Immunotherapy side effects Dr Fiona Taylor

Consultant in Medical Oncology

• How does immunotherapy work?

• Side effects

• Treatment principles

• Case studies

Immunotherapies are novel agents

• Increasing use NHS Research Neo-adjuvant/Adjuvant/Palliative settings

• Therefore more likely to encounter patients with immunotherapy toxicities

• Toxicities are becoming more complicated • Combination with chemotherapy, radiotherapy and other immunotherapies

Immunotherapy rationale • ‘Switching on’ the immune system should work in all cancers

Elimination

Cancer surveillance

Equilibrium

Cancer dormancy

Escape

Cancer progression

Effective antigen processing

CD8/CD4 T-cells

NK cells

Adapted from Gogas H, ESMO preceptorship 2015

Tumour cells ‘escape”

the immune system

•Non-foreign/undetectable tumour

antigens

•Inhibit destruction of cancer cells

Inhibit T lymphocytes & reverse immune

response

Recruit immunosuppressive T

lymphocytes

Immunotherapy check point inhibitors CTLA4 inhibitors

• Ipilimumab, tremelimumab

• Modulate early T-cell activation

• Widespread autoimmune effects (any toxicity ~90%)

PD1 inhibitors

• Pembrolizumab, nivolumab • Modulate T-cell effector pathway

• Fewer immune-related adverse effects (any toxicity ~70%)

PDL1 inhibitors

• Atezolizumab, avelumab, durvalumab

• Modulate T-cell effector pathway

• Fewer immune-related adverse events (any toxicity ~70%)

Why do toxicities develop?

• Immunotherapies work to activate the immune system against cancer

• Toxicities occur because the immune system attacks ‘self’

• Results in inflammation and dysfunction

• Hence tend to exclude patients with pre-existing autoimmune conditions where there is already a condition present that attacks ‘self’

S. Champiat et al.

Ann Oncol 2016;27:559-574

There is a broad spectrum of potential immunotherapy

toxicities

Just about every part of the body…!

1 in 10 get G3 or G4 toxicity (better than chemotherapy)

1 in 20 stop due to toxicity

Most toxicities reversible with

treatment apart from endocrine and neurological

Champiat et al Ann Oncol 2016;27:559-574

Toxicities

Toxicity in melanoma

68.8% of patients who discontinued the combination therapy due to toxicity achieved either complete or partial response

Larkin et al. The New England Journal of Medicine Issue: Volume 373(1), 2 July 2015, p 23–34

COMBINATION (ipi and nivo)

Ipilimumab alone CTLA4

Nivolumab alone PD1

Red flag symptoms

Diarrhoea/colitis Abdominal pain, bleeding, mucous, nocturnal diarrhoea

Hypophysitis Headache, visual changes, extreme fatigue

Adrenal insufficiency Low BP, dizzyness, fatigue, electrolyte disturbance

Thyroiditis Tremor, diarrhoea, anxiety, palpitations, delirium

Pneumonitis SOB, dry cough, check exertional sats if normal at rest

Neurological toxicity Numbness, weakness, double vision, SOB, confusion, drowsiness, headache

Myocarditis Chest pain

Rash vesicles, blistering or mucous membrane involvement

General principles for managing toxicities

Education, education, education!

• Critical role of staff to educate patients and colleagues

Management

• Early assessment and intervention is key

• Algorithms

• Initially high dose steroids (oral or IV)

• Exclude non-immunotherapy causes

• Supportive measures

• Monitor response

• Multi-disciplinary approach

Guidelines

STH General Algorithm

CTCAE for grading

Based on ESMO

guidelines and UKONS

Case Studies

Case 1 57 year old female

BRAF WT metastatic melanoma (lung metastases)

June 2016: commenced pembrolizumab

August 2016: CT imaging after 4 cycles – stable disease

September 2016: seen in clinic for cycle 5

clinically very well

What are you going to do?

