DILI Caused by Immune Checkpoint Modulators Used to Treat Cancer

Cyril Konto, MD

Clinical Lead, Executive Director

Early Oncology Development & Clinical Research

Disclosure

• Current employee and shareholder of Pfizer

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Berman, D. et al. 2015. Pharmacology & TherapeutiCS 148: 132-153.

tl/l) WORLDWIDE RESEARCH & DEVELOPMENT 3

Immune Checkpoint Modulators in Advance Melanoma

so 40

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d

Thr NEW ENGLAND JOURNAL of MEDICINE

ORIGINAL ARTICLE

Nivolumab in Previously Untreated Melanoma without BRAF Mutation

Caroline Robert, M.D., Ph.D., Georgina V. Long, M.D., Ph.D., Benjamin Brady, M.D.,

Caroline Dutriaux, M.D., Michele Maio, M.D., Laurent Mortier, M.D., Jessica C. Hassel, M.D., Piotr Rutkowski, M.D., Ph.D., Catriona McNeil,M.D., Ph.D.,

Ewa Kalinka-Warzocha, M.D., Ph.D., Kerry J. Savage, M.D., Micaela M. Hernberg, M.D., Ph.D., Celeste Lebbe, M.D., Ph.D.,

Julie Charles, M.D., Ph.D., Catalin Mihalcioiu, M.D., Vanna Chiarion-Sileni, M.D., Cornelia Mauch, M.D., Ph.D., Francesco Cognetti, M.D.,Ana Arance, M.D., Ph.D.,

Henrik Schmidt, M.D., D.M.Sc., Dirk Schadendorf, M.D., Helen Gogas, M.D.,

Overall Survival

100

90

Hazard ratio for death, 0.42 (99.79% Cl, 0.25-0.73) P<0.001

Lotta Lundgren-Eriksson, M.D., Christine Horak, Ph.D., Brian Sharkey, Ph.D., ian M. Waxman, M.D., Victoria M4111.11111.D., and Paolo A. Ascierto, M.D. - 80

?ft. 70 bO

·s; 60 ·s;

llo.. ::::s

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+-1 s:::: QJ "+I 30 cc.u.

20

10

0

Patients Who Died no.jtotal no.

Nivolumab 50/210 Dacarbazine 96/208

0 3 6 9

Median Survival

mo (95% Cl)

Not reached 10.8 (9.3-12.1)

12 15 18

Months

WORLDWIDE RESEARCH & DEVELOPMENT 4

Robert, C et al. (CheckMate 066) 2015. N Engl J Med 372: 320-330

Immune Mediated Adverse Events Induced by Checkpoint Modulators

• Nivolumab: fully human IgG4 PD-1 immune checkpoint inhibitor antibody

Select DRAE Organ Category Patients, n (%)

Nivolumab (N = 268)a

Any Grade

Grade 3–4

Skin

78 (29)

1 (<1)

Gastrointestinal

31 (12)

3 (1)

Endocrine

21 (8)

0 (0)

Hepatic 12 (5) 2 (1)

Pulmonary 6 (2) 0 (0)

Hypersensitivity/infusion reaction

5 (2)

1 (<1)

Renal

4 (2)

1 (<1)

5 a Included all treated patients and events reported between the first dose and 30 days after the last dose of study therapy

Weber, J. S. et al (CheckMate 037) 2015. Lancet Oncol 16: 375-84

6

DILI due to Immune Checkpoint Modulators: Immune-Mediated Hepatitis

• Most frequently clinical diagnosis

– Few patients had liver biopsies (mainly with ipilimumab)

• Hepatitis defined by:

– LFT elevation after ruling out other etiologies

– Requiring corticosteroid therapy

– Variable imaging findings according to clinical severity

– Mostly asymptomatic

– Rare clinical symptoms:

• General weakness, nausea/vomiting, dizziness

N=787

Hepatitis N (%)

Any grade

18 (2.3%)

Grade 2

4 (0.5%)

Grade 3

11 (1.4%)

Grade 4

3 (0.4%)

