Immune-related adverse

events

Dr Lavinia Spain MBBS BMedSci FRACP

Research Fellow, Skin & Renal Unit

Royal Marsden Hospital, London

Disclosures

• I have no relevant disclosures

Overview

• Background principles

• Gastrointestinal irAEs

– Colitis

• Cardiac and Neurological Toxicity

• Treating patients who have experienced prior irAEs

• Impact of irAEs and their treatment on disease

outcomes

CD4+

Treg

CD8+

T Cell

B

Cell

CD8+

T CellPD-L1

CTLA-4

CD80 / 86

CD80 / 86

CD28TCR

MHC

TCR

MHC

Tumour

APC

PD-1

Normal

Mechanisms of immune related adverse events (irAEs)

Slide adapted, original courtesy of Dr Samra Turajlic

Shared antigens

between tumour &

normal

Loss of self-tolerance

with treatment

Exaggerated response

to non-self antigens

after insult (eg

gastroenteritis, flu

vaccine)

Stimulation of humoral

immunity

Gain of CD8 T cells/loss

of Tregs

From Champiat et al,

Ann Onc 2016

0

5

10

15

20

25

30

35

40

45

50

Ipilimumab

Nivolumab

Ipi+Nivo

Frequency of

irAEs by ICI type in

melanoma

0

5

10

15

20

25

30

35

40

45

50

Ipilimumab

Nivolumab

Ipi+Nivo

All-grade

Grade 3&4

Adapted from Spain et al, Can Treat Rev 2016

%

%

Khoja & Day et al,

Ann Onc 2017

Timing of onset of G3/4 irAEs with nivolumab and

combination ipi+nivo in St IV melanoma

Larkin J et al. Efficacy and safety in key patient subgroups of nivolumab

(NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in

treatment-na ̈ıve patients with advanced melanoma (MEL) (CheckMate

067). Eur J Cancer 2015; 51 (Suppl 3): S664–S665.

Toxicity grading – CTCAE v4

CTCAE guidelines, National Cancer Institute

Treatment ICI Location of

care

MILD Supportive

measures

Continue

(except some

pneumonitis/neurol

ogical/cardiac

irAEs)

Outpatient

MODERATE Corticosteroids

Immediate vs

delayed

Withhold ICI Outpatient

with close team

contact or inpatient

SEVERE Immediate

corticosteroids

& additional IMM

if required

Withhold or

discontinue ICI

Inpatient

(some exceptions eg

skin & hepatitis)

LIFE

THREATENING

Immediate

corticosteroids

with early use of

additional IMM

Discontinue ICI Inpatient

& consider transfer

to experienced

centre

General approach to management of irAEs

If likely to be an ir-AE – start steroids in a compromised patient

GASTROINTESTINAL IR-AE’S

Colitis - the flag-bearer of irAEs

Assessment:

Scope & biopsy

Treatment:

Steroids, infliximab

Outcome:

Most patients did well

Eggermont et al Lancet 2015 – adjuvant ipi trial:

It’s not just the colon

• Oesophagitis– Case reports

• Duodenitis– 11/22 (50%) in Marthey et al series (with concurrent colitis)

• Pancreatitis– Michot et al – only 3/21 (14%) with an elevated lipase had

clinical pancreatitis

• Enteritis – Terminal ileum in 20% (Marthey et al)

• Enteric nervous system– Case reports of constipation (Bhatia et al)

• (Liver)

Marthey et al J Crohn’s colitis, Michot et al J Immunotherapy 2018; Bhatia et al J Immunotherapy 2009

Oncologists Gastroenterologists

Patient with colitis

Lower dose steroids

Enteral feeding

No loperamide

High dose steroids

Nil by mouth

Loperamide

Multi-disciplinary care is essential but ideally should be led by the

Oncologist

Anti-CTLA-4 vs anti-PD-1 colitis

Anti-CTLA-4 Anti-PD-1

• Ipi monotherapy G3/4 8%

• Ipi+Nivo G3/4 8%

• Often occurs early

• Macroscopic colitis

predominates

• CD4+ T cells enriched in

mucosa

• Elevated mucosal TNF-

alpha

• Pembro G3/4 2%

• Nivo G3/4 1%

• Can occur later

• Microscopic colitis 20-35%

• CD8+ T cells enriched in

mucosa and intraepithelial

zone

Spain et al Can Treat Rev 2016; Coutzac et al, J Crohn’s Colitis 2017; Collins et al Ann Onc 2017; Spain et al BSG 2018

ir-coli�s ≠ onset of Crohn’s or Ulcerative Colitis

Management- acute (72hrs)

• Assessment of severity

• Decide upon steroids (moderate to severe cases)

