powerpoint presentation · 2017-03-10 · management of advanced/decompensated hcv cirrhosis...

1392GR1700862-01 3/2017

Management of advanced/decompensated HCV cirrhosis

Nivolumab in advanced HCC

Konstantinos Mimidis, MD, PhD

Associate Professor in Internal Medicine-Gastroenterology

Democritus University of Thrace

1392GR1700862-01 3/2017

Disclosures

• Advisory / Lectures : Abbvie, Gilead, Novartis,

Bristol-Myers Squibb, MSD

• Research : Bristol-Myers Squibb, Gilead, Novartis

Management of Patients with HCV decompensated cirrhosis

• HCV-induced decompensated liver cirrhosis is a life-threatening illness with an average 5 year survival rate of 50%

• Patients should be managed by physicians with appropriate training and experience (eg, tertiary referral centers)

• Clinical decisions are more complicated• What is the most appropriate treatment regimen(s)

• How often should the patient be monitored

• Is the patient experiencing any unusual complications

Ohkoshi S, rt al. World J Gastrointest Pharmacol Ther 2015;6:114-119

EASL guidelines 2016:Treatment of patients with severe liver disease

• Patients with decompensated cirrhosis no HCC, with an indication for liver transplantation



• Patients with HCC, without cirrhosis or with compensated cirrhosis with an indication for liver transplantation




• Post-liver transplantation recurrence





• Patients with decompensated cirrhosis without an indication for liver transplantation






• Patients with HCC without an indication for liver transplantation







CTP B CTP C Post-Transplant

90

Pros of treating patients with end-stage liver disease before liver transplantation

• Liver function often improves

• May obviate the need for LT

• Save an organ thus benefiting the organ pool

• Prevent post-LT HCV recurrence

• May be the only option in situations where LT is unavailable or contraindicated

91

Effect of antiviral therapy on patients awaiting liver transplantation

92

Cons of treating patients with end-stage liver disease before liver transplantation

• Eliminate the opportunity to have a curative treatment (LT) of liver

• Preclude the use of anti-HCV-positive organs

• Still at risk of progressive liver disease

• Still at risk of hepatocellular carcinoma

• In those who failed therapy, exposure to NS5A inhibitors may compromises the SVR rates when retreating after LT

93

Η SVR συσχετίζεται με μειωμένη θνητότητα από όλες τις αιτίες και αυξάνει την επιβίωση (??? μείωση ΗΚΚ)

Η SVR pre-LT βελτιώνει τη φλεγμονή, τη συνθετική ικανότητα και τη πυλαία υπέρταση και a) μπορεί να αποτρέψει τη μεταμόσχευση (είναι αυτό καλό ???), b) να κάνει την χειρουργική επέμβαση της μεταμόσχευσης ευκολότερη

HCV RNA (-) για 30-90 days pre-LT, αποτρέπει την επαναμόλυνση

Μεταμοσχευμένοι HCV-RNA (-) έχουν καλύτερη πρόγνωση μετά την LT

Βελτίωση εξωηπατικών επιπλοκών λόγω HCV (νεφρική νόσος/κρυοσφαιρίνες)

Ελεγχος και τροποποίηση των ανοσοκατασταλτικών με τη χρήση DAAs

Barsa JE et al, Clin Transpl 2015;29:859-865, Saxena V, Terrault N, Clin Liver Dis 2015;19:669-688, Carrion A et al, Liver Transpl 2016, doi:10.1002/lt.24383, Deterding K et al, APT 2015;42:889-901, van der Meer A et al, JAMA 2012;308:2584-2593

Pros for pre-LT treatment:

94

Ασθενείς με σοβαρή νόσο είναι περισσότερο ευάλωτοι για SAEs και θνητότητα λόγω θεραπείας με DAAs (πιο συχνά με MELD>20)

ο MELD μπορεί να βελτιώνεται και η μεταμόσχευση να αποτρέπεται αλλά ο ασθενής είναι ακόμα σε κίνδυνο (MELD purgatory)

Η δεξαμενή δοτών HCV(+) σε λήπτες HCV (+) περιορίζεται

Η θεραπεία με DAAs μετά την μεταμόσχευση (ιδιαίτερα σε πρώιμα στάδια ηπατικής νόσου) έχει καλύτερη αποτελεσματικότητα και ασφάλεια

Barsa JE et al, Clin Transpl 2015;29:859-865, Saxena V, Terrault N, Clin Liver Dis 2015;19:669-688, Carrion A et al, Liver Transpl 2016, doi:10.1002/lt.24383

Cons for pre-LT treatment:

95

Patients with decompensated cirrhosis no HCC, with an indication for liver transplantation

