Immune-related adverse events and management
Seoul National University Hospital Department of Internal Medicine
Tae Min Kim
Introdcution
Cancer immunotherapy
Nat Rev Drug Discov 2011;10:591
2014-2015 FDA approval of nivolumab for
melanoma/SqNSCLC and pembrolizumab for melanoma/NSCLC FDA breakthrough therapy for CTL019
http://bcove.me/1xr0xjty
T-cell activation and immune tolerance
T-cell activation Immune tolerance by CTLA-4
• Initial signal: tumor-associated antigen (TAA) bound to MHC on APC
• Second (co-stimulatory) signal: binding of CD28 on T-cell wit B7 on APC → PI3K/AKT activation & Bcl-2/Bcl-xL upregulation → T-cell activation
• TCR activation → CTLA-4 upregulation → exocytosis of CTLA-4 containing vesicles → CTLA-4 phosphorylation prevents AP-2 binding → CTLA-4 surface expression↑ → Competing with CD28 for B7 binding
Clin Cancer Res 2011;17:4622
TGN1412 disaster (1)
N Engl J Med 2006;355:1018
• Trial conduct
– TeGenero sponsored/Parexel International conducted phase I trial
– TGN1412: a novel superagonist anti-CD28 MAB, humanized, IgG4κ
TGN1412 disaster (2)
N Engl J Med 2006;355:1018
‘Elephant Man’ drug trial victim set to win £2 million
payout for horrific injuries…. "He lost all his toes and the tops of some of his fingers. He cannot walk unaided and because the skin won't heal properly on his left foot he still cannot have prosthetics fitted.“
- News last updated at 7:36 AM on 29
thApril 2008
BMJ 2007;334:566
Cytokine release syndrome
Nat Rev Drug Discov 2010;9:325
CD3-specific muromonab, CD52-specific alemtuzumab, CD20-specific rituximab
CD19 CAR T-cell therapy
Immune checkpoints regulation
Nat Rev Cancer 2012;12:252 Signal dampener at initial stage
Signal dampener in peripheral tissues
Immune-related adverse events
Immune-related adverse events
Ipilimumab
J Clin Oncol 2012;30:2691
빈도 시기 임상/병리학적 양상
Skin/mucosa 47-68% 3.6 주 - Diffuse, maculopapular rash, pruritus - CD4+ and melan-A-specific CD8+ T cells
Diarrhea/colitis 44% 6-7 주
-Diarrhea, abdominal pain, bloody or mucous stool, bowel perforation, peritoneal signs, ileus
-Neutrophilic (46%), lymphocytic (15%), or mixed (38%) infiltrations
Hepatotoxicity 3-9% 6-7 주 - Asymptomatic increase of bilirubin and transaminases - Diffuse T-cell infiltration
Hypophysitis 1-6% 6 주
- Headache, nausea, vertigo, behavior change, visual disturbance
- Enlarged or inhomogenous pituitary gland on MRI
http://www.yervoy.com/hcp/rems.aspx
Clinical trial results of PD-1 pathway inhibitors
Prior to Dec 2015
N=5,118
Cancer Treat Rev 2016;45:7
Pooled incidences of adverse drug reactions
Cancer Treat Rev 2016;45:7
Incidences of immune-related adverse events
Cancer Treat Rev 2016;45:7
Immune-related adverse events
Anti-PD-1 antibodies
Immune-related adverse events
Skin events
Skin irAEs of immune checkpoint blockade
Curr Opin Oncol 2016;28:254 Grade 1 pruritic maculopapular rash Grade 2 pruritic maculopapular rash
Skin irAEs of immune checkpoint blockade
Lichenoid dermatitis
Curr Opin Oncol 2016;28:254
Diffuse Localized
Skin irAEs of immune checkpoint blockade
Psoriasis
Curr Opin Oncol 2016;28:254 Inverse psoriasiform eruption Acral lesion of psoriasis
Acral lesion of psoriasis
Skin irAEs of immune checkpoint blockade
Vitiligo
Curr Opin Oncol 2016;28:254 Generalized Eyelash and eyebrow hair depigementation
Pembrolizumab and cutaneous AEs (1)
JAMA Dermatol 2015;151:1206
• UCSF retrospective cohort in NCT01295827 and NCT0186319 (N=83)
• Median follow-up 15 weeks (range, 2-105 weeks)
• Median cycle 6 (range, 1-51 cycles)
Macular papular eruption Macular papular eruption
Hypopigmentation (vitiligo) Scaly macular papular eruption
JAMA Dermatol 2015;151:1206
Pembrolizumab and cutaneous AEs (2)
JAMA Dermatol 2015;151:1206
Melanoma treated with PD-L1 inhibitor plus TKI
72/F
• Melanoma (rectum, wild-type BRAF/NRAS), M/spleen, LNs s/p Excision (13.12.18)
s/p CVD#4 (14.7.28-10.17)→SD, PD
• C1D1 14.12.16 / C19D1 16.6.3
• Best response: PR
Baseline After cycle 2 After cycle 10
Melanoma treated with PD-L1 inhibitor plus TKI
72/F, at 9
thcycle
Which type of skin adverse events?
1. Maculopapular rashes 2. Lichenoid dermatitis 3. Vitiligo
4. Psoriasis
5. Pruritus
Immune-related adverse events
Pulmonary events
Pneumonitis of immune checkpoint blockade
Curr Opin Oncol 2016;28:269
PD-1 inhibitors
Pneumonitis of immune checkpoint blockade
Curr Opin Oncol 2016;28:269
CTLA-4 inhibitors
PD-L1 inhibitors
Pneumonitis management
Cancer Treat Rev 2016;44:51
Immune-related adverse events
Endocrine events
Endocrine irAEs
Curr Opin Oncol 2016;28:278
Endocrine irAEs
Hypophysitis uder ipilimumab
Curr Opin Oncol 2016;28:278
Metastatic NSCLC treated with pembrolizumab
68/M
Baseline PR after 2 cycles: -68.2% reduction
At 8
thcycle, new-onset type 1 DM was diagnosed and he admitted via
emergency department due to diabetic ketoacidosis (c-peptide < 0.1 ng/mL).
At 20
thcycle, hypothyroidism was diagnosed
Diagnosis and prevention of irAEs
Cancer Treat Rev 2016;45:7
