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MANAGEMENT OF IMMUNE-RELATED GI AND LIVER TOXICITY

Alberto FusiCharité Comprehensive Cancer Centre - Berlin

St. George´s University - London

TAO Meeting - Cancer Toxicity Management

Paris - 8th-9th December 2016

• 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 irAEIpilimumab 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 dysfunctionHypo 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

All % (G3/4 %)

Ibrahim JCO 2011Pembrolizumab PI, 2014Nivolumab, safety management BMS, 2014

0

10

20

30

40

Diarrhoea Colitis Rash Hepatotoxicity Hypophysitis Pneumonitis Thyroid dysfunction Nephritis Neuropathies

11

5

3

11

15

2

13

01

10

3

1111

18

0

32

1

3

1

33

8

37

Ipilimumab Pembrolizumab Nivolumab

Frequency of irAEGI toxicities

Skin toxicities

Endocrine toxicities

85%

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 2.3Hypothyroidism 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

0

10

20

30

40

50

Diarrhoea Colitis Hepatotoxicity

Frequency of GI and Liver Toxicity

Ipilimumab Pembrolizumab Nivolumab Ipi + Nivo

37(6.9)

18(2)

13(1)

46(14)

8(4.9)

1(0.2) 2(1)

12(8)

3(1.7) 3(1.5)5(<1)

30(19)

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.

• 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 dose-dependent

• 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

GI Toxicity

Ipilimumab - DTIC study

Primary endpoint• OS (intent-to-treat population) Secondary and other endpoints• ORR by RECIST v1.1• PFS• Safety profile

Unresectable ormetastatic melanoma

• Previously untreated

• 502 patients

Manteinance with ipi/placebo every 12 weeks

for pts with ORR or SD

ipilimumab (10mg/kg) + DTIC (850mg/mq)

DTIC + placebo

Randomize1:1

n=250

n=252

Randomized, double-blinded phase 3 study to compare ipilimumab + DTIC with DTIC + placebo

Stratification• metastasis stage• study site• ECOG ps

Safety

Robert C, et al. NEJM 2011

• 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%)

Representa t i ve photomic rographs o f 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).

GI Toxicity

Beck K et al. JCO 2016

General Management Algorithm

Boutros et al. Nature Rev 2016

• 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)

GI Toxicity: Management

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

AwarenessGI 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

THANK YOU