• Patients with a MELD score <18-20 can be treated prior to liver transplantation

• Protease inhibitors should not be used in Child-Pugh B or C decompensated cirrhosis

• Due to the limited amount of safety data, frequent clinical and laboratory assessment is necessary

• Patients with a MELD score >18-20 should be transplanted first, without antiviral treatment. HCV infection should be treated after liver transplantation

EASL Guidelines 2016

Patients who are Pre-Liver Transplants with decompensated cirrhosis

GT Regimen

GT1, GT4, GT5 and GT6

SOF/LDV + RBV

SOF/VEL + RBV

SOF + DCV + RBV

12 wk

GT2

SOF + DCV + RBV

SOF/VEL + RBV 12 wk

GT3

SOF + DCV + RBV

SOF/VEL + RBV 24 wk


97








98

Post-liver transplantation recurrence

1. Berenguer M et al. Hepatology 2002;36:202-10; 2. Prieto M et al. Hepatology 1999;29:250-256; 3. Berenguer M et al. J Hepatol 2001;35:666-78; 4. Berenguer M et al. J Hepatol 2000;32:673-684. 5. Firpi RJ et al. Liver Transpl 2009;15:1063-71; 6. Bhat I, Mukherjee S. Panminerva Med 2009;51:235-47ι

Transplantation

HCV infection recurrence: > 98%

Acute hepatitis: 25–45%

• HCV-chronic hepatitis: 80–100%

• HCV-cirrhosis: 8–30%

• Cholestatic hepatitis : 2–8%

Follow-up: 3.5 m (1–13 m)

Follow-up: 5 years

• HCV infection recurrence is universal

• The course of HCV-related liver disease is

accelerated

– 1/3 develop cirrhosis within 5 years

– High-risk of graft loss

– Reduction in survival rate

99

Post-liver transplantation recurrenceand risk of graft-loss

.

Berenguer M et al. Hepatology. 2002;36:202-10

Log-rank p=0.0001

HCV–

HCV+

0.0

Time post-transplant (years)

1 2 3 4 5 6 7 8 9

20

40

60

80

100

0

Pat

ien

t su

rviv

al (

%)

HCV+

77

65

61

55

HCV–

87

83

76

70

Year

1

3

5

7

Patient survival (%)

Prospective study of 522 transplanted HCV- patients between 1991-2000

Post-liver transplantation recurrence

• All patients with post-transplant recurrence of HCV infection should be considered for therapy

• Treatment should be initiated as early as possible when the patient is stabilized (generally after the first 3 months post-transplant), because the SVR12 rates diminish in patients with advanced post-transplant liver disease

• Acute cholestatic hepatitis or the presence of moderate to extensive fibrosis or portal hypertension one year after transplantation predict rapid disease progression and graft loss and indicate urgent antiviral treatment

• In patients with decompensated cirrhosis, ribavirin can be started at the dose of 600 mg daily and adjusted depending on tolerance


Patients who are Post-Liver Transplants with no cirrhosis, compensated or decompensated cirrhosis

GT Regimen

GT1, GT4, GT5 and GT6LDV/SOF + RBV

SOF + DCV + RBV12 wk

GT2 SOF + DCV + RBV 12 wk

GT3 SOF + DCV + RBV 24wk

If ribavirin intoleranceLDV/SOF (1,4,5,6)

SOF + DCV (all genotypes)24 wk

No dose adjustment is required for tacrolimus or cyclosporine with SOF+RBV, LDV/SOF or SOF+DCV*Requires immunosuppressant drug dose adjustmentAvoid cyclosporine


Benefits of Achieving SVR

↓ Cirrhosis↓ Decompensation

↓ HCC↓ Transplantation

↓ All-cause mortalityImproved QoL

MalignancyDiabetes

CVDRenal

Neurocognitive

Cure

Improved clinical outcomes[1,2]

1. Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. 2. Negro F, et al. Gastroenterology. 2015;149:1345-1360. 3. George SL, et al. Hepatology. 2009;49:729-738

Hepatic Extrahepatic

Decreased transmission[1]

SVR in Child-Pugh B and C

•30-50%: improve liver function (bilirubin, albumin, INR)

SVR and reduction in the risk of HCC

Patients with decompensated cirrhosis without an indication for liver transplantation

• Patients with decompensated cirrhosis (Child-Pugh B and Child-Pugh C up to 12 points) not on the waiting list for liver transplantation and without concomitant comorbidities that could impact their survival should be treated urgently

• Protease inhibitors should not be used

• Due to the limited amount of safety data, frequent clinical and laboratory assessment is necessary


Patients with decompensated cirrhosis not on the waiting list for transplantation and without concomitant comorbidities that could impact their survival

