Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis

Ahmad A. Tarhini; Ni Kang; Sandra J. Lee; F. Stephen Hodi; Gary I. Cohen; Omid Hamid; Laura F. Hutchins; Jeffrey A. Sosman; Harriet M. Kluger; Zeynep Eroglu; Henry B. Koon; Donald P. Lawrence; Kari L. Kendra; David R. Minor; Carrie B. Lee; Mark R. Albertini; Lawrence E. Flaherty; Teresa M. Petrella; Howard Streicher; Vernon K. Sondak; John M. Kirkwood

doi:10.1136/jitc-2021-002535

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis

Ahmad A. Tarhini^*, Ni Kang, Sandra J. Lee, F. Stephen Hodi, Gary I. Cohen, Omid Hamid, Laura F. Hutchins, Jeffrey A. Sosman, Harriet M. Kluger, Zeynep Eroglu, Henry B. Koon, Donald P. Lawrence, Kari L. Kendra, David R. Minor, Carrie B. Lee, Mark R. Albertini, Lawrence E. Flaherty, Teresa M. Petrella, Howard Streicher, Vernon K. SondakJohn M. Kirkwood

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Background The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. Patients and methods E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Results Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Conclusions Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.

Original language	English (US)
Article number	e002535
Journal	Journal for immunotherapy of cancer
Volume	9
Issue number	5
DOIs	https://doi.org/10.1136/jitc-2021-002535
State	Published - May 7 2021

Funding

Competing interests AT reports grants from National Cancer Institute, National Institute of Health, ECOGACRIN, grants from Bristol Myers Squibb, during the conduct of the study; grants from Bristol Myers Squibb, personal fees from Bristol Myers Squibb, grants from Merck, personal fees from Merck, personal fees from Novartis, personal fees from Genentech-Roche, personal fees from Array Biopharma, grants from Incyte, personal fees from Incyte, personal fees from NEWLINK Genetics, personal fees from HUYA, personal fees from BioNTech, grants from Prometheus, personal fees from Immunocore, grants from Greenpeptide, grants from Amgen, outside the submitted work. SJL has nothing to disclose. FSH reports clinical trial support from Eastern Cooperative Oncology Group, during the conduct of the study; grants, personal fees and other from Bristol Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants and personal fees from Novartis, personal fees from Takeda, personal fees from Surface, personal fees from Genentech/Roche, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Bayer, personal fees from Aduro, personal fees from Partners Therapeutics, personal fees from Sanofi, personal fees from Pfizer, personal fees from Pionyr, from 7 Hills Pharma, personal fees from Verastem, other from Torque, personal fees from Rheos, outside the submitted work; in addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and Uses Thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immunecheckpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent Therapeutic Peptides Patent number: 9402905 issued, and a patent Methods of Using Pembrolizumab and Trebananib pending. GC has nothing to disclose. OH reports personal fees from BMS, during the conduct of the study; and Contracted Research for Institution: Amgen, Arcus, Astellas, AstraZeneca, BMS, Celldex, CytomX,Genentech, GSK, Immunocore, Incyte, Iovance, Merck, Merck Serono, MedImmune,Nextcure, Novartis, Parker, Pfizer, Polynoma, Regeneron and Roche. LFH has nothing to disclose. JAS reports personal fees from BMS, personal fees from Array, personal fees from Curis, personal fees from MSD, personal fees from Roche, outside the submitted work. HMK reports grants from Merck, grants from Bristol Myers Squibb, grants from Apexigen, personal fees from Regeneron, personal fees from Alexion, personal fees from Prometheus, personal fees from Corvus, personal fees from Nektar, personal feesfrom Biodesix, personal fees from Roche-Genentech, personal fees from Pfizer, personal fees from lovance, personal fees from lmmunocore, personal fees from Celldex, outside the submitted work. HBK reports grants from BMS, during the conduct of the study; other from BMS, outside the submitted work; and he is currently employed by BMS. DPL has nothing to disclose. KLK reports clinical trial support from Immunocore, clinical trial support from Medspace, clinical trial support from Regeneron, clinical trial support from Novartis, grants from BMS, clinical trial support from GlaxoSmithKline, clinical trial support from Karyopharm, grants from Merck outside the submitted work. DRM reports stock ownership from Nektar, Inc and BMS outside of submitted work. CL reports personal fees from Delcath, Inc, outside the submitted work. MRA reports grants from NIH, during the conduct of the study; research collaboration with Bristol Myers Squibb and Apeiron Biologics, outside the submitted work. LF has nothing to disclose. ZE reports advisory role with Array, Regeneron, and Compugen and grants from Novartis, outside the submitted work. TMP reports personal fees from BMS, personal fees from Merck, during the conduct of the study; grants and personal fees from Novartis, grants from Roche, personal fees from Sanofi Genzyme, outside the submitted work. HS has nothing to disclose. VKS reports personal fees from Merck, Bristol Myers Squibb, Novartis, Array, Polynoma, Pfizer and Regeneron, outside the submitted work. JMK reports grants and personal fees from BMS, grants and personal fees from Immunocore, personal fees from Novartis, personal fees from Iovance, grants from Merck, personal fees from Amgen, grants from Checkmate, personal fees from Elsevier, outside the submitted work. Contributors Conception and design: AT, SJL and NK. Provision of study material or patients: AT, JMK, FSH, VKS, GC, OH, LFH, JAS, HK, ZE, HBK, DPL, KK, DRM, CBL, MRA, LF and TMP. Collection and assembly of data: AT, JMK, SJL, FSH, VKS, GC, OH, LFH, JAS, HK, ZE, HK, DPL, KK, DRM, CBL, MRA, LF and TMP. Data analysis: AT, SL and NK. Data interpretation: AT, SL, NK, FSH, JMK, VKS, GC, OH, LFH, JAS, HK, ZE, HK, DPL, KK, DRM, CBL, MRA, LF and TMP. Manuscript writing: all authors. Final approval of manuscript: all authors. Accountable for all aspects of the work: all authors. Funding This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J O'Dwyer, MD, and Mitchell D Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, U10180794, U10CA180821, U10CA180863, U10CA180888, UG1CA189859, UG1CA233163, UG1CA233180, UG1CA233184, UG1CA233196, UG1CA233234, UG1CA233237, UG1CA233270, UG1CA233331, UG1CA233373, UG1CA233320, UG1CA233337, Canadian Cancer Society #704 970. This study was also supported by Bristol-Myers Squibb.

