2018 03 13 GIM SPR Teaching Immunotherapy Management

Immuno-Oncology Adverse Event
Management
Why is it different?
Why is it important?
Dr Avinash Gupta
Consultant in Medical Oncology
Melanoma Team – Christie NHS Foundation Trust
The Era of Immunotherapy
Cancer Type Approved Immunotherapy Drug
Melanoma Ipilimumab, Nivolumab, Pembrolizumab
Lung cancer Nivolumab, Pembrolizumab
Renal cancer Nivolumab
Urothelial cancer Nivolumab, Pembrolizumab,
Atezolizumab, Avelumab, Durvalumab
Hodgkins’s lymphoma Nivolumab, Pembrolizumab
Head & Neck cancer Nivolumab
Merkel cell cancer Avelumab
CTLA-4 inhibitor PD-1 inhibitor PDL-1 inhibitor

Generally administered intravenously every 2-3 weeks
Mechanism of action of ipilimumab
A B C
APC APC APC
MHC MHC MHC
Signal 1
Signal 1
Signal 1
B7 B7 B7 Ipilimumab
Signal
Signal
Signal
Ag Ag Ag
CD28 CTLA4 CTLA4 CD28

CD28 CTLA4
2
2
TCR TCR TCR
T - cell T - cell T - cell
T-cell proliferation, T-cell downregulation Restoration of

differentiation and functional T-cell proliferation,
and survival inactivation differentiation and survival
Figure 1. A: Activation of T-cells requires 2 signals; presentation of antigen to TCR by MHC and interaction between co-stimulatory
molecule B7 and CD28. B: T-cell activation upregulates CTLA4, which binds to B7 with greater affinity than CD28 and blocks signal 2,
thus down-regulating the T-cell. C: Anti-CTLA4 antibodies bind and block CTLA4, thus allowing resumption of signal 2 and restoration
of T-cell activation.
APC – Antigen Presenting Cell, MHC – Major Histocompatibility Complex, TCR – T-cell receptor, Ag – Antigen, B7 – peripheral
membrane protein, CTLA4 – Cytotoxic T Lymphocyte Antigen 4, CD – Cluster of Differentiation
Mechanism of action of PD1/PDL1 inhibitors
Antigen Antigen
A Presenting
B Presenting
cell cell
Co-stimulatory signal
Co-stimulatory signal
MHC PDL- MHC PDL-
B7 B7
PDL-1
1/PDL- 1/PDL-
2 2 1 /
-
Inhibitory
Inhibitory
Ag Ag
PD tors
hib i
signal
signal
CD28 PD-1 CD28
in
PD-1
TCR TCR
Resting Active
T - cell T - cell
Inhibitory signals
Inhibitory signals
PD-1 PD-1
inhi bitors
-1
D-1 / P DL
PDL-1 P
PDL-1
Tumour cell Tumour cell

BENEFIT
Patients with unresectable Stage III or Stage IV melanoma
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Wolchok, NEJM, 2017; 377: 1345-1356
RISK
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Wolchok, NEJM, 2017; 377: 1345-1356
Time to onset of grade 3-4 toxicity
ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

Ann Oncol. 2017;28(suppl_4):iv119-iv142. doi:10.1093/annonc/mdx225
Current Patient Pathway for AEs
Key points
Patient/Carer
Primary and 111 and 24 Hour Urgent Acute

Patient/
Community 999 Advice Care Oncology
Carer
Care Services Lines ED/AMU Services
Christie - Acute Oncology Service
Emergency referrals
from other
Outpatient clinics hospitals/outreach
sites
If URGENT & cannot admit to OAU– info &

guidance provided to A&E staff & AO staff
notified
Specially trained AO nurses with

clinical experience
Accredited triage scoring system
Liaise with relevant medical, nursing
& research teams
Provide advice to GPs also
access to patient notes, calls
documented & notes updated
A consultant led & delivered service Each hospital has it’s own
Working collaboratively with oncologists AO consultant & nurses
Daily OAU ward round for all patients
24 Hour
Advice Lines
• 24 Hour Advice Lines - primary

function to provide telephone
assessment and triage for
patients who are receiving or
have received non surgical anti-
cancer treatment
• Also provide advice for

professionals
• Usually use the UKONS 24 Hour

Triage Tool (a common language
shared across boundaries)
• UKONS guidelines for managing

immune-related toxicity being
drafted…
24 Hour
Advice Lines
• 24 Hour Advice Lines - primary

function to provide telephone
assessment and triage for
patients who are receiving or
have received non surgical anti-
cancer treatment
• Also provide advice for

professionals
• Usually use the UKONS 24 Hour

Triage Tool (a common language
shared across boundaries)
• UKONS guidelines for managing

immune-related toxicity being
drafted…
ESMO guidelines for managing diarrhoea/colitis

ESMO guidelines for managing pneumonitis

Key Points
• Patient presents unwell on/previously treated with immunotherapy
• THINK IMMUNE – RELATED TOXICITY
• Exclude possible infective causes

• Diarrhoea: viral/bacterial gastroenteritis, C. Diff, CMV
• SOB/Cough: LRTI, PCP
• Arrange key investigations

• FBC, U&Es, LFTs, TFTs, baseline cortisol (9am if possible, else random)
• Other pituitary axis bloods: ACTH, LH/FSH, prolactin
• AXR, CT abdo/pelvis, sigmoidoscopy/colonoscopy (with biopsies to look for colitis and CMV
infection)
• CXR, HRCT chest, PCP tests, Lung function tests, bronchoscopy + BAL
• Liver screen, renal screen, etc…
• Have low threshold for starting high dose steroids (and taper slowly)
• Discuss with local Acute Oncology Service / Christie Hotline / Oncology

SpR/Consultant on call
Summary
• Increasing use of immunotherapy across multiple tumour
types
• Signs and symptoms of toxicity are different to

chemotherapy
• irAEs occur even after finishing treatment
• Key issues
• Experience of managing toxicities
• Early recognition and prompt management of immune-
mediated toxicity
• Access to 2nd line immunosuppressive drugs like infliximab
Additional slides
Hyper / Hypothyroidism

Hypophysitis

Immune-mediated hepatitis

Immune mediated nephritis

Peripheral Neuro-toxicity (1)

Peripheral Neuro-toxicity (2)

Central Neuro-toxicity

Skin toxicity

Arthralgia


2018 03 13 GIM SPR Teaching Immunotherapy Management

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Immuno-Oncology Adverse Event

CTLA-4 inhibitor PD-1 inhibitor PDL-1 inhibitor

CD28 CTLA4 CTLA4 CD28

T - cell T - cell T - cell

T-cell proliferation, T-cell downregulation Restoration of

Tumour cell Tumour cell

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

Primary and 111 and 24 Hour Urgent Acute

If URGENT & cannot admit to OAU– info &

Specially trained AO nurses with

• 24 Hour Advice Lines - primary

• Also provide advice for

• Usually use the UKONS 24 Hour

• UKONS guidelines for managing

• 24 Hour Advice Lines - primary

• Also provide advice for

• Usually use the UKONS 24 Hour

• UKONS guidelines for managing

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

• Exclude possible infective causes

• Arrange key investigations

• Discuss with local Acute Oncology Service / Christie Hotline / Oncology

• Signs and symptoms of toxicity are different to

• irAEs occur even after finishing treatment

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

ESMO Clinical Practice Guidelines for management of toxicities from immunotherapy.

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