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Multicenter Study
. 2022 Dec 1;8(12):1794-1801.
doi: 10.1001/jamaoncol.2022.5041.

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

Olivier J van Not  1   2 , Rik J Verheijden  2 , Alfonsus J M van den Eertwegh  3 , John B A G Haanen  4 , Maureen J B Aarts  5 , Franchette W P J van den Berkmortel  6 , Christian U Blank  4   7 , Marye J Boers-Sonderen  8 , Jan-Willem B de Groot  9 , Geke A P Hospers  10 , Anna M Kamphuis  2 , Ellen Kapiteijn  11 , Anne M May  12 , Melissa M de Meza  1   13   14 , Djura Piersma  15 , Rozemarijn van Rijn  16 , Marion A Stevense-den Boer  17 , Astrid A M van der Veldt  18 , Gerard Vreugdenhil  19 , Willeke A M Blokx  20 , Michel J M Wouters  1   13   14 , Karijn P M Suijkerbuijk  2
Affiliations
Multicenter Study

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

Olivier J van Not et al. JAMA Oncol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr van den Eertwegh reported serving on the advisory boards for Bristol Myers Squibb, MSD, Amgen, Pierre Fabre, Roche, Sanofi, Ipsen, Pfizer, Merck, and Novartis; grants from Sanofi, Roche, Bristol Myers Squibb, Idera, and Teva; travel expenses from MSD Oncology, Roche, Pfizer, and Sanofi; and speaker honoraria from Bristol Myers Squibb and Novartis. Prof Haanen reported grants from Asher Bio, Amgen, Bristol Myers Squibb, MSD, BioNTech, Neogene Therapeutics, and Novartis, as well as personal fees from Aimm, Achilles Therapeutics, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, BioNTech, GSK, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Novartis, Neogene Therapeutics, Pfizer, Roche/Genentech, Sanofi, Scenic, Seattle Genetics, Third Rock Ventures, T-Knife, and Vaximm, all paid to institution. Dr Aarts reported consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD/Merck, Merck/Pfizer, Pierre Fabre, Sanofi, Astellas, and Bayer, as well as grants from Merck/Pfizer, all paid to institution. Dr Boers-Sonderen reported consultancy honoraria from Pierre Fabre, MSD, and Novartis. Dr Blank reported grants from Novartis, Bristol Myers Squibb, and NanoString; serving on the advisory boards for Bristol Myers Squibb, MSD, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, and Pierre Fabre; and ownership interest in Uniti Cars, Neon Therapeutics, and Forty Seven. Dr de Groot reported personal fees from Bristol Myers Squibb, MSD, Pierre Fabre, Servier, and Novartis. Dr Hospers reported consultancy honoraria from Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, and Pierre Fabre, as well as grants from Bristol Myers Squibb and Seerave, paid to institution. Dr Kapiteijn reported consultancy honoraria from Bristol Myers Squibb, Novartis, Merck, and Pierre Fabre, as well as grants from Bristol Myers Squibb and Pierre Fabre. Dr Piersma reported personal fees from Novartis, Bristol Myers Squibb, and Pierre Fabre, paid to institution. Dr van Rijn reported consultancy honoraria from Pfizer and an expert meeting fee from Roche. Dr van der Veldt reported consultancy honoraria from Bristol Myers Squibb, MSD, Eisai, Roche, Merck, Sanofi, Pierre Fabre, Pfizer, Ipsen, and Novartis, paid to institution. Dr Suijkerbuijk reported grants from Bristol Myers Squibb, TigaTx, and Philips, as well as personal fees from Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, and AbbVie, paid to institution. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Survival Stratified by Management of Toxic Effects in Patients With Advanced Melanoma Treated With First-line Ipilimumab and Nivolumab
The dashed lines represent the median survivals.
Figure 2.
Figure 2.. Cox Proportional Hazard Model of Survival Stratified by Management of Toxic Effects in Patients With Advanced Melanoma Treated With First-line Ipilimumab and Nivolumab
ECOG PS indicates Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase. To convert LDH to microkatals per liter, multiply by 0.0167.
See this image and copyright information in PMC

Comment in

References

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