Keywords

melanoma

ASJC Scopus subject areas

Molecular Medicine
Oncology
Cancer Research
Immunology and Allergy
Pharmacology
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/jitc-2021-002535

Cite this

Tarhini, A. A., Kang, N., Lee, S. J., Hodi, F. S., Cohen, G. I., Hamid, O., Hutchins, L. F., Sosman, J. A., Kluger, H. M., Eroglu, Z., Koon, H. B., Lawrence, D. P., Kendra, K. L., Minor, D. R., Lee, C. B., Albertini, M. R., Flaherty, L. E., Petrella, T. M., Streicher, H., ... Kirkwood, J. M. (2021). Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis. Journal for immunotherapy of cancer, 9(5), Article e002535. https://doi.org/10.1136/jitc-2021-002535

@article{8ca0c42b5421476fa0f9d84e71b5d26f,

title = "Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis",

abstract = "Background The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. Patients and methods E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Results Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Conclusions Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.",

keywords = "melanoma",

author = "Tarhini, {Ahmad A.} and Ni Kang and Lee, {Sandra J.} and Hodi, {F. Stephen} and Cohen, {Gary I.} and Omid Hamid and Hutchins, {Laura F.} and Sosman, {Jeffrey A.} and Kluger, {Harriet M.} and Zeynep Eroglu and Koon, {Henry B.} and Lawrence, {Donald P.} and Kendra, {Kari L.} and Minor, {David R.} and Lee, {Carrie B.} and Albertini, {Mark R.} and Flaherty, {Lawrence E.} and Petrella, {Teresa M.} and Howard Streicher and Sondak, {Vernon K.} and Kirkwood, {John M.}",

note = "Publisher Copyright: {\textcopyright} 2020 Author(s). Published by BMJ.",