Nivolumab: Increased Incidence of Liver Test Abnormalities Compared to Baseline and Hepatitis

Nivolumab (N=268)

Investigator Choice of Chemotherapy (N=102)

AST

28%

12% ALT

16%

5%

Alkaline Phosphatase

22%

13%

• Median time to onset: 3.7 months (range: 6 days to 9 months) • Dosing Modification:

– Permanent discontinuation in 5 patients (0.6%) – Withholding in 6 patients (0.8%)

• Treatment: – All 18 patients received high dose corticosteroids (>40mg prednisone equivalents) for a median duration of 28 days

(range: 5 days to 2 months) – 1 patient with Grade 3 hepatitis required the addition of mycophenolic acid to high-dose corticosteroids.

• Outcome: – complete resolution in 72% patients (defined as improved to baseline with completion of corticosteroids)

• Retreatment: – 4 patients resumed therapy after resolution – 1 had a recurrence of immune-mediated hepatitis

a. defined as requirement for corticosteroids and no clear alternate etiology

Weber, J. S. et al (CheckMate 037) 2015. Lancet Oncol 16: 375-84 7 Robert, C. et al. (CheckMate 066) 2015. N Engl J Med 372: 320-330

Larkin, J et al (CheckMate 067) 2015. N Engl J Med 373: 23-34

8

Ipilimumab: Dose-Proportional Incidence of Hepatitis

• Anti-CTLA4 IgG4 mAb • 3mg/kg (advanced melanoma) - q3w for a total of 4 doses

– 2% Grade 3-5 hepatitis • 0.2% fatal hepatic failure • 0.4% hospitalization

– 2.5% Grade 2 hepatitis – Early onset of injury is usually after 2 to 4 cycles, 3 to 9 weeks after initiation of treatment – Pattern of enzyme elevation is most frequently hepatocellular, but can be mixed

• 10mg/kg (adjuvant melanoma) - 4 induction doses q3w + maintenance doses q3m up to 3 years:

Hepatitis

Rate Median Time to Onset

Resolution Systemic Corticosteroids

Median Duration of Corticosteroids

Grade 3-4 11% (a) 2.0 mo 94% complete resolution 4% to grade 1 2% did not improve

90% pts 4.4 mo (up to 56 mo)

Grade 2 5% 1.4 mo 91% complete resolution 9% did not improve

73% pts 2.6 mo (up to 41mo)

a. Liver biopsy in 6 Pts: evidence of toxic or autoimmune hepatitis Hodi, F. S. et al. 2010. (MDX010-20) N Engl J Med 363: 711-23

Eggermont, A. M. et al 2015. (EORTC 18071). Lancet Oncol 16: 522-30

30

a. .J < 20

-t 1- Ul < 1000 1- 10

< 500

50

Mechanism of Action for anti-CTLA4 and anti-PD1 mAb

Tumor Microenvironment

Actiation (cytokines, lysis, proliferation

migratio to tumor)

CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) , WORLDWIDE RESEARCH & DEVELOPMENT 10

MHC, major histocompatibility complex; TCR, T-cell receptor.

208 192 178 108 105 98 88 80 76 74 63 50 31 24 9 210 195 181 142 134 123 112 106 105 96 88 79 42 36 13 202 183 166 82 72 59 44 39 35 31 26 22 12 8 3

Combination of Nivolumab and lpilimumab Cause for Optimism and Concerns

Tht NEW ENGLAND JOURNAL of MEDICINE

ORIGINAL ART I CLE

Combined Nivolumab and Ipilimumab

or Monotherapy in Untreated Melanoma J. Larkin, V. Chiarion-Sileni, R. Gonzalez,J.J. Grab, C.L. Cowey, C.D. lao,

D. Schadendorf, R. Dummer, M. Smylie, P. Rutkowski, P.F. Ferrucci, A. Hill,

A Intention-to-Treat Population

100

90 80

70

60

50 40

30

20

'"-,-....