GT Regimen

GT1, GT4, GT5 and GT6

SOF/LDV + RBV

SOF/VEL + RBV

SOF/DCV + RIB

12 wk

GT2SOF/VEL + RBV

SOF/DCV + RIB12 wk

GT3 SOF + DCV + RBV

SOF/VEL + RBV24 wk

Contraindications or

poor tolerance to RBV

SOF/LDV (gen 1,4,5,6)

SOF/VEL (all genotypes)

SOF/DCV (all genotypes)

24 wk


• a highly selective NS5A replication complex inhibitor1

• pangenotypic anti-HCV activity,1

• once-daily dosing

• lacks significant drug interactions2-6

• clinical efficacy in a variety of difficult-to-treat patient populations

Molecular weight: 738.88 g/mol Molecular formula: C40H50N8O6

1. Gao et al. Nature. 2010, 2. Nettles et al. Hepatology. 2011, 3. Gao et al. Curr Opin Virol. 2013, 4. Bifano et al. AASLD 2011, Poster 1362; 5. Bifano et al. AASLD 2010., 6. Eley et al. 8th Intl Workshop on Clinical Pharmacology of Hepatitis Therapy. 2013. Oral presentation 014 PK; 7. Bifano et al. Antivir Ther. 2013;18:931.; 8.

Bifano et al. AASLD 2013, 9 Bifano et al. EASL 2013, 10. Everson et al. AASLD 2012., 11. Sulkowski et al. AASLD 2012., 12. Lok et al. N Engl J Med. 2012, 13. Chayama et al. Hepatology. 2012, 14. Hezode et al. Hepatology. 2012, 15. Sulkowski et al. N Engl J Med 2014

Daclatasvir (DCV)

DaclatasvirIndications and Usage

Recommended Treatment Regimen and Duration with Daclatasvir

Genotype Patient Population Treatment and Duration

Genotype 1

Without cirrhosis Daclatasvir + Sofosbuvir

for 12 weeksCompensated (Child-Pugh A) cirrhosis

Decompensated (Child-Pugh B or C) cirrhosis Daclatasvir + Sofosbuvir +

Ribavirin for 12 weeksPost-transplant

Genotype 3

Without cirrhosisDaclatasvir + Sofosbuvir for 12

weeks

Compensated (Child-Pugh A) cirrhosis or Decompensated (Child-Pugh B or C) cirrhosis Daclatasvir + Sofosbuvir +

Ribavirin for 12 weeksPost-transplant

Daclatasvir Adverse Effects

Adverse Reactions Reported at ≥5% Frequency, Daclatasvir + Sofosbuvir x 12 Weeks*

Adverse Reaction^n (%)

n = 152

Headache 21 (14%)

Fatigue 21 (14%)

Nausea 12 (8%)

Diarrhea 7 (5%)

*Note: based in data from the ALLY-3 trial (Nelson DR, et al. Hepatology 2015;61:1127-35.)

^Transient, asymptomatic lipase elevations of greater than 3 times the upper limit of normal

(ULN) were observed in 2% of subjects in ALLY-3.

Daclatasvir Drug-Drug Interactions

Drugs that are Contraindicated for use with Daclatasvir

Mechanism of Interaction Clinical CommentDrugs that are Contraindicated for

use with Daclatasvir*

Strong induction of CYP3A by

coadministered drug

May lead to loss of

virologic response to

daclatasvir

• Anticonvulsants- Phenytoin, - Carbamazepine

• Antimycobacterial agents- Rifampin

• Herbal Products- St. John’s wort

(Hypericum perforatum)

*Note: this table is not a comprehensive list of all drugs that strongly induce CYP3A


• Data from clinical trials

• Data from real world studies

ALLY-1: Multicenter, Open-Label Phase 3 Study

112

Follow-up

DCV 60 mg QD +SOF 400 mg QD + RBV

Week 0 Week 24SVR12a

Week 36

DCV 60 mg QD +SOF 400 mg QD + RBV

Week 12

Advanced cirrhosisN = 60

Post-liver transplantN = 53

• Primary endpoint: SVR12 in GT1 in each cohort

• 12 weeks of treatment: DCV 60 mg + SOF 400 mg + RBV

• RBV initially 600 mg/day, adjusted to 1000 mg/d based on Hb and CrCl

• Advanced cirrhosis patients with trx interrupted by liver transplantation could receive an additional 12 wks of trx immediately post-transplant

Poordad F et al, EASL 2015

ALLY 1: Genotypes 1-6

SVR12 by Cohort

113

a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals.

