Immunotherapy toxicities toxicities Fiona.pdf · General principles for managing toxicities...

Immunotherapy toxicities Dr Fiona Taylor

Outline

• Understand toxicities

• Anticipate toxicities

• Manage toxicities

Key steps to safely using and achieving the most benefits from immunotherapies for patients

Immunotherapies are novel agents

• Increasing use • NICE/CDF approved • Clinical Trials

• Therefore more likely to encounter patients with immunotherapy toxicities • On the wards, in clinics, calling the hotline…

• Toxicities may become more complicated • Combination with chemotherapy, radiotherapy and other immunotherapies

Patient assessment How are you going to assess a patient commencing immunotherapy?

Baseline assessment Clinical

• PS 0 or 1 or 2

• Co-morbidities Autoimmune diseases

• Medications ≤7.5mg prednisolone, potential drug interactions

Bloods

• FBC U+E LFTs

• Blood borne viruses HIV, Hep B and C

• Quantiferon test active or latent TB

• Baseline hormone/endocrine profile

FSH, LH, oestradiol/testosterone

prolactin

9am cortisol, ACTH

TSH, free T4

glucose, IGF-1

(Additional bloods for combination immunotherapy Amylase, lipase)

Toxicities

Outline





How common are toxicities?

Immune related adverse events (IrAE) occur in

• up to 90% patients administered ipilimumab

• up to 70% patients administered PD1/PDL1 inhibitors

(pembrolizumab, nivolumab, atezolizumab)

First line pembrolizumab (PD1) in lung cancer

• 1 in 10 had a G3 or G4 toxicity (better than chemotherapy)

• 1 in 20 stopped treatment due to toxicity

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-exisiting 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 toxicities

Just about every part of the body…!

What might the patient complain of? • LUNGS

• BOWEL AND STOMACH

• LIVER

• KIDNEYS

• HORMONE PRODUCING GLANDs

• HEART

• MUSCLES

• SKIN

• OTHER

• SOB, cough

• Diarrhoea (watery, loose or soft stool), blood or mucous in stool, pain or tenderness stomach area or abdomen

• Yellow eyes, pain right sided of stomach area, tiredness, nausea

• Decreased urine output

• Headaches, blurring or double vision, fatigue, weight changes, behavioural changes (loss of libido, forgetfulness, irritability)

• Chest pain, irregular heart beat, palpitations

• Muscle pain, stiffness, confusion, fatigue

• Rash, itch, skin blistering, skin peeling, ulcers, dry skin

• Eye pain, redness, blurred vision, decreased appetite, nausea/vomiting

• Tingling, numbness arms and legs, fever, seizures, weakness and drowsiness

S. Champiat et al.

Ann Oncol 2016;27:559-574

There is a broad spectrum of potential toxicities

Just about every part of the body…!

Immune related adverse events in advanced melanoma

COMBINATION (ipi and nivo)

Ipilimumab alone CTLA4

Nivolumab alone PD1

Pembrolizumab alone PD1

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

Toxicity patterns - Ipilimumab

Hypothyroidism

Fusi, ESMO immunotherapy preceptorship 2015

Outline





How do we treat immune-mediated toxicities? • Suppress the immune system

• Aiming to suppress the body's reaction against ‘self’ • Steroids

• Oral prednisolone • IV methylprednisolone

• Steroid sparing agents • Infliximab • Mycophenylate • Tacrolimus and cyclosporin

• Supportive measures

• Monitor response

General principles for managing toxicities Understand and Anticipate

• Education, education, education!