GRADE ASSESSMENT MANAGEMENT FOLLOW UP

Exclude other causes Supportive measures Monitor

• Admitted, commenced on 2mg/kg IV methylprednisolone

• No more pembrolizumab possible

• Proceeded to join a clinical trial upon disease progression

• Typical presents with raised liver enzymes • May develop without clinical symptoms • Exclude other causes • Life-threatening hepatitis develops in 1% patients

Hepatitis

Case 2

• 49 year old male

• BRAF WT metastatic melanoma (brain & lung mets)

• Diagnosed 2011, had surgical excision of brain mets, followed by post-op whole brain RT

• Commenced on Temozolomide, stopped after 2 cycles due to disease progression

• Commenced on Ipilimumab late 2011 had 3 cycles

• Diarrhoea 8 times in the last 24 hours

What are you going to do?

GRADE ASSESSMENT MANAGEMENT

Supportive measures Monitor response Exclude other causes

Failed to respond to IV steroids Needed infliximab Ipilimumab stopped Developed white forelock Eventually stopped having scans Got driving license back Remains alive and well, last seen in clinic 2019 (> 9 years since diagnosis)

Colitis

• Early treatment is key • Severe and potentially fatal immune-mediated colitis seen in

7% patients on ipilimumab • Patients may present with: – Diarrhoea – Blood or mucus in stool +/-fever – Abdominal pain – Signs of bowel perforation or ileus

Case 3

• 55 year old female

• T4N3M1b (bone) squamous cell lung cancer

• Attended with increased SOB following ipilimumab/nivolumab

• Sats 80% air, RR 30/min

• Pyrexial 39

• Pulse 120 bpm

What are you going to do?

Exclude other causes Supportive measures Monitor

GRADE ASSESSMENT MANAGEMENT

• Respiratory failure

• HRCT-

• Admitted to ITU <24 hours from admission

• Treated for infection, prednisolone 30mg orally

• On 100% oxygen but still deteriorating

• Planned not to be intubated

• Oncology input 2mg/kg IV methylprednisolone

• Discharged from ITU 3 days later

• Not given further immunotherapy

In hospital on 15L Oxygen 2 months later

Pneumonitis • Uncommon

(monotherapy 5% lung, renal, 2% melanoma)

(combination 5-10%)

• Median onset 3 months (1-19 months)

• Symptoms/signs include breathlessness, cough, haemoptysis & hypoxia

• Investigations

• CXR

• Sputum sample

• HRCT: ground glass opacities, may look like ARDS/non specific pneumonias

• Consider referral to respiratory and bronchoscopy

Further events… • Rash (morphea like)

• Hypothyroidism

• Levothyroxine

• Endocrinologists

• Inflammatory arthralgia

• Multiple small joint arthropathy

• Difficult to control

• Rheumatology

• prednisolone, sulphasalazine, hydroxychloroquine, Jak inhibitor

Skin Toxicities

• Common 30-50%

• Range of presentations • Maculopapular rash

• 39% with pembro, 21% with ipi

• Vitiligo • 10% with pembro, 2% with ipi • Remember sun protection

• Follicular/urticarial dermatitis • Mucositis • Sweet’s syndrome

• (acute febrile neutrophilic dermatosis)

• Bullous pemphigoid

Case 4

• 52 year old male with metastatic melanoma BRAF WT

• 3rd cycle of ipilimumab and nivolumab 3 weeks ago

• Attended WAU due to pyrexia and found to have a postural blood pressure drop

What are you going to do?