8295

0

20

40

60

80

100

SVR12,

%a

Post-transplantAdvancedcirrhosis

SVR12 by Cohort

8394

0

20

40

60

80

100

Post-transplantAdvancedcirrhosis

All Patients GT 1 (Primary Endpoint)

■ In a regression analysis, no difference by gender, age, IL28B, or HCV RNA in the advanced

cirrhosis cohort with GT 1


SVR12 by HCV Genotype

114

SVR12 by HCV Genotype

76

9710090

80 8391

100 100

0

20

40

60

80

100

SVR

12

, %

1a 1b 2 3 4 6

Genotype

1a 1b 2 3 4 6

Advanced cirrhosis cohort N = 60

Post-transplant cohort N = 53


92 94

56

0

20

40

60

80

100

A B C

Child-Pugh class

91 96

78 76

9184

8997

75 75

56

100

73

No Yes No Yes >3.5 2.8to3.5

<2.8

SVR12 by Baseline Disease SeverityCirrhosis Cohort

SVR

12

, %

<1.7 1.7to2.3

>2.3 <2.0 2.0to3.0

>3.0

Ascites HE Albumin INR bil

SVR12 by Child-Pugh ClassAdvanced cirrhosis cohort, all genotypes


NHS England Early Access Program (EAP) SOF+NS5A ± RBV for 12 Weeks in 467 Patients with History of Decompensated Cirrhosis

Foster GR, et al. J Hepatol 2016

Daclatasvir (DCV) Plus Sofosbuvir (SOF) regimens in chronic hepatitis C virus (HCV) infected patients with advanced fibrosis or cirrhosis. A

HEllenic multicenter ReAl life CLInical Study (HERACLIS)

Ioannis S. Elefsiniotis (1), George Dalekos (2), John Koskinas (3), Panagiota Ioannidou (4), Evangelos Cholongitas (5), Spilios Manolakopoulos (3), John Goulis (5), John Vlachogiannakos(4), Melani Deutsch (3), Christos Triantos (6), Andreas Kapatais (7), Vassilios A. Sevastianos (8),

Maria Schina (8), Stylianos Karatapanis (9), Ioannis Ketikoglou (3), Emmanuel Manesis (3), Maria-Vasiliki Papageorgiou (4), Emmanuel Sinakos (5), Nikolaos K Gatselis (2), Dimitrios

Karagiannakis (4), Athanasia Tasovasili (1), Argyro Koukoufiki (5), Theodoros A. Voulgaris (8), Chrysostomos Tsolias (6), Evangelos Akriviadis (5), George V. Papatheodoridis (4)

(1) University Department of Internal Medicine-Hepatogastroenterology Unit, National & Kapodistrian University of Athens ,General and Oncology Hospital of Kifisia “Agioi Anargyroi”, (2) Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece, (3) 2nd Department of Internal Medicine, National & Kapodistrian University of Athens, Hippokratio General Hospital of Athens, (4) Department of

Gastroenterology, National & Kapodistrian University of Athens, Laiko General Hospital, Athens, (5) 4th Medical Department, Hippokratio Hospital, Aristotle University of Thessaloniki , (6) Gastroenterology Department, University Hospital of Patras, (7) General Hospital of Nikaia-Piraeus “Agios Panteleimon”, General Hospital of Western Attica “Agia Varvara”, Greece, (8) Evangelismos General Hospital, Athens, Greece, (9) General Hospital of Rhodes, Rhodes,

Greece

Baseline CharacteristicsAll Patients(N=146)

Age (mean / median), years 53.6 / 54

Male/Female, n (%) 97 (66.4) / 49 (33.6)

Caucasians, n (%) 141 (96.6%)

Body Mass Index (mean / median) 27.47 / 25.25

Diabetes, n (%) 16 (11%)

FIBROSIS (TE), n (%)

F0-2

F3

F4

Decompensated cirrhosis

5 (3.44%)

28 (19.2%)

93 (63.7%)

20 (13.7%)

HCV genotype, n (%)

1a

1b

2

3

4

7 (4.8%)

20 (13.7%)

1 (0.7%)

105 (71.9%)

13 (8.9%)

HCV-RNA (median, IU/ml ) 919.861

77.4%

%

100

90 9287 89

84/946/6 18/20 48/55 12/13

DCV/SOF±RBV (12w): 87% (67/77)DCV/SOF±RBV (24w): 100% (17/17)

p=0.20, NS

94 / 146 SVR-12

%

48/552/2 8/9 31/35 7/9

SOLAR-2: LDV/SOF+RBV for 12 or 24 Wks in 329 Decompensated and Post-Liver Transplant

HCV-1 and 4 Pts

Manns, EASL, 2015, GO2

CTP C (10–12)Pre-Transplant

Post-Transplant

Fibrosis (F0–F3)

