MANAGEMENT OF IMMUNE-RELATED GI AND LIVER TOXICITY

MANAGEMENT OF IMMUNE-RELATED GI AND LIVER TOXICITY Alberto Fusi Charité Comprehensive Cancer Centre - Berlin St. George s University - London TAO Meeting - Cancer Toxicity Management Paris - 8th-9th December 2016 1

Immune check point blockade with CTLA-4, anti-pd-1 and anti-pd-l1 is a major advance in cancer management Associated with novel immune mediated toxicity different from other classes of antineoplastic agents Require specialised management

Frequency of irae All % (G3/4 %) Ipilimumab Pembrolizumab Nivolumab Diarrhoea 37 (6.9) 18 (2) 13 (1) Colitis 8 (4.9) 1 (0.2) 2 (1) Rash 33.2 (2.5) <1 15 (0) Hepatotoxicity 3 (1.7) 5 (<1) 3 (1.5) Hypophysitis 2.7 (2.1) 0.5 (0.2) <1 (<1) Pneumonitis <2 2.9 (0.2) 3 (1) Thyroid dysfunction Hypo 1.8 (0.1) Hyper 1.2 (0.2) Hypo 8.3 (0.2) Hyper 1 (<1) Hypo 4 (<1) Nephritis <2 0.7 (0.5) 1 (0) Neuropathies <1 <1 <1 Ibrahim JCO 2011 Pembrolizumab PI, 2014 Nivolumab, safety management BMS, 2014

Frequency of irae 40 37 GI toxicities Skin toxicities 33 30 85% 20 18 13 15 Endocrine toxicities 10 8 10 5 0 3 3 3 3 2 2 1 1 1 1 1 1 1 1 1 1 0 0 1 Diarrhoea Colitis Rash Hepatotoxicity Hypophysitis Pneumonitis Thyroid dysfunction Nephritis Neuropathies Ipilimumab Pembrolizumab Nivolumab

Treatment-Related Select AEs Reported in 10% of Patients (Checkmate 067) Patients Reporting Event, % NIVO + IPI (n=313) NIVO (n=313) IPI (n=311) Any Grade Grade 3 4 Any Grade Grade 3 4 Any Grade Grade 3 4 Skin 59.1 5.8 41.9 1.6 54.0 2.9 Pruritus 33.2 1.9 18.8 0 35.4 0.3 Rash 28.4 2.9 21.7 0.3 20.9 1.6 Rash maculo-papular 11.8 1.9 4.2 0.3 11.9 0.3 Gastrointestinal 46.3 14.7 19.5 2.2 36.7 11.6 Diarrhoea 44.1 9.3 19.2 2.2 33.1 6.1 Colitis 11.8 7.7 1.3 0.6 11.6 8.7 Hepatic 30.0 18.8 6.4 2.6 7.1 1.6 Increase in alanine aminotransferase 17.6 8.3 3.8 1.3 3.9 1.6 Increase in aspartate aminotransferase 15.3 6.1 3.8 1.0 3.5 0.6 Endocrine 30.0 4.8 14.4 0.6 10.9 2.3 Hypothyroidism 15.0 0.3 8.6 0 4.2 0 With immune modulatory agents, resolution rates for the majority of grade 3 4 select AEs were: 85-100% for NIVO + IPI, 50-100% for NIVO, and 83-100% for IPI As observed in prior studies, most endocrine events did not resolve Larkin et al. NEJM 2015

Frequency of GI and Liver Toxicity 50 46(14) 40 Ipilimumab Pembrolizumab Nivolumab 37(6.9) 30(19) 30 20 Ipi + Nivo 18(2) 13(1) 10 12(8) 8(4.9) 1(0.2) 2(1) 0 Diarrhoea Colitis 3(1.7) 5(<1) 3(1.5) Hepatotoxicity

Toxicity Pattern Published in: André P. Fay; Raphael Brandão Moreira; Paulo R. S. Nunes Filho; Caroline Albuquerque; Carlos H. Barrios; Expert Review of Quality of Life in Cancer Care 2016, 1, 89-97.

GI Toxicity Diarrhoea: an increase in the frequency of stools vs. colitis: abdominal pain ± peritoneal symptoms or imaging and/or endoscopic evidence of colonic inflammation G3-4 diarrhoea occurs in 7% of pts on ipilimumab and around 2% of pts on anti- PD-1 antibodies G3-G4 Enterocolitis is observed in 5% of pts on ipilimumab and around 1.5% of patients on anti-pd-1 antibodies The incidence of diarrhoea and colitis in patients receiving ipilimumab is dosedependent Grade 3 diarrhoea is the most frequent adverse event leading to discontinuation of treatment by patients receiving ipilimumab Incidence reduced with combination with chemotherapy (Dacarbazine, Fotemustine) Patients with enterocolitis usually present with watery diarrhoea, severe abdominal pain and occasionally haematochezia Around 20% of the patients with enterocolitis present extra-intestinal manifestation (most commonly arthralgia) Perforation < 1% cases

Ipilimumab - DTIC study Randomized, double-blinded phase 3 study to compare ipilimumab + DTIC with DTIC + placebo n=250 ipilimumab (10mg/kg) + DTIC (850mg/mq) Unresectable or metastatic melanoma Previously untreated 502 patients Randomize 1:1 Stratification metastasis stage study site ECOG ps Manteinance with ipi/placebo every 12 weeks for pts with ORR or SD n=252 DTIC + placebo Primary endpoint OS (intent-to-treat population) Secondary and other endpoints ORR by RECIST v1.1 PFS Safety profile

