Immune-related adverse events. DrLaviniaSpain MBBS BMedSci FRACP Research Fellow, Skin & Renal Unit Royal Marsden Hospital, London

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1 Immune-related adverse events DrLaviniaSpain MBBS BMedSci FRACP Research Fellow, Skin & Renal Unit Royal Marsden Hospital, London

2 Disclosures I have no relevant disclosures

3 Overview Background principles Gastrointestinal iraes Colitis Cardiac and Neurological Toxicity Treating patients who have experienced prior iraes Impact of iraesand their treatment on disease outcomes

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5 Mechanisms of immune related adverse events (iraes) Loss of self-tolerance with treatment Gain of CD8 T cells/loss of Tregs TCR MHC CD8+ T Cell CD28 CD80 / 86 Tumour B Cell PD-L1 PD-1 MHC TCR CD8+ T Cell Shared antigens between tumour& normal Exaggerated response to non-self antigens after insult (eg gastroenteritis, flu vaccine) APC CD80 / 86 CD4+ Treg CTLA-4 Normal Stimulation of humoral immunity Slide adapted, original courtesy of Dr Samra Turajlic

6 From Champiatet al, Ann Onc2016

7 % Ipilimumab Nivolumab Ipi+Nivo Frequency of iraesby ICI type in melanoma All-grade % Ipilimumab Nivolumab Ipi+Nivo Grade 3&4 Adapted from Spain et al, Can Treat Rev 2016

8 Khoja& Day et al, Ann Onc2017

9 Timing of onset of G3/4 iraeswith nivolumaband 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.

10 Toxicity grading CTCAE v4 CTCAE guidelines, National Cancer Institute

11 General approach to management of iraes MILD MODERATE SEVERE LIFE THREATENING Treatment ICI Locationof care Supportive measures Corticosteroids Immediate vs delayed Immediate corticosteroids & additionalimm if required Immediate corticosteroids with early use of additional IMM Continue (except some pneumonitis/neurol ogical/cardiac iraes) Withhold ICI Withhold or discontinue ICI Discontinue ICI Outpatient Outpatient with close team contact or inpatient Inpatient (some exceptions eg skin & hepatitis) Inpatient & consider transfer to experienced centre If likely to be an ir-ae start steroids in a compromised patient

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13 GASTROINTESTINALIR-AE S

14 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:

15 It s not just the colon Oesophagitis Case reports Duodenitis 11/22 (50%) in Marthey et al series (with concurrent colitis) Pancreatitis Michotet al only 3/21 (14%) with an elevated lipase had clinical pancreatitis Enteritis Terminal ileum in 20% (Martheyet al) Enteric nervous system Case reports of constipation (Bhatia et al) (Liver) Martheyet al J Crohn scolitis, Michotet al J Immunotherapy 2018; Bhatia et al J Immunotherapy 2009

16 Oncologists Gastroenterologists High dose steroids Nil by mouth Loperamide Lower dose steroids Enteral feeding No loperamide Patient with colitis Multi-disciplinary care is essential but ideally should be led by the Oncologist

17 Anti-CTLA-4 vsanti-pd-1 colitis ir-colis onset of Crohn s or Ulcerative Colitis Anti-CTLA-4 Anti-PD-1 IpimonotherapyG3/4 8% Ipi+Nivo G3/4 8% Often occurs early Macroscopic colitis predominates CD4+ T cells enriched in mucosa Elevated mucosal TNFalpha 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; Coutzacet al, J Crohn scolitis 2017; Collins et al Ann Onc2017; Spain et al BSG 2018

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19 Management-acute (72hrs) Assessment of severity Decide upon steroids (moderate to severe cases) +/-other agents, egloperamide 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

20 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

21 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) Foppenet al, ESMO Open 2018

22 Distribution & features of ir-colitis Pancolitis/Extensi ve colitis Right-sided colitis Ulcers Ileitis % 1,2,3 8% %% 1,2,3 20% 3 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) Foppenet al ; Verschuren et al ; Martheyet al ; Spain et al BSG abstract ; Collins et al Ann Onc2017 5

23 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 steroidrequirement 92% in a series of ptstreated with ipilimumab (Garcia-Neue et al Can Imm Res 2017) AXR Not sensitive Colon can be empty Useful in daily monitoring for possible megacolon

24 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 (Foppenet al ESMO Open 2017; Jain et al WJG 2017): - Ulcers - Pancolitis - High Mayo or van der Heidescore (endoscopic) Bergqvist et al, Can Immunol Immun 2017

25 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)

26 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

27 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

28 CARDIAC AND NEUROLOGICAL IR- AE S

29 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

30 ir-cardiac toxicity Johnson et al cases of fulminant myocarditis with ipi+nivo Occurred after 1 dose Prompted increased recognition and reporting

31 Lyon et al, Lancet 2018

32 Of N=35 patients with myocarditis: 46% melanoma, 11% NSCLC Mahmoodet al J Am CollCardiology 2018

33 Mahmoodet al J Am CollCardiology 2018

34 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) 2 nd line: infliximab or MMF; ATG as last resort Look out for pneumonitis that is actually cardiac failure Lyon et al, Lancet 2018

35 Neurological Toxicity is common Spain et al Ann Onc 2016 Cuzzubboet al EJC 2016 Kao et al JAMA Neurology 2017 Voskenset al PLOS One 2013 Zimmer et al EJC 2016 Anti-CTLA4 Anti-PD-1 Combination CTLA4 & PD-1 1% 3% 14% 3.8% 6.1% 12% - 2.9% - 1.5% % - ~ 1/3 are left with some impairment

36 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 Onc2017

37 Spain et al, Ann Onc2017

38 Spain et al, Ann Onc2017

39 Spain et al, Ann Onc2017

40 From Wang et al JAMA Onc2018

41 RE-TREATING PATIENTS WITH IR- TOXICITY

42 De-escalation from Ipi to PD-1 is generally safe Menzieset al Ann Onc2016 Gutzmeret al EJC 2017 See page 267 of the ESMO Immuno- Oncology handbook! Caution with cardiac toxicity, pneumonitis, neurological toxicity and toxicity that is not steroidresponsive Risk:benefit

43 What about after ipi+nivotox? 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 ptsre-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

44 WHAT DO IR-AE S & THEIR TREATMENT MEAN FOR DISEASE OUTCOMES?

45 Does treatment of iraes reduce efficacy of ICIs? Not when initiated for toxicity Schadendorfet al JCO 2017-no outcome detriment in those who stopped ipi+nivofor 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 Horvatet al JCO 2016 no detriment with steroids for iraesin ipilimumabtreated pts Reduced benefit from ICI in patients who are on steroids or other immunosuppression at baseline Arbouret al JCO lung cancer series Menzieset al Ann Onc2016, Gutzmeret 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 (Derosaet al Ann Onc2018)

46 Iatrogenic toxicity Baseline Ix : - LFT/TFT - Brain imaging - ECG - Viral serology From Champiat et al, Ann Onc 2016

47 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

48 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

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