– +/- other agents, eg Loperamide – some question use

– Dosing controversy- gastroenterologists prefer 40mg oral

prednisolone, traditionally have used hydrocortisone

• Exclusion of other causes– May be more important in PD-1 related ir-AEs (Collins et al Ann Onc

2017)

• Plan for escalation of Rx – ie ensure baseline serology

for viral hepatitis & TB risk Ax

To scope or not to scope

• Scope ✔– Enables direct look to stratify severity

– Histology important (especially for microscopic colitis diagnosis)

– Helps diagnose superimposed infection (CMV, C difficile)

– Can repeat to assess mucosal healing

• However:– Access to this service can be limited & availability should

not delay acute management

– Invasive (extremely small risk of perforation)

– If flexible sigmoidoscopy – only distal colon is viewed

– If C’scopy normal – could still be small bowel

Discrepancy between symptom grade

and endoscopic appearance

“Grade 2”

Different patients

“Grade 3”

Different patients

“Grade 1”

Same patient (left colon normal,

right colon severe colitis)

Foppen et al, ESMO Open 2018

Distribution & features of ir-colitis

Pancolitis/Extensi

ve colitis

Right-sided colitis Ulcers Ileitis

66-100%1,2,3 8%1 32-79%%1,2,3 20%3

Foppen et al 20171; Verschuren et al 20162; Marthey et al 20163; Spain et al BSG abstract 20184; Collins

et al Ann Onc 20175

Colitis can not be excluded on the basis of a normal flexible sigmoidoscopy

Enteritis can not be excluded by a normal colonoscopy

Biopsies should be taken (especially if mucosa is normal)

Imaging?

• CT– If no immediate access to scope in a patient with

moderate to severe symptoms it’s reasonable to obtain a CT

– Positive predictive value of colitis 96% and steroid-requirement 92% in a series of pts treated with ipilimumab (Garcia-Neue et al Can Imm Res 2017)

• AXR– Not sensitive

– Colon can be empty

– Useful in daily monitoring for possible megacolon

Beyond steroids

• Infliximab (5mg/kg)

– Low threshold if worsening,

or not improving with high

dose steroids in 72hrs

– Use if colitis occurs whilst on steroids

• Mycophenolate mofetil (1-1.5gm bd)

– Takes time to work (days to weeks)

– Good choice if concurrent hepatitis

– Can be stopped

• Vedolizumab

– Alternative to infliximab & may work in refractory cases (Berqvist et al series)

– Gut specific

– Takes a long time for maximal onset of action (14 weeks)

• Other strategies

– Diet modification

– Other agents eg tacrolimus, ustekinumab

Predictive of infliximab use (Foppen et

al ESMO Open 2017; Jain et al WJG 2017):

- Ulcers

- Pancolitis

- High Mayo or van der Heide score

(endoscopic)

Bergqvist et al, Can Immunol Immun 2017

Steroid wean

• IV methylprednisolone 1mg/kg until improvement to G1/2

• Oral prednisolone 1mg/kg, weaning over 4-8 weeks – by ~10mg each week

– if patient relapses – re-institute dose at which Sx controlled and have a low threshold for initiation infliximab

• Iatrogenic impact of steroids is significant– Educate

• insomnia, mood change

– Minimise harm • bone protection, monitor blood pressure & glucose

– Prophylax against infection (consider)• PJP prophylaxis suggested if steroids >20mg for >4wks (Dendle et al IMJ 2015,

JCO 2018)

Colectomy

• A last resort

• We have seriously considered colectomy in 5

melanoma pts at Royal Marsden:

– 2/5 – proceeded to colectomy (one had CMV colitis)

– 3/5 – did not proceed (including a case with severe

superimposed C difficile)

Early surgical involvement

Collaborative decision making

Where to next?

• Further research

– Understand pathological spectrum of ir-colitis

– Biomarkers of susceptibility & severity

– Optimise treatment paradigm

• Tailor to endoscopic and histopathological information

• Can we spare systemic steroids in some?

• Should infliximab be introduced early ie ‘top-down

approach’

• Gut microbiome

CARDIAC AND NEUROLOGICAL IR-

AE’S

When the uncommon becomes

common

• 30% treated with ipi+nivo have >1 toxicity (Sznol

et al JCO 2017)

• 2 of the more insidious ones:

– Cardiotoxicity ~1% (often ‘NR’ in pharma studies)

• Concomitant myositis noted in 23% (Mahmood et al 2018)

– Neurotoxicity ~3-14% (~1% in pharma studies)