CTP B (7–9)

FCH

CTP A (5–6)

Week 0 12 24 36

CTP B (7–9)

CTP C (10–12)

SVR12

SVR12LDV/SOF + RBV

LDV/SOF + RBV

Broad inclusion criteria:– No hepatocellular carcinoma (HCC) – Total bilirubin ≤ 10 mg/dL, Haemoglobin ≥ 10 g/dL – CrCl ≥ 40 mL/min, Platelets > 30,000/mL

RBV dosing-F0–F3 and CTP A cirrhosis: weight-based (< 75 kg = 1000 mg; ≥ 75 kg = 1200 mg)

– CTP B and C cirrhosis: dose escalation, 600–1200 mg/d

Overall Efficacy Pre-Transplant in GT 1

27 subjects in the 24 week arm have not reached SVR127 subjects who were transplanted and 3 subjects did not meet inclusion criteria are excluded.Error bars represent 2-sided exact 90% confidence intervals.

SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV

CTP C

20/23 17/20 13/18

CTP B

22/23

SV

R1

2 (

%)

12 Weeks 24 WeeksLDV/SOF + RBV

SOLAR-2: LDV/SOF + RBV in Decompensated and Post-LT Patients

Manns, EASL, 2015, GO2

ASTRAL-4: Sofosbuvir/Velpatasvirin Decompensated Cirrhosis

• Open-label trial; HCC and liver transplantation excluded

• In pts with BL MELD > 15, SVR12, score improved in 84%, worsened in 8%;

• in pts with BL MELD < 15, SVR12, score improved in 52%, worsened in 27%

• AEs consistent with advanced liver disease and RBV toxicity

Charlton MR, et al. AASLD 2015. Abstract LB-13.Curry MP, et al. N Engl J Med. 2015;[Epub ahead of print].

All Pts 1 3

HCV Genotype

n/N =

SVR

12

(%

)

SOF/VEL 12 wks SOF/VEL + RBV 12 wks SOF/VEL 24 wks

2, 4, and 6

100

80

60

40

20

0

8394

86 8896 92

50

85

50

100 10086

75/90 82/87 77/90 60/68 65/68 65/71 7/14

11/13

6/12

8/8

6/6

6/7

Incidence of HCC after SVR

IntroductionCheckMate 040 Dose Escalation & Expansion

oHepatocellular carcinoma (HCC) is among the leading causes of cancer-related deaths1

oCurrent standard of care for patients with advanced HCC is treatment with the multikinase inhibitor sorafenib

– Effective treatment options are limited for patients who progress with sorafenib

Nivolumab is a fully human immunoglobulin G4 monoclonal antibody inhibitor of the programmed death-1 (PD-1) receptor that restores

T-cell–mediated antitumor activity

– Treatment with nivolumab has extended survival in multiple tumor types, and is approved in the US and EU for metastatic melanoma, unresectable/metastatic non-small cell lung cancer, advanced renal cell carcinoma, and for Hodgkin lymphoma and recurrent or metastatic squamous cell carcinoma of the head and neck (US only)3–6

1. GLOBOCAN 2012 v1.0. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed March 18, 2016;

2. McGlynn KA, et al. Clin Liver Dis. 2015;19:223–38; 3. Weber JS, et al. Lancet Oncol. 2015;16:375–84;

4. Borghaei H, et al. N Engl J Med. 2015;373:1627–39; 5. Motzer RJ, et al. N Engl J Med. 2015;373:1803–13;

6. nivolumab US Prescribing Information, Bristol-Myers Squibb, August 2016.

T cell activation can be augmented by targeting immune checkpoints

Adapted from Mellman, et al. Nature, 2011:480;481-9Pardoll DM. Nat Rev Cancer 2012;12:252-64

T-cell responses are regulated though a complex balance of inhibitory (“checkpoints”) and activating signals

Tumors can dysregulate checkpoints and activating pathways, and consequentlythe immune response

Targeting checkpoints and activating pathways is an innovative approach to cancer therapy, designed to promote an immune response

PD-1

CTLA-4

Inhibitory receptorsActivating receptors

TIM-3

LAG-3

Blocking antibodiesAgonistic antibodies

T-cell stimulation

CD28

OX40

CD137

Bruno Sangro,1 Ignacio Melero,1 Thomas Yau,2 Chiun Hsu,3

Masatoshi Kudo,4 Todd S. Crocenzi,5 Tae-You Kim,6 Su-Pin Choo,7

Jörg Trojan,8 Tim Meyer,9 Theodore H. Welling, III,10 Winnie Yeo,11

Akhil Chopra,12 Jeffrey Anderson,13 Christine dela Cruz,13

Lixin Lang,13 Jaclyn Neely,13 Hao Tang,13 Anthony B. El-Khoueiry14

1Clinica Universidad de Navarra and CIBERehd, Pamplona, Spain; 2University of Hong Kong, Hong Kong, China; 3National Taiwan University Hospital, Taipei, Taiwan; 4Kindai University Faculty of Medicine, Osaka, Japan;

