Immune-Related Adverse Events (IRAEs) due to Cancer...
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Immune-Related Adverse Events (IRAEs) due to Cancer
Immunotherapy
Philip Mease MDDirector, Rheumatology Clinical Research, Swedish-
Providence St. Joseph HealthClinical Professor, University of Washington
Seattle, Washington
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Disclosures
Research grants, consultation fees, and/or speaker honoraria: Abbvie, Amgen, Boehringer Ingelheim, Bristol Myers, Celgene, Genentech, Janssen, Lilly,
Merck, Novartis, Pfizer, SUN, UCB
Acknowledgments: Len Calabrese (Cleveland Clinic) for use of slides and ideas; Laura Cappelli (Hopkins) for clinical experience, ideas, and case example
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Cancer Immunotherapy 2016
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Immune Checkpoints Regulate Different Components in the Evolution of an Immune Response
Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
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Approved Checkpoint Inhibitors
1. Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2014-2016; 2. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2017; 3. Tecentriq [package insert]. South San Francisco, CA: Genentech, Inc; 2016; 4. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Co; 2015.
Agent Molecular Target Malignancy Approved for Year Approved
Pembrolizumab
(Keytruda)1
PD-1 Non-small cell lung cancer
Melanoma
2015
2014
Nivolumab
(Opdivo)2
PD-1 Hodgkin lymphoma
Renal cell carcinoma
Non-small cell lung cancer
Melanoma
Head and neck
2016
2015
2014
2013
2016
Atezolizumab
(Tecentriq)3
PDL-1 Urothelial carcinoma
Non-small cell lung cancer
2016
Ipilimumab
(Yervoy)4
CTLA-4 Melanoma, in combination with
nivolumab
Melanoma
2014
2011
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Improved Survival with Ipilimumab (Anti-CTLA4) in Patients with Metastatic Melanoma
Hodi FS, et al. N Engl J Med. 2010;363(8):711-723.
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PDLOMAS Activity in 2015
Michot JM, et al. Eur J Cancer. 2016;54:139-148.
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Michot JM, et al. Eur J Cancer. 2016;54:139-148.
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irAEs from Cancer Immunotherapy with Checkpoint Inhibitors
CNS = central nervous system; GI = gastrointestinal; PG = pyoderma gangrenosum; PMR = polymyalgia rheumatica. Adapted from J Am Acad Dermatol. 2016;2(3):264-268.
Rheumatic• Inflammatory
arthritis• Sicca syndrome
• “PMR”• Myositis• VasculitisNeurologic/
OphthalmologicNeuropathies
• Demyelination• Uveitis
• CNS VI & VII paresis• Guillain-Barré
Myasthenia
Renal• Nephritis
Endocrine• Thyroid disease• Hypophysitis
• Adrenal Failure• HypopituitarismInsulin-dependent
diabetes
Pulmonary• Pneumonitis• Sarcoidosis
GI• Colitis
• Hepatitis• Pancreatitis
Cutaneous• Pruritus
• Dermatitis• Vitiligo
• Sarcoidosis• Inverse psoriasiform
eruption• PG
• Sweet’s syndrome
irAEs
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Clinical Characteristics of iRAEs – How to Distinguish from Cancer or Infection Symptoms?
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General Features of Checkpoint Therapy IRAEs
• irAEs occur in up to 90% of patients with CTLA4 and 70% of PDI-treated patients
• Data on irAEs are not uniformly collected, and grading systems are suboptimal
• irAEs may predict favorable response to certain tumors
• Autoantibodies are generally absent
Michot JM, et al. Eur J Cancer. 2016;54:139-148.
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Timeline with AE Checkpoint Inhibitors
Weber JS, et al. J Clin Oncol. 2012; 30:2691-2697.
Dermatologic ++++Gastroenerologic ++++Endocrine +++Neuro/Eye +Rheumatic +Renal +
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irAEs with Checkpoint Inhibitor Therapy
• General – More common with anti-CTLA4 vs anti-PD1– Greater at high doses compared with low doses– More common with combination therapy– Immunosuppressive therapy is often required– Can exacerbate underlying AID?
• Single-center experience with ipilimumab (LD)– Of 298 patients treated with anti-CTLA4, 254 (85%)
developed irAEs and 104 (35%) required therapy– Corticosteroids were needed in 103 patients (35%)– TNFi was needed in 29 patients (10%)
• Combo (CTLA4-Ig and anti-PD1)– irAE 55% - 27% - 15%
TNFi = TNF inhibitor. Horvat TZ, et al. J Clin Oncol. 2015;33:3193-3198.
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Rheumatic Complications
• Rheumatic complications are among the most poorly defined
irAEs, with a prevalence of 5%? Underdiagnosis?
• Severity grading non-standardized
• Arthralgia, arthritis, PMR, GCA, myalgia/myositis, sicca, SLE
• May be transient to chronic
• Often require high-dose glucocorticoids (0.5 to 1.0
mg/kg/day)
• Immunomodulatory therapy being explored on a case by case
basis: oral DMARDs, TNFi, ?abatacept, ?other
– Concern re. blunting or reversal of cancer treatment?
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“We retrospectively characterized the clinical outcomes of 30 patients with preexisting autoimmune disorders who received ipilimumab and observed that 15 patients (50%) experienced irAEs or flares of their underlying autoimmune disorder, which were generally manageable with standard treatment.”
Johnson DB, et al. JAMA Oncol. 2016;2(2):234-240.
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Hopkins Case Example
Case courtesy of Laura Cappelli
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Hopkins Case Example
Case courtesy of Laura Cappelli
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Hopkins Case Example
Case courtesy of Laura Cappelli
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Characteristics of Rheumatologic Complications – Hopkins Experience
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Characteristics of Rheumatologic Complications – Hopkins Experience
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Hopkins Case Example
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Unresolved Questions
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Evolving Paradigms of Care for IRAEs
• Multidisciplinary team care– Identification of clinicians interested in learning
about and caring for IRAEs: Heme-onc, GI, pulmonary, rheumatology, endocrine, dermatology, etc.
– Case conferences, journal clubs
– Studies of care of patients with established autoimmune disease
– Clinical registries
– Partnership with pharma