellen11,May Anne M.12,de Meza Melissa M.11314,Piersma Djura15,van Rijn Rozemarijn16,Stevense-den Boer Marion A.17,van der Veldt Astrid A. M.18,Vreugdenhil Gerard19,Blokx Willeke A. M.20,Wouters Michel J. M.11314,Suijkerbuijk Karijn P. M.2

Affiliation:

1. Scientific Bureau, Dutch Institute for Clinical Auditing, Leiden, the Netherlands

2. Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, the Netherlands

3. Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, the Netherlands

4. Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands

5. Department of Medical Oncology, GROW School for Oncology and Reproduction, Maastricht University Medical Centre+, Maastricht, the Netherlands

6. Department of Medical Oncology, Zuyderland Medical Centre Sittard, Sittard-Geleen, the Netherlands

7. Department of Medical Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands

8. Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands

9. Isala Oncology Center, Zwolle, the Netherlands

10. Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands

11. Department of Medical Oncology, Leiden University Medical Centre, Leiden, the Netherlands

12. Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands

13. Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands

14. Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands

15. Department of Internal Medicine, Medisch Spectrum Twente, Enschede, the Netherlands

16. Department of Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, the Netherlands

17. Department of Internal Medicine, Amphia Hospital, Breda, the Netherlands

18. Departments of Medical Oncology and Radiology and Nuclear Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands

19. Department of Internal Medicine, Maxima Medical Centre, Eindhoven, the Netherlands

20. Department of Pathology, University Medical Centre Utrecht, Utrecht, the Netherlands

Abstract

ImportanceManagement of checkpoint inhibitor–induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti–tumor necrosis factor on checkpoint-inhibitor efficacy.ObjectiveTo determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy.Design, Setting, and ParticipantsThis population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months.Main Outcomes and MeasuresThe PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS.ResultsOf 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P = .01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P = .04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P = .006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P = .05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P = .04) compared with those receiving steroids alone.Conclusions and RelevanceIn this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also other tumor types.

Publisher

American Medical Association (AMA)

Subject

Oncology,Cancer Research

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