5Providence Cancer Center, Portland, OR, USA; 6Seoul National University Hospital, Seoul, Korea; 7National Cancer Center, Singapore; 8Goethe University Hospital and Cancer Center, Frankfurt, Germany;

9Royal Free Hospital, London, UK; 10University of Michigan School of Medicine, Ann Arbor, MI, USA; 11Chinese University of Hong Kong, Hong Kong, China; 12Johns Hopkins Singapore International Medical Centre, Singapore;

13Bristol-Myers Squibb, Princeton, NJ, USA;14USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA

Nivolumab in Patients With Advanced

Hepatocellular Carcinoma

the CheckMate 040 Study

CheckMate 040: Phase 1/2 Study of Nivolumabin Patients With Advanced HCC

CT, computed tomography; MRI, magnetic

resonance imaging.

o Disease assessment imaging (CT or MRI) every 6 weeks

o Interim analysis data cutoff date: March 15, 2016

Key Eligibility Criteria and Study EndpointsCheckMate 040 Dose Escalation & Expansion

Eligibility criteria

Inclusion

o Histologically confirmed advanced HCC not amenable to curative resection

o Child-Pugh scores ≤ 7 (escalation) or ≤ 6 (expansion)

o Progression on 1 prior line of systemic therapy, or intolerant of or refused sorafenib

o AST and ALT ≤ 5 × upper limit of normal; bilirubin ≤ 3 mg/dL

o For HBV-infected patients, viral load < 100 IU/mL and concomitant effective antiviral therapy

Exclusion

o Any history of hepatic encephalopathy

o Prior or current clinically significant ascites

o Active HBV and HCV co-infection

Study endpoints

Primary

o Safety and tolerability (escalation)

o Objective response ratea (expansion)

Secondary

o Objective response rate (escalation)

o Disease control rate

o Time to response

o Duration of response

o Overall survival

Exploratory

o Biomarker assessments

a RECIST v1.1 by BICR (blinded independent central review); BICR data are not yet available, and all efficacy assessments are per local investigator analysis.

Baseline Characteristics and Prior Treatment HistoryCheckMate 040 Dose Escalation & Expansion

Parameter

Uninfected

(n = 135)

HCV Infected

(n = 61)

HBV Infected

(n = 66)

All Patients

(n = 262)

Age, median (range), years 65 (19–83) 65 (53–83) 56 (22–81) 63 (19–83)

Male, n (%) 106 (79) 49 (80) 52 (79) 207 (79)

Race, n (%)

White 90 (67) 38 (62) 5 (8) 133 (51)

Asian 40 (30) 20 (33) 59 (89) 119 (45)

Black 4 (3) 2 (3) 2 (3) 8 (3)

Other 1 (1) 1 (2) 0 2 (1)

Extrahepatic metastases, n (%) 103 (76) 36 (59) 59 (89) 198 (76)

Vascular invasion, n (%) 7 (5) 6 (10) 8 (12) 21 (8)

Child-Pugh score, n (%)a

5 98 (73) 35 (57) 58 (88) 191 (73)

6 36 (27) 23 (38) 8 (12) 67 (26)

> 6 1 (1) 3 (5) 0 4 (2)

α-fetoprotein > 200 mg/L, n (%)b 49 (36) 21 (34) 35 (53) 105 (40)

Prior treatment, n (%)

Surgical resection 81 (60) 27 (44) 53 (80) 161 (61)

Radiotherapyc 30 (22) 7 (11) 14 (21) 51 (19)

Local treatment for HCCd 69 (51) 37 (61) 52 (79) 158 (60)

Systemic therapy 97 (72) 38 (62) 61 (92) 196 (75)

Sorafenib 87 (64) 35 (57) 54 (82) 176 (67)a Four patients in the expansion cohort had Child-Pugh scores of 5 or 6 at screening and were enrolled; they later had scores of 7 to 9 on the first day of dosing. b Baseline α-fetoprotein (AFP) levels were not reported in 19 patients; c Internal or external, and could include radioembolization.d Includes transcatheter arterial chemoembolization, transcatheter embolization, radiofrequency ablation, and percutaneous ethanol injection.