Definition of a ‘common’ AE:

occurs in 1/10 to 1/100

ir-cardiac toxicity

• Johnson et al 2016

– 2 cases of fulminant myocarditis with ipi+nivo

• Occurred after 1 dose

– Prompted increased recognition and reporting

Lyon et al, Lancet 2018

Of N=35 patients with myocarditis: 46% melanoma, 11% NSCLC

Mahmood et al J Am Coll Cardiology 2018

Mahmood et al J Am Coll Cardiology 2018

Ir-Cardiac Toxicity–Ix & Mx

• Investigations

– ECG

– Tn, BNP

– Echocardiogram

– Cardiac MRI

– Endomyocardial biopsy

• Treatment

– Low threshold to stop ICI

– Cardiac supportive medication eg diuresis, ACEI, beta-blockers

• Management in a centre with coronary care unit

– Immunosuppression

• Early steroids where indicated (500mg-1gm Methylpred)

• 2nd line: infliximab or MMF; ATG as last resort

Lyon et al, Lancet 2018

Look out for

‘pneumonitis’ that is

actually cardiac failure

Neurological Toxicity is common

Anti-CTLA4 Anti-PD-1 Combination

CTLA4 & PD-1

Spain et al Ann

Onc 2016

1% 3% 14%

Cuzzubbo et al

EJC 2016

3.8% 6.1% 12%

Kao et al JAMA

Neurology 2017

- 2.9% -

Voskens et al

PLOS One 2013

1.5% - -

Zimmer et al EJC

2016

- 3.2% -

~ 1/3 are left with some impairment

Insights from our Marsden experience

with neurological toxicity

• Onset of neuro irAEs is variable in relation to

commencement therapy

• Patients present with atypical symptoms/syndromes

• Some are steroid-responsive (even with GBS-like

syndromes)

• Permanent morbidity may result

• Survival outcomes are very good (small series)

Spain et al, Ann Onc 2017

Spain et al, Ann Onc 2017

Spain et al, Ann Onc 2017

Spain et al, Ann Onc 2017

From Wang et al JAMA Onc 2018

RE-TREATING PATIENTS WITH IR-

TOXICITY

‘De-escalation’ from Ipi to PD-1 is

generally safe

• Menzies et al Ann Onc 2016

• Gutzmer et al EJC 2017

• Caution with cardiac toxicity, pneumonitis,

neurological toxicity and toxicity that is not steroid-

responsive

• Risk:benefit

See page 267 of the

ESMO Immuno-

Oncology handbook!

What about after ipi+nivo tox?

• Pollack et al looked at re-starting PD-1 after ipi tox

– 6% developed recurrent colitis

– 17% developed recurrent hepatitis

• Royal Marsden case series of first 3 pts re-treated

with ipi+nivo, all of whom had prior G3 toxicity:

– 2/3 developed ir-tox

– 1/3 did not develop further ir-tox

– Responses: 2/3 PR, 1/3 SD

Pollack et al Ann Onc 2017; Spain et al, Cancer Immunology Immunotherapy 2016

WHAT DO IR-AE’S & THEIR TREATMENT

MEAN FOR DISEASE OUTCOMES?

Does treatment of irAEs reduce

efficacy of ICIs?

• Not when initiated for toxicity– Schadendorf et al JCO 2017- no outcome detriment in those who stopped ipi+nivo for

toxicity in pooled analysis of melanoma pts

– Weber et al ASCO 2017 – no detriment in ORR with high dose steroids or infliximab in

pts with GI toxicity

– Horvat et al JCO 2016 – no detriment with steroids for irAEs in ipilimumab treated pts

• Reduced benefit from ICI in patients who are on steroids or

other immunosuppression at baseline– Arbour et al JCO 2018 - lung cancer series

– Menzies et al Ann Onc 2016, Gutzmer et al EJC 2017

• patients with autoimmune disease already on immunosuppression had a lower response rate

to anti-PD-1

• Antibiotics within first 30 days of ICI treatment may reduce efficacy in

NSCLC & RCC (Derosa et al Ann Onc 2018)

From Champiat et al, Ann Onc 2016

Baseline Ix :

- LFT/TFT

- Brain imaging

- ECG

- Viral serology

Iatrogenic

toxicity

Issues moving into the adjuvant space

• Endocrine implications

– Fertility, reduced life expectancy if develop

hypopituitarism

• Rheumatologic – interferes with work

• Neurological – resulting morbidity

• Toxic deaths will occur

Take home messages

• Research is needed! Management of ir-colitis has not

changed in >10yrs

• Myocarditis and neurological toxicity are ‘common’ and have

a high fatality rate

• Re-treatment with anti-PD-1 after ipilimumab is feasible in a

carefully informed patient

• Treatment of toxicity does not appear to compromise

outcomes – patients should be reassured

• Iatrogenic harm with immunosuppression can impact quality

of life

Thank you

Skin & Renal Unit: Martin Gore, James Larkin, Samra Turajlic, Lisa Pickering