Immunotherapy toxicities

1 Immunotherapy toxicities Dr Fiona Taylor Outline Understand toxicities Key steps to safely using and Anticipate toxicities achieving the most benefits from immunotherapies for patients Manage toxicities 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 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).

2 toxicities Outline Understand toxicities Key steps to safely using and Anticipate toxicities achieving the most benefits from immunotherapies for patients Manage toxicities 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'. There is a broad spectrum of potential toxicities Just about every part of the body ! S. Champiat et al. Ann Oncol 2016;27:559-574.

3 What might the patient complain of? SOB, cough Diarrhoea (watery, loose or soft stool), blood or mucous in stool, pain or tenderness stomach LUNGS area or abdomen BOWEL AND STOMACH Yellow eyes, pain right sided of stomach area, tiredness, nausea LIVER Decreased urine output KIDNEYS Headaches, blurring or double vision, fatigue, weight changes, behavioural changes (loss of HORMONE PRODUCING GLANDs libido, forgetfulness, irritability). Chest pain, irregular heart beat, palpitations Muscle pain, stiffness, confusion, fatigue HEART. Rash, itch, skin blistering, skin peeling, ulcers, MUSCLES dry skin Eye pain, redness, blurred vision, decreased SKIN appetite, nausea/vomiting OTHER Tingling, numbness arms and legs, fever, seizures, weakness and drowsiness There is a broad spectrum of potential toxicities Just about every part of the body ! S. Champiat et al. Ann Oncol 2016;27:559-574. Pembrolizumab alone Nivolumab alone Ipilimumab alone COMBINATION. PD1 PD1 CTLA4 (ipi and nivo).

4 Immune related adverse events in advanced melanoma Toxicity in melanoma COMBINATION Nivolumab alone Ipilimumab alone (ipi and nivo) PD1 CTLA4. 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. Toxicity patterns - Ipilimumab Hypothyroidism Fusi, ESMO Immunotherapy preceptorship 2015. Outline Understand toxicities Key steps to safely using and Anticipate toxicities achieving the most benefits from immunotherapies for patients Manage toxicities 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!

5 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 Hepatitis Typical presents with raised liver enzymes Laboratory abnormalities eg elevations in LFTs (AST/ALT, total bilirubin).

6 May develop without clinical symptoms Exclude other causes Life-threatening hepatitis develops in 1% patients 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 Endocrinopathies 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 Thyroid dysfunction More common with anti-PD1 agents (pembro, nivo) 4-10%.

7 Grade 3 or 4 toxicities rare Hypothyroidism TSH >10 mU/L. Free T4 <12 pmoll Hyperthyroidism TSH < 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 Neurological Toxicity Rare but can be irreversible 1% incidence of serious and fatal immune-mediated neurological adverse reactions: Sensory and motor neuropathy Guillain-Barr 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 Larkin J, ESMO preceptorship presentation 2015. S. Champiat et al. Ann Oncol 2016;27:559-574.

8 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.

9 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? Exclude other causes Supportive measures Monitor GRADE ASSESSMENT MANAGEMENT FOLLOW UP. 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 What are you going to do? GRADE ASSESSMENT MANAGEMENT. Exclude other causes Needed steroids and infliximab Supportive measures Ipilimumab stopped Monitor Developed white forelock Eventually stopped having scans Got driving licence back Remains alive and well, last seen in clinic 2018(aprox 8 years).

10 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 What are you going to do? Exclude other causes Supportive measures Monitor 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 < , free T4 (hyperthyroid). LSH < ( ), FSH ( ), testosterone < ( ). 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 < 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.