Patient DispositionCheckMate 040 Dose Escalation & Expansion

Escalation Cohort

Patients, n (%)

Uninfected(n = 23)

HCV Infected(n = 10)

HBV Infected(n = 15)

All Patientsa

(n = 48)

Reasons for discontinuation

Disease progression 17 (74) 8 (80) 15 (100) 40 (83)

Study drug toxicity 1 (4) 0 0 1 (2)

Unrelated AE 1 (4) 0 0 1 (2)

Patient requestb 1 (4) 0 0 1 (2)

Expansion Cohort

Uninfected (n = 112)

Patients, n (%)

SorafenibNaive/Intolerant

(n = 54)

SorafenibProgressors

(n = 58)



All Patients(n = 214)

Reasons for discontinuation

Disease progression 21 (39) 30 (52) 16 (31) 26 (51) 93 (43)

Study drug toxicity 3 (6) 0 5 (10) 0 8 (4)

Unrelated AE 0 2 (3) 2 (4) 0 4 (2)

Patient requestb 2 (4) 1 (2) 2 (4) 0 5 (2)a Two patients in the uninfected cohort and 1 patient in the HCV-infected cohort achieved a complete response; b Includes patients who withdrew consent.

SafetyCheckMate 040 Dose Escalation & Expansion

Uninfected

(n = 135)

HCV Infected

(n = 61)

HBV Infected

(n = 66)

All Patients

(n = 262)

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Any

Grade

Grade

3/4

Treatment-related serious AEs, n (%) 11 (8) 4 (3) 6 (10) 5 (8) 2 (3) 2 (3) 19 (7) 11 (4)

Patients with any treatment-related AE, n (%) 91 (67) 24 (18) 45 (74) 21 (34) 41 (62) 6 (9) 177 (68) 51 (19)

Treatment-related AEs reported

in ≥ 5% of all patients, n (%)

Fatigue 32 (24) 2 (1) 7 (11) 0 9 (14) 1 (2) 48 (18) 3 (1)

Pruritus 14 (10) 0 12 (20) 0 14 (21) 0 40 (15) 0

Rash 19 (14) 1 (1) 9 (15) 0 9 (14) 0 37 (14) 1 (< 1)

Diarrhea 18 (13) 2 (1) 4 (7) 0 2 (3) 1 (2) 24 (9) 3 (1)

Nausea 9 (7) 0 7 (11) 0 0 0 16 (6) 0

Decreased appetite 7 (5) 0 2 (3) 0 4 (6) 0 13 (5) 0

Laboratory treatment-related AEs

reported in ≥ 5% of all patients, n (%)

AST increase 13 (10) 4 (3) 10 (16) 10 (16) 0 0 23 (9) 14 (5)

ALT increase 11 (8) 3 (2) 9 (15) 6 (10) 2 (3) 0 22 (8) 9 (3)

Amylase increase 10 (7) 4 (3) 3 (5) 1 (2) 2 (3) 1 (2) 15 (6) 6 (2)

Lipase increase 10 (7) 7 (5) 5 (8) 4 (7) 2 (3) 2 (3) 17 (6) 13 (5)

o Treatment-related AEs led to discontinuation in 4% of patients

o No treatment-related deaths occurred in either the escalation or expansion cohorts

Best Overall Response by Investigator AssessmentCheckMate 040 Dose Escalation & Expansion

Escalation Cohort

Parameter, n (%)

Uninfected(n = 23)




Objective responsea 3 (13) 3 (30) 1 (7) 7 (15)

Complete response 2 (9) 1 (10) 0 3 (6)

Partial response 1 (4) 2 (20) 1 (7) 4 (8)

Stable disease 13 (57) 5 (50) 6 (40) 24 (50)

Progressive disease 6 (26) 2 (20) 7 (47) 15 (31)

Not evaluable 1 (4) 0 1 (7) 2 (4)

Expansion Cohort

Uninfected (n = 112)

Parameter, n (%)

SorafenibNaive/Intolerant

(n = 54)

SorafenibProgressors

(n = 58)




Objective responsea 11 (20) 11 (19) 7 (14) 6 (12) 35 (16)

Complete response 0 2 (3) 0 0 2 (1)

Partial response 11 (20) 9 (16) 7 (14) 6 (12) 33 (15)

Stable disease 32 (59) 27 (47) 29 (57) 23 (45) 111 (52)

Progressive disease 11 (20) 18 (31) 12 (24) 22 (43) 63 (29)

Not evaluable 0 2 (3) 3 (6) 0 5 (2)a RECIST v1.1.

o Overall, disease control was reported in 117 of 262 patients (68%)

Best Change in Target Lesions From BaselineCheckMate 040 Dose Escalation & Expansion

Dose-Escalation Cohort Dose-Expansion Cohort

Ch

an

ge in

Targ

et

Lesio

n

Fro

m B

aselin

e (

%)

