TY - JOUR
T1 - Association of Immune-Related Adverse Event Management With Survival in Patients With Advanced Melanoma
AU - van Not, Olivier J
AU - Verheijden, Rik J
AU - van den Eertwegh, Alfonsus J M
AU - Haanen, John B A G
AU - Aarts, Maureen J B
AU - van den Berkmortel, Franchette W P J
AU - Blank, Christian U
AU - Boers-Sonderen, Marye J
AU - de Groot, Jan-Willem B
AU - Hospers, Geke A P
AU - Kamphuis, Anna M
AU - Kapiteijn, Ellen
AU - May, Anne M
AU - de Meza, Melissa M
AU - Piersma, Djura
AU - van Rijn, Rozemarijn
AU - Stevense-den Boer, Marion A
AU - van der Veldt, Astrid A M
AU - Vreugdenhil, Gerard
AU - Blokx, Willeke A M
AU - Wouters, Michel J M
AU - Suijkerbuijk, Karijn P M
N1 - Publisher Copyright:
© 2022 American Medical Association. All rights reserved.
PY - 2022/12
Y1 - 2022/12
N2 - IMPORTANCE: Management 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.OBJECTIVE: To 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 PARTICIPANTS: This 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 MEASURES: The 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.RESULTS: Of 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 RELEVANCE: In 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.
AB - IMPORTANCE: Management 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.OBJECTIVE: To 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 PARTICIPANTS: This 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 MEASURES: The 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.RESULTS: Of 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 RELEVANCE: In 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.
KW - Antineoplastic Combined Chemotherapy Protocols/adverse effects
KW - Cohort Studies
KW - Female
KW - Humans
KW - Immune System Diseases/chemically induced
KW - Immunosuppressive Agents/therapeutic use
KW - Ipilimumab/adverse effects
KW - Male
KW - Melanoma/pathology
KW - Middle Aged
KW - Nivolumab/therapeutic use
KW - Retrospective Studies
KW - Steroids/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85144586761&partnerID=8YFLogxK
U2 - 10.1001/jamaoncol.2022.5041
DO - 10.1001/jamaoncol.2022.5041
M3 - Article
C2 - 36301521
SN - 2374-2445
VL - 8
SP - 1794
EP - 1801
JO - JAMA Oncology
JF - JAMA Oncology
IS - 12
ER -