year = "2021",

month = may,

day = "7",

doi = "10.1136/jitc-2021-002535",

language = "English (US)",

volume = "9",

journal = "Journal for immunotherapy of cancer",

issn = "2051-1426",

publisher = "BMJ Publishing Group",

number = "5",

}

Tarhini, AA, Kang, N, Lee, SJ, Hodi, FS, Cohen, GI, Hamid, O, Hutchins, LF, Sosman, JA, Kluger, HM, Eroglu, Z, Koon, HB, Lawrence, DP, Kendra, KL, Minor, DR, Lee, CB, Albertini, MR, Flaherty, LE, Petrella, TM, Streicher, H, Sondak, VK & Kirkwood, JM 2021, 'Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis', Journal for immunotherapy of cancer, vol. 9, no. 5, e002535. https://doi.org/10.1136/jitc-2021-002535

TY - JOUR

T1 - Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome

T2 - ECOG-ACRIN E1609 study analysis

AU - Tarhini, Ahmad A.

AU - Kang, Ni

AU - Lee, Sandra J.

AU - Hodi, F. Stephen

AU - Cohen, Gary I.

AU - Hamid, Omid

AU - Hutchins, Laura F.

AU - Sosman, Jeffrey A.

AU - Kluger, Harriet M.

AU - Eroglu, Zeynep

AU - Koon, Henry B.

AU - Lawrence, Donald P.

AU - Kendra, Kari L.

AU - Minor, David R.

AU - Lee, Carrie B.

AU - Albertini, Mark R.

AU - Flaherty, Lawrence E.

AU - Petrella, Teresa M.

AU - Streicher, Howard

AU - Sondak, Vernon K.

AU - Kirkwood, John M.

PY - 2021/5/7

Y1 - 2021/5/7

N2 - Background The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. Patients and methods E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Results Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Conclusions Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.

AB - Background The impact of immune-related adverse events (irAEs) occurring from adjuvant use of immunotherapy and of their management on relapse-free survival (RFS) and overall survival (OS) outcomes is currently not well understood. Patients and methods E1609 enrolled 1673 patients with resected high-risk melanoma and evaluated adjuvant ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus interferon-α. We investigated the association of irAEs and of use of immunosuppressants with RFS and OS for patients treated with ipilimumab (n=1034). Results Occurrence of grades 1-2 irAEs was associated with RFS (5 years: 52% (95% CI 47% to 56%) vs 41% (95% CI 31% to 50%) with no AE; p=0.006) and a trend toward improved OS (5 years: 75% (95% CI 71% to 79%) compared with 67% (95% CI 56% to 75%) with no AE; p=0.064). Among specific irAEs, grades 1-2 rash was most significantly associated with RFS (p=0.002) and OS (p=0.003). In multivariate models adjusting for prognostic factors, the most significant associations were seen for grades 1-2 rash with RFS (p<0.001, HR=0.70) and OS (p=0.01, HR=0.71) and for grades 1-2 endocrine+rash with RFS (p<0.001, HR=0.66) and OS (p=0.008, HR=0.7). Overall, grades 1-2 irAEs had the best prognosis in terms of RFS and OS and those with grades 3-4 had less RFS benefits and no OS advantage over no irAE. Patients experiencing grades 3-4 irAE had significantly higher exposure to corticosteroids and immunosuppressants than those with grades 1-2 (92% vs 60%; p<0.001), but no significant associations were found between corticosteroid and immunosuppressant use and RFS or OS. In investigating the impact of non-corticosteroid immunosuppressants, although there were trends toward better RFS and OS favoring cases who were not exposed, no significant associations were found. Conclusions Rash and endocrine irAEs were independent prognostic factors of RFS and OS in patients treated with adjuvant ipilimumab. Patients experiencing lower grade irAEs derived the most benefit, but we found no significant evidence supporting a negative impact of high dose corticosteroids and immunosuppressants more commonly used to manage grades 3-4 irAEs.

KW - melanoma

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U2 - 10.1136/jitc-2021-002535

DO - 10.1136/jitc-2021-002535

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C2 - 33963015

AN - SCOPUS:85105687692

SN - 2051-1426

VL - 9

JO - Journal for immunotherapy of cancer

JF - Journal for immunotherapy of cancer

IS - 5

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ER -

Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis

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