Uninfected

HCV infected

HBV infected

100

80

40

20

0

–20

–60

–80

–100

–40

60

100

80

40

20

0

–20

–60

–80

–100

–40

60

Uninfected

Sorafenib

Naive/Intolerant

(n = 53)

Uninfected

Sorafenib

Progressors

(n = 54)

HCV

Infected

(n = 47)

HBV

Infected

(n = 50)

o Objective responses were observed at all dose levels and in all etiologic subtypes

Time to Response and Duration of ResponseCheckMate 040 Dose Escalation & Expansion


o Median DOR: not reached

o Ongoing responses: 30 patients

Time Since First Dose (months)

0 3 6 9 12 15 18 21 24 27 30

HBV: 0.1 mg/kg

HCV: 3 mg/kg

HCV: 1 mg/kg

HCV: 0.3 mg/kg

Uninfected: 10 mg/kg

Uninfected: 3 mg/kg

Uninfected: 1 mg/kg

DOR, months

24

NR

18

15

17

6

7

*

= First response

= Last nivolumab dose

= Ongoing response

*= Retreatment after recurrence

= Retreatment

HCV infected

HBV infected

Uninfected

sorafenib

naive/intolerant

Uninfected

sorafenib

progressors


0 3 6 9 12 15

o Median DOR: 17 months

o Ongoing responses: 1 patient

DOR; duration of response.

Overall SurvivalCheckMate 040 Dose Escalation & Expansion

Overall Survival Rate, % (95% CI)Dose-Escalation Cohort

(n = 48)Dose-Expansion Cohort

(n = 214)

6 months 66 (51–78) 83 (76–88)

9 months 66 (51–78) 71 (57–81)a

12 months 59 (44–72) NC

18 months 44 (29–58) NC

Median OS, mo (95% CI) 14.3 (9.6–18.9) NC

NC, not available/not calculated.a Data cut-off March 15, 2016.

Kaplan-Meier Overall Survival by Prior Sorafenib Treatment in the Dose-Escalation Cohort

Median OS, mo(95% CI)

Escalation Cohort(n = 48)

Sorafenib naive 14.1 (3.2–28.6)

Sorafenib treated 15.0 (5.0–18.9)

Median OS was not reached in the Dose-Expansion Cohort. Time Since First Dose (months)

Pro

po

rtio

n S

urv

iva

l

Naive TreatedCensored

Individual Tumor Burden Over TimeCheckMate 040 Dose Escalation & Expansion

Ch

an

ge

in

Ta

rget

Le

sio

n F

rom

Ba

se

lin

e (

%)


0 3 6 9 12 15 18 21 24 27

–100

–80

–60

–40

–20

0

20

40

60

80

100

180

Responders are patients with a best overall response (BOR) of complete/partial response and non-responders are patients with a BOR of stable disease/progressive disease.

0 3 6 9 12

–100

–80

–60

–40

–20

0

20

40

60

80

100

180



+ = First occurrence of new lesion

Uninfected / Responder

HCV / Responder

HBV / Responder

Uninfected / Non-Responder

HCV / Non-Responder

HBV / Non-Responder

Exploratory BiomarkersCheckMate 040 Dose Escalation & Expansion

PD-L1 Expression on Tumor Cells (≥ 1%)

Dose-Escalation Cohort (n = 41)

Dose-Expansion Cohort(n = 128)

PD-L1 (+)(n = 8)

PD-L1 (-)(n = 33)

PD-L1 (+)(n = 26)

PD-L1 (-)(n = 102)

Objective response, n (%) 2 (25) 5 (15) 5 (19) 20 (20)

PD-L1, programmed death-ligand 1; PD-L1 (+), PD-L1 expression on ≥ 1% of tumor cells; PD-L1 (-), PD-L1 expression on < 1% of tumor cells.

o Responses were observed irrespective of PD-L1 expression on tumor cells

o 8/41 patients (20%) in the dose-escalation cohort

o 26/128 patients (20%) in the dose-expansion cohort

Summary and ConclusionsCheckMate 040 Dose Escalation & Expansion

o In patients with HCC, safety and efficacy results were consistent acrossdose-escalation and dose-expansion cohorts in Study CheckMate 040

o Objective responses to nivolumab monotherapy in patients with HCC:

• Occurred early and were durable irrespective of infection status

• Were observed regardless of prior sorafenib treatment

• Occurred in patients irrespective of PD-L1 expression on tumor cells

o The OS rate was encouraging and notable disease stabilization was observed

• Including in some patients who progressed on prior sorafenib therapy

o The manageable safety profile was similar to what has been observed in othertumor types without any new safety signals

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