• Critical role of staff to educate patients and colleagues

Management

• Early assessment and intervention (initiation of steroids if grade 2 or above) is key

• Exclude non-immunotherapy causes

• Think of rarer toxicities (pituitary failure, GBS)

• Multi-disciplinary approach • early involvement of specialists

• Algorithms are available: use them

• Monitor closely

• Consider further immunosuppressive agent if symptoms don’t start to resolve within 2-3 days (infliximab, mycophenylate)

• Taper steroids slowly when symptoms back to grade 1 or less (usually over a month)

STH General Algorithm

CTCAE for grading

Specific toxicities

• Colitis

• Hepatitis

• Pneumonitis

• Rash

• Endocrine

• Neurological

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

Diarrhoea/Colitis

• Typical presents with raised liver enzymes

• Laboratory abnormalities eg elevations in LFTs (AST/ALT, total bilirubin)

• May develop without clinical symptoms • Exclude other causes • Life-threatening hepatitis develops in 1% patients

Hepatitis

Hepatitis

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

Pnemonitis

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

Skin toxicity

Usually irreversible 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 Abnormal thyroid function tests and/or serum chemistries

Endocrinopathies

Thyroid dysfunction More common with anti-PD1 agents (pembro, nivo) 4-10% Grade 3 or 4 toxicities rare Hypothyroidism TSH >10 mU/L Free T4 <12 pmoll Hyperthyroidism TSH <0.4 mU/L Free T4 >22 pmol/L

Hypopituitarism Combination 8% Ipi 4% PDL1 <1% Commonly 6-13 weeks (up to 19 months) Vague symptoms- fatigue, arthralgia, behavioural changes Specific symptoms-headache, visual changes, dizziness, nausea

Hypoadrenalism Likely if 9am cortisol <100 and possible if 100-400 Vague symptoms Specific symptoms dizzyness/collapse, nausea vomiting

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

Neurological toxicity

Larkin J, ESMO preceptorship presentation 2015

S. Champiat et al.

Ann Oncol 2016;27:559-574

Steroid tapering

• Length of tapering depends on severity of side effect • Need close monitoring as risk of recurrence of toxicity • PPI cover (lansoprazole) Oral steroids • Taper over 4-6 weeks • Reduce prednisolone 10mg every 3 days (as toxicity allows) until dose is

10mg/day then reduce by 5mg every 5 days and stop IV steroids • Taper over at least 6 weeks • Reduce prednisolone 10mg every 5-7 days (as toxicity allows) until dose is

10mg/kg then reduce by 5mg every 5 days and stop

Potential steroid side effects

• 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

How are you going to assess a patient for immunotherapy

toxicities?

Immunotherapy toxicity assessment Clinical history +/- examination Skin Rash, itch, examine GI Diarrhoea, abdominal pain, nausea, vomiting Neurological Loss of sensation,weakness,p+n, behavioural change Endocrine tiredness, nausea, dizzyness, postural BP drop Fatigue Blood tests Liver Function Tests Endocrine profile Renal profile FBC

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

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

• Diarrhoea 8 times in the last 24 hours after 3 cycles

• Needed steroids and infliximab

• Ipilimumab stopped

GRADE ASSESSMENT MANAGEMENT


Developed white forelock Eventually stopped having scans Got driving licence back Remains alive and well, last seen in clinic 2018(aprox 8 years)

Case 3

• 55 year old male

• T4N3M1b (bone) squamous cell lung cancer

• Admitted with increased SOB following 1 cycle of pembrolizumab

• Sats 80% air, RR 30/min

• Pyrexial 39

• Pulse 120 bpm


GRADE ASSESSMENT MANAGEMENT

In hospital on 15L Oxygen 2 months later

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

• 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)

• MRI pituitary gland

• Oral prednisolone 1mg/kg once a day

Sequence of events

• 7th June cortisol >500 , TSH <0.12

• Seen in WAU 2 weeks ago with a headache- sent home

• Calls hot line 1 week ago 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

Please note

• Some patients will still think that they are on chemotherapy- get the names of the drugs

• 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 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)

Summary

• Increasing use of immunotherapy agents means that more patients will present to hospital 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

• Need to monitor response as patients can relapse

• Less likely but toxicities can still occur months later

Thanks for listening any questions?

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Immunotherapy toxicities toxicities Fiona.pdf · General principles for managing toxicities...

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