Nivolumab

------------- Nivolumab plus

J. Wagstaff, M.S. Carlino,J.B. Haanen, M. Maio, I. Marquez-Rodas, GA McArthur, PA Ascierto, G.V. Long, M.K. Callahan, M.A. Postow,

10 lpilimumab ipi limum ab

K. Grossmann, M. Sznol, B. Dreno, L. Bastholt, A. Yang, l.M. Rollin, C. Horak, o+--.-,.-.--.--.-.--.--.-.--.--.-.--.--.-.--.--.-.--.--.-. F.S. Hodi, and J.D. Wolchok 0

No. at Risk

10 11 12 13 14 15 16 17 18 19 20 21

Months

Event

Nivolumab (N 313)

Nivolumab plus lpilimumab (N 313)

lpilimumab (N 311)

Nivolumab N ivolumab plus i pilimumab lpil imumab

316 292 271 177 170 160 147 136 132 124 106 86 50 38 314 293 275 219 208 191 173 164 163 151 137 116 65 54 315 285 265 137 118 95 77 68 63 54 47 42 24 17

14 9 18 11 7

Any Grade 3 or 4

Any Grade 3 or 4

Any Grade 3 or 4

8 Patients with PO-Ll-Positive Tumors

number of patients with event (percent) 100

90 Any adverse event

Treatment·related adverse eventt

Diarrhea

Fatigue

Pruritus

311 (99.4)

257 (82.1)

60 (19.2)

107 (34.2)

59 (18.8)

136 (43.5)

51 (16.3)

7 (2.2)

4 (1.3)

0

312 (99.7)

299 (95.5)

138 (44.1)

110 (35.1)

104 (33.2)

215 (68.7)

172 (55.0)

29 (9.3)

13 (4.2)

6 (1.9)

308 (99.0)

268 (86.2)

103 (33.1)

87 (28.0)

110 (35.4)

173 (55.6) 80

85 (27.3) 70 60

19 (6.1) 50

3 (1.0) 40

l(0.3) 30

---- .... - ,_-

L------- Nivolumab

Nivolum a b plus ipilimumab

Rash 81 (25.9) 2 (0.6) 126 (40.3) 15 (4.8) 102 (32.8) 6 (1.9) 20 10

- - - - - - lpil imumab

Nausea 41 (13.1) 0 81 (25.9) 7 (2.2) 50 (16.1) 2 (0.6) o+--.--.-.--.--.-.--.--.-.--.--.-.--.--.-.--.-. Pyrexia

Decreased appetite

18 (5.8) 0

34 (10.9) 0

58 (18.5)

56 (17.9)

2 (0.6)

4 (1.3)

21 (6.8)

39 (12.5)

l (0.3)

l (0.3)

0

No. at Risk

Months

10 11 12 13 14 15 16 17

Increase in alanine amino- transferase level

12 (3.8) 4 (1.3) 55 (17.6) 26 (8.3) 12 (3.9) 5 (1.6) Nivolumab N ivolumab plus ipilimumab lpilimumab

80 76 71 57 56 54 51 49 49 43 38 32 16 13 U U D n 0 « a a H M M U U

75 69 66 40 33 24 22 21 21 17 16 15 9 6 Vomiting 20 (6.4) l(0.3) 48 (15.3) 8 (2.6) 23 (7.4) l(0.3)

Increase in aspartate amino- transferase level

Hypothyroidism

Colitis

Arthralgia

Headache

Dyspnea

Treatment-related adverse event l eading to discontinuation

12 (3.8)

27 (8.6)

4 (1.3)

24 (7.7)

23 (7.3)

14 (4.5)

24 (7.7)

3 (1.0)

0

2 (0.6)

0

0

l(0.3)

16 (5.1)

48 (15.3)

47 (15.0)

37 (11.8)

33 (10.5)

32 (10.2)

32 (10.2)

114 (36.4)

19 (6.1)

l(0.3)

24 (7.7)

l(0.3)

l(0.3)

2 (0.6)

92 (29.4)

11 (3.5)

13 (4.2)

36 (11.6)

19 (6.1)

24 (7.7)

13 (4.2)

46 (14.8)

2 (0.6)

0

27 (8.7)

0

l(0.3)

0

41 (13.2)

C Patients with PO-Ll-Negative Tumors 100

90 80

70 60

50 40

30 20

10

Nivolumab

'- _ N ivolumab plus - - ..._ ._ .... _ L- _ _ _ ipilimumab

lpil im umab o+--.--.-.--.--.-.--.--.-.--.--.-.--.--.-.--.--.-.--.--.-.

