immune related adverse events (irae) from checkpoint ... · retrospective studies suggest it may be...
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Immune Related Adverse Events (irAE) from Checkpoint Inhibitor
Immunotherapy
Michael Postow, MDMelanoma and Immunotherapeutics Service
Memorial Sloan Kettering Cancer Center
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Disclosures
Advisory Board: Array BioPharma, Aduro, BMS, Incyte, Merck, NewLink Genetics, Novartis
Honoraria: BMS and Merck
Institutional Support: RGenix, Infinity, BMS, Merck, Array BioPharma, Novartis
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Cancer historically understood as disorder of dividing cells
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Cancer historically understood as disorder of dividing cells
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Oncologists stop dividing cells
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What happened in 1891?
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Immunotherapy = Immune cell kills a cancer cell
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Ways to enhance T cell attack
Mellman et al. Nature 2011
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Turning up The Activating
Ways to enhance T cell attack
Mellman et al. Nature 2011
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Turning up The Activating Blocking the Inhibiting
Ways to enhance T cell attack
Mellman et al. Nature 2011
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Turning up The Activating Blocking the Inhibiting
FDA Approved Targets
Mellman et al. Nature 2011
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Oncologists turn up immune system
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What kind of side effects happen?
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All organs can be involved
Postow, Sidlow, Hellmann N Eng J Med 2018
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When do side effects happen?
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Most nivolumab side effects happen in first 3 months
(Any Grade; N = 474)
Weber et al. Journal of Clin Oncol 2016Circles indicate median and bars indicate ranges
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Why do side effects happen?
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Postow, Sidlow, Hellmann N Eng J Med 2018
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Norwood et al. JITC 2017
T cells infiltrating myocardium
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Hematopoietic cell infiltration of the pituitary gland in mice injected with a CTLA-4 blocking antibody
Shintaro Iwama et al., Sci Transl Med 2014;6:230ra45
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Lim et al. Clin Cancer Res 2019
Peripheral cytokines associated with adverse events
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What do I do if I have a problem?
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National Comprehensive Cancer Network (NCCN) Guidelines
www.nccn.org
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www.uptodate.com
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Does immunosuppression hurt immunotherapy
benefit?
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Steroids (to treat side effects) do not seem to affect ipilimumab efficacy
Horvat et al. J Clin Oncol 2015
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Infliximab does not seem to affect efficacy of ipilimumab
Arriola et al. Clin Cancer Res 2015
Retrospective study of 113 patients32 patients with diarrhea (19 patients Grade ≥ 2 diarrhea)
29 patients received steroids7 patients had infliximab
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BUT high dose steroids (>7.5mg daily) for ipilimumab hypophysitis was associated with worse outcomes (n=98)
Faje et al. Cancer 2018
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• Can mechanism based immunosuppression mitigate toxicity from steroids?
• What can toxicities teach us about autoimmune diseases?
• Long-term complications?
Future Questions
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Thank you!
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Back-up slides in case of questions
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What about safety in patients with autoimmune
conditions?
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1. Knowledge is limited since patients with autoimmunity not included in clinical trials
2. Retrospective studies suggest it may be safe
3. Risk/benefit discussion with patients
Kyi and Postow JITC 2014Johnson et al. JAMA Oncol 2016Menzies et al. Annals of Onc 2017
Safety in patients with underlying autoimmunity
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When is it safe to restart immunotherapy after toxicity?
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Santini et al. Cancer Immunol Res 2018
38 patients with NSCLC who discontinued PD1/PDL1 due to toxicity and retreated with PD-1
• 26% recurrence rate of same irAE that caused discontinuation
• 84% improved to grade 1 or resolved but some recurrent toxicities were severe with 2 treatment related deaths
• No clear association between intensity of prior toxicity and likelihood of recurrent toxicity
• No clear benefit to resuming PD-1 in patients who responded prior to initial toxicity
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Immunosuppression does not seem to affect nivolumab efficacy
NIVO monotherapywith
immunosuppression to treat a side effect
N = 139
NIVO monotherapywithout
immunosuppression to treat a side effect
N = 437
ORR, n (%), [95% CI]40 (28.8)
[21.4–37.1]141 (32.3)
[27.9–36.9]
Median duration of response, mo (95% CI)NR
(9.3–NR)22.0
(22.0–NR)
Median time to response, mo (range) 2.1 (1.2–8.8) 2.1 (1.4–9.2)
Weber et al. Journal of Clin Oncol 2016
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Most nivolumab + ipilimumab side effects happen in first 3 months
(Any Grade; N = 448)
Sznol et al. Journal of Clin Oncol 2017
Circles indicate median and bars indicate ranges
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[1] Pollack, Betof, et al. Ann of Oncol 2017
[2] Santini et al. Cancer Immunol Res 2018
80 patients who discontinued CTLA4+PD1 due to toxicity of whom 77 (96% required steroids) [1]
• 18% recurrence rate of same irAE that caused discontinuation
• Some recurrent toxicities were severe
• No clear association between recurrent toxicity and prior steroid duration or use of additional immunosuppression
• Some association with lower recurrent toxicity risk with being off steroids and time since prior toxicity
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Pneumonitis
3/30/20112/21/2011
Two doses of ipilimumab and four of nivolumab
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Sznol et al. Journal of Clin Oncol 2017
Most side effects resolve
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Schadendorf, …. and Postow JCO 2017
Outcomes look similar in patients who discontinue due to toxicity vs. those who
continue treatment longer
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Schadendorf, …. and Postow JCO 2017
Outcomes look similar in patients who discontinue due to toxicity vs. those who
continue treatment longer