• Cortisol 15

• TSH <0.02, free T4 22.4 (hyperthyroid)

• LSH <0.1 (1.7-8.6), FSH 2.4 (1.5-12), testosterone <0.4 (6.7-25.7)

• Prolactin 25 (86-324)

Bulky pituitary on MRI for a man of age 52 with heterogenous uptake post IV contrast

• Endocrinology involvement

• Hydrocortisone 20mg tds (IM or IV if not eating or drinking)

• Oral prednisolone 1mg/kg once a day after MRI head

Sequence of events

• In clinic pre 3rd cycle , cortisol >500 , TSH <0.12

• Seen in WAU 1 week later with a headache- sent home

• Called hot line 2 weeks later to inform them his BP is low 83 systolic, asked to get GP to check. BP by GP > 90 and noted that ‘he had a bit of a postural drop’ – no other action taken

• Day before pre-assesment for 4th cycle called hot line as temp >38 oC

• Seen in WAU was noted to have a significant postural BP drop.

• Cortisol 15

• Restarted nivolumab

• 6 months later developed G2 diarrhoea • 3 times/day

• Abdominal pain

• Abdomen soft and non tender

• Started on oral steroids 1mg/kg

• CRP, ESR normal

• Abdominal Xray nad

• CT Abdomen/Pelvis

• Lactate 5.0

• Admitted for IV methylprednisolone 2mg/kg

• Responded very quickly

• Flexible sigmoidoscopy- biopsies showed resolving colitis

• Prolonged weaning off steroids over about 10 weeks as increased on 2 occasions due to infection

• Allergic reaction to Septrin

Thickening of colon wall at hepatic flexure. Fluid throughout large bowel

• Re-challenged with nivolumab

• G1 diarrhoea

• Few weeks after continuing on 5mg prednisolone diarrhoea re-occurred G1.

• Responded to increased steroids

• Flexible sigmoidoscopy- no active inflammation

• Steroids weaned again

• Plan to give infliximab if diarrhoea worsens again

• Acute back pain

• Loss of height L2 and L5

• DEXA showed osteoporosis

• Vit D replacement and annual bisphosphonates

• Complete response to treatment maintained to date (2 years since diagnosis)

• He would say a ‘small price to pay’

Steroid side effects

Usually taper steroids 4-6 weeks at least • Hyperglycaemia

• Monitor random BMs afternoon • Insomnia • Infection

• PCP prophylaxis (co-trimoxazole Mon/Wed/Fri) (>4 weeks 25mg pred) • Oral thrush

• Osteoporosis • Check Vitamin D and calcium consider bisphosphonate if on steroids for

>3months

Usually irreversible Have to be on replacement therapy for life 4% incidence of severe to life-threatening endocrinopathies:

Hypopituitarism, adrenal insufficiency, hyper- or hypothyroidism

Common signs and symptoms: Often vague Fatigue Mental status changes/ behavioral changes Unusual bowel habits Headache Abdominal Pain Hypotension/dizzyness

Endocrinopathies

Rare but can be irreversible 1% incidence of serious and fatal immune-mediated neurological adverse reactions:

Sensory and motor neuropathy Guillain-Barré syndrome Myasthenia gravis

Early recognition and treatment are critical Need to distinguish from non-drug related causes (eg, cancer, infection, stroke) Presentation:

Unilateral or bilateral muscle weakness, sensory alterations, and paresthesia.

Neurological Toxicity

Please note • Some patients will still think that they are on chemotherapy- get the

names of the drugs.

• Patients are given alert cards

• Symptoms of side effects can be subtle, may appear mild but can worsen if left untreated

• Alarm bells must ring when patients are on combination immunotherapy treatment as the chance of a G3/G4 toxicity is 1 in 2

• Signs/symptoms can be delayed and may occur weeks to months after last injection (cf chemotherapy < 6 weeks, for Immunotherapy we accept patients <6months from last treatment)

Immunotherapy summary

• Increasing use of immunotherapy agents means that more patients will present with toxicities

• Toxicities occur due to over activation of the immune system against ‘self’

• Early assessment and recognition is vital

• Treatment of toxicities is with immunosuppressant agents • Steroids • Steroid sparing agents- infliximab/mycophenylate

• Need to monitor response as patients can relapse

• Less likely but toxicities can still occur months later

Thanks for listening any questions?

Please do not hesitate to call WPH

for advice