WORLDWIDE RESEARCH & DEVELOPMENT

0

No. at Risk Nivolumab Ni volumab plus ipilimumab lpil imumab

10 11 12 13 14 15 16 17 18 19 20 21

Months

12

Larkin, J et al (CheckMate 067) 2015. N Engl J Med 373: 23-34

Hepatitis N (%)

Any grade

51 (12.5%)

Grade 1

1 (0.2%)

Grade 2

5 (1.2%)

Grade 3

37 (9.0%)

Grade 4

8 (2.0%)

Immune-Mediated Hepatitis with Ipilimumab- Nivolumab Combination (N=407)

• Median time to onset: 2.1 months (range: 15 days to 11 months)

• Dosage modification – Permanent discontinuation in 26 patients (6%) – Drug interruption in 21 patients (5%)

• Treatment – 57 patients received high-dose corticosteroids (at

least 40 mg prednisone equivalents) for a median duration of 1.1 month (range: 1 day to 13.2 months)

– 1 patient (Grade 3 hepatitis) required infliximab – 4 patients (3 patients with Grade 3 or 4

transaminase increases and 1 patient with Grade 3 autoimmune hepatitis) required mycophenolic acid in addition to high-dose corticosteroids.

• Complete resolution occurred in 38 patients • Retreatment: 9 patients resumed combo after resolution

– 1 had recurrence of hepatitis

Combination of Ipilimumab and Vemurafenib Synergistic Liver Toxicity Resulting in Phase 1 Study Termination

Ipilimumab

Induction phase q3w x 4

Maintenance phase q3m

D1 D22 D43 Vemurafenib lead-

in phase

D64

D85 D162

D-27 Vemurafenib bid continuous dosing

• Phase 1 primary objective: MTD • Vemurafenib lead-in phase for 4 weeks prior to start ipilimumab • DLT observation period during the combo phase only • 3+3 patients treated in cohort 1 • 3+3 patients treated in cohort -1A

13

14

Ribas, A. et al. 2013. N Engl J Med 368: 1365-1366

Hepatotoxicity Findings: 6 out of 10 patients experienced Grade 3/4 Transaminase Elevations including 2 patients with Grade 2/3 Total Bilirubin Elevation

• No liver biopsy! • Expected overlapping

toxicity of ipilimumab and vemurafenib, but higher than sum of the 2 agents

– Ipi : 1.8% severe hepatitis (USPI)

– Vem: 2.8% severe LFT elevation (USPI)

• Asymptomatic: detected by lab monitoring

• Worst was Grade 3 • Reversible with

established management guide

4-1BB and Urelumab • CD137 (4-1BB or TNFRSF9), TNF superfamily Type 1 membrane glycoprotein receptor

expressed on the surface of lymphoid organs and detected on activated T cells (CD4+ and CD8+), activated NK cells, NKT cells, Tregs, and others.

• Natural ligand: CD137L, a TNF superfamily Type II membrane glycoprotein – Expressed on activated T cells, macrophages, monocytes, DCs and B Cells – Enhance the ability of CD137+ DCs to potentiate T cell responsiveness to alloantigens – May augment T cell trafficking into tumors via CD137 expression on tumor-associated

endothelial cells • Urelumab (BMS-663513): First agonistic anti CD137 fully human IgG4 mAb non blocking

CD137L.