Safety Robert C, et al. NEJM 2011

GI Toxicity Colonoscopy or sigmoidoscopy should be considered for all the patients with severe diarrhoea (grade > 2) to assess presence of colitis, ulceration and need for more aggressive immunosuppression (! risk of perforation) Endoscopic investigations in patients with enterocolitis usually show erythema, mucosal friability, oedema, erosions, and bleeding, predominantly in the distal colon. In severe cases microscopic findings include neutrophilic inflammation, destruction of surface epithelium and crypts, and crypt microabcesses. Immune infiltrate vary and include neutrophilic infiltrate (46% of pts treated with ipi), lymphocytic infiltrate (15%), and mixed neutrophilic lymphocytic infiltrate (38%) Representative photomicrographs of histopathologic features of enterocolitis. (A) Neutrophilic infiltration with colonic crypt destruction (hematoxylin and eosin, 400). (B) Small bowel mucosa showing markedly increased surface intraepithelial lymphocytes and expansion of lamina propria with mononuclear cells (hematoxylin and eosin, 200). (C) Two adjacent colonic glands showing cryptitis in the upper gland and intraepithelial lymphocytosis and crypt cell apoptosis in the lower gland (hematoxylin and eosin, 400). Beck K et al. JCO 2016

General Management Algorithm Boutros et al. Nature Rev 2016

GI Toxicity: Management Exclude other causes of diarrhoea and enterocolitis such as ischaemia and/or infection, by using a stool test for viral cytomegalovirus, bacterial pathogens and Clostridium difficile toxins Grade 1 and 2 diarrhoea (less than six stools per day) should be managed with antidiarrheal medications (e.g. loperamide), oral hydration and electrolyte supplements Persistent (>3 days) grade 2 diarrhoea (between 4 and six stools per day) should be treated with oral steroids (0.5 mg/kg of prednisolone or equivalent). Temporary suspend treatment. Consider colonoscopy and CT scan abdo

GI Toxicity: Management Grade 3-4 diarrhoea or colitis (more than seven stools per day, peritoneal symptoms and/or severe abdominal pain) should be treated with high dose intravenous steroids (methylprednisolone 1 2 mg/kg/day or equivalent) and consider further immunosuppresion (e.g infliximab, etc) if symptoms not improve within 2-3 days. Discontinue treatment permanently (discuss risk/benefit in case of grade 3). Colonoscopy and CT scan abdo recommended. Generally improvement is usually seen within 48-72 hours from i.v. steroid treatment start and patients fully recover within a median time of 16 days from steroid treatment start Steroids and infliximab are contraindicated if perforation is suspected (seek advise from surgeon)

Infliximab Class: Monoclonal antibody blocking TNF-alpha Dose: 5 mg/kg, can be repeated at week 2. Maintenance treatment not necessary AEs: increased risk of serious infections, haematological abnormalities, deranged LFTs, reactivation of HBV & TB, infusion reactions can occur

Hepatic Toxicity Hepatotoxicity is reported in 3 9% of patients receiving ipilimumab and in 4 10% of patients receiving anti-pd-1 antibodies, with grade 3 or 4 toxicity in 1%. In pts receiving the combination nivo + ipi the hepatic toxicity occurs in 30% of the cases with 18% G3-G4. Increased hepatic toxicity with combination checkpoint blockade + chemotherapy (see DTIC + Ipi; Nivo +Cisplatin-based chemotherapy; Fotemustine + Ipi; etc) Dose limiting for the combination Vemurafenib + ipilimumab (Phase I study stopped) and increased for the combination anti-pd1 antibody + targeted agent (nivo +panzopanib; nivo+ sunitinib; etc) Liver toxicity due to drug metabolism vs. autoimmune hepatitis. The formal diagnosis of autoimmune hepatitis requires a liver biopsy showing T-cell infiltrates

Hepatitis Radiologic appearances include hepatomegaly, periportal oedema, and periportal lymphadenopathy On biopsy hepatic inflammation with ballooning degeneration with diffuse lymphocytic infiltrates. Immunohistochemistry demonstrated predominantly CD4+ cells in the periportal regions and CD8+ cells in hepatic lobules. Possible sinusoidal histiocytic infiltrates and central vein damage with endothelialitis A and B. Case 1. There is diffuse inflammation throughout portal areas and parenchyma, with lobular disarray and hepatocyte rosette formation. C. Case 2. There is confluent necrosis and early fibrosis with milder inflammation and ballooning injury. D. Case 3. Numerous foci of spotty lobular inflammation are seen near a large central vein. Kleiner et at. Dig Dis Sci. 2012

Hepatic Toxicity: Management Exclude other causes (viral, progressive disease, metabolic, etc) Grade 1 and 2 hepatic toxicity requires close monitoring of the LFTs In case of grade 2 toxicity treatment should be temporary suspended In case of grade 2 hepatic toxicity persisting for more than 5-7 days intermediate dose steroids and liver biopsy should be considered Grade 3 or 4 should be treated with iv high dose steroids. If no improve within 48h immunosuppression with mycofenolate mofitel should be considered. Tacrolimus as second choice or to further increase immunosuppresion. Liver biopsy and imaging recommended Infliximab not recommended because of its hepatotoxic potential A case report describes successful use of anti-thymocyte globulin in a patient with severe ipilimumab related hepatic failure

Awareness GI and Liver toxicity are common with checkpoint blockades. Frequent G3-G4 toxicities in combination, but manageble. Their effective management depends on: Patient education Early recognition (! exclude other causes) Appropriate monitoring Prompt initiation of immunosuppressive therapy Utilisation of treatment algorithms

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