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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
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