• Non-clin Toxicology: Administration of surrogate BMS-469492 at doses of 10 or 50 mg/kg twice weekly for 4 weeks to CD-1 mice resulted in skin and liver toxicity / Monkey studies showed good tolerability

• Hepatotoxicity, was the most frequent clinically important toxicity in clinic – Occurrence and severity increased from 1 mg/kg – 2 fatal cases of drug-related hepatotoxicity at 1 and 5 mg/kg q3w on study CA186006

responsible for clinical hold

• Most frequent grade 2+ laboratory abnormalities were increases in ALT (15%) and AST (12%), N=106

• Most recent clinical trials conducted at < 1 mg/kg q3w. • Anti-tumor activity as well as PD activity observed across a wide dose range (0.1 to 10mg/kg)

Li, S. Y. & Liu, Y. 2013. Clin Pharmacol 5: 47-53

Sanmamed, M. F. et al. 2015. Semin Oncol 42: 640-55 15 Ascierto, P. A. et al. 2010. Semin Oncol 37: 508-16

16

PF-05092566 anti-4-1BB (0.005 to 10mg/kg)

Treatment-Related TEAEs in ≥2 Patients Treated with Single Agent PF-05082566

(Portion A, N= 60)

Adverse Event Grade 1-2 (%) Grade 3-4 (%) Grade 5 Total (%) Fatigue 4 (6.70) 1 (1.70) 0 5 (8.30)

Pyrexia

5 (8.30)

0

0

5 (8.30) Rash (including papular and

pruritic rash)

5 (8.30)

0

0

5 (8.30)

Decreased appetite 3 (5.00) 0 0 3 (5.00) Dizziness 3 (5.00) 0 0 3 (5.00) Nausea 3 (5.00) 0 0 3 (5.00)

Vomiting 3 (5.00) 0 0 3 (5.00) Abdominal pain 2 (3.30) 0 0 2 (3.30)

Diarrhoea 2 (3.30) 0 0 2 (3.30) Dyspnoea 2 (3.30) 0 0 2 (3.30)

Paraesthesia 2 (3.30) 0 0 2 (3.30) Weight decreased 2 (3.30) 0 0 2 (3.30)

Source: SAF09 data as of 18Dec15

17

Urelumab (BMS) vs PF-05082566

Urelumab

PF-05082566

Human 4-1BBL binding region

Signal peptide

CDR1 (22 aa)

CDR2 (40 aa)

CDR3 (32 aa)

CDR4 (41 aa)

TM (27 aa) Cytoplasmic

(23 aa) (27 aa) (42 aa)

4-1BB

Mouse 4-1BBL binding region

Galectin-9 binding region

PF-05082566 Urelumab (BMS) Affinity ~10 nM ~10 nM Epitope Epitope within CRD 3-4 Epitope within CRD 1-2 4-1BB Ligand competition Yes No Isotype IgG2 IgG4

18

Key Elements of Safety Management for Liver Toxicity

• Monitor patients for abnormal liver tests prior to and periodically during treatment

• Rule out other etiologies rapidly

• Administer corticosteroids promptly at a dose of

– 0.5-1 mg/kg/day prednisone equivalents for moderate transaminase elevations, with or without concomitant elevation in total bilirubin

– 1-2 mg/kg/day prednisone equivalents for Grade 3-4 transaminase elevations, with or without concomitant elevation in total bilirubin

– Taper off over a minimum of 4 weeks

• Withhold therapy for moderate hepatitis

• Permanently discontinue for Grade 3-4 hepatitis

• In case of severe steroid-refractory hepatitis, use immunosuppressive agents (mycophenol acid)

– Anti-TNF Infliximab responsible for acute liver failure and hepatitis

19

Take Home Messages

• Benefit of immune checkpoint modulators outweighs the risks

• Mild-to-moderate serum aminotransferase elevations are common during anti-CTLA4 and anti-PD1 therapies

• Asymptomatic DILI, detected by frequent LFT monitoring

• Most frequently hepatocellular pattern of enzyme elevation, but can be mixed, particularly at the onset of injury

• Severe hepatitis in 2-10% of patients depending on checkpoint, dose and combination

• Early onset of injury (usually 3 to 15 weeks after initiation of treatment)

• Immune mediated hepatitis with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells

• Corticosteroids are the main treatment, often successful