mmune checkpoint inhibitorslivercancer.or.kr/file/general/general_11_07.pdf · nivolumab...

mmune CheckPoint Inhibitors

for HCC

Jeong-Hoon Lee, M.D., Ph.D.

Department of Internal Medicine and Liver Research Institute

Seoul National University College of Medicine

Disclosure

I declare that I have no conflict of interest.

Some slides are kindly provided from

and .

http://www.bms.com/

1. Cancer immunity and Immune Checkpoint - PD-1 (programmed death-1)/PD-L1, CTLA-4 (cytotoxic T lymphocyte-associated protein-4)

2. History of Immunotherapy and ICPIs (immune checkpoint inhibitors)

3. ICPIs for HCC

- Rationale

- Clinical Trial Data

- Combination therapy

4. Questions about ICPIs

5. Summary

Contents

ancer Immunity

and Immune Checkpoint

T-cell Response: First Signal

Snyder A et al. Curr Opin Genet Dev. 2015;30:7-16.

Second Co-stimulatory Signals of T-cell Response

Mellman I et al. Nature 2011;480:480-9.

CD28

OX40

GITR

CD137

CD27

HVEM

CTLA-4

PD-1

TIM-3

BTLA

VISTA

LAG-3

Activating Signals Inhibitory Signals

T-Cell Stimulation T-Cell Inhibition

T-cell

* First Signal: Recognition of MHC-peptide complex by TCR

Stimulatory / Inhibitory Molecules during Immune Tumor Surveillance

Chen DS et al. Immunity. 2013;39:1-10.

Cancer antigen presentation TNF-α IL-10

IL-1 IL-4

IFN-α IL-13

CD40L/CD40

CDN

ATP

HMGB1

TLR

Killing of cancer cells

IFN-γ

T-cell granule content

PD-L1/PD-1 LAG-3

PD-L1/B7.1 Arginase

IDO MICA/MICB

TGF-β B7-H4

BTLA TIM-3/phospholipids

VISTA

Trafficking of T-cells to tumors

CX3CL1 CXCL10

CXCL9 CCL5

Priming and activation CD28/B7.1

CD137/CD137L

OX40/OX40L

CD27/CD70

HVEM

GITR

IL-2

IL-12

CTLA-4/B7.1

PD-L1 (B7-H1)/PD-1

PD-L1 (B7-H1)/B7.1

prostaglandins

Lymph

node

Blood vessel

Tumor

Stimulatory factors

Inhibitors

3

4

Infiltration of T-cells into tumors

LFA1/ICAM1

Selectins

VEGF

Endothelin B receptor

5

Recognition of cancer cells

by T-cells

T-cell receptor

Reduced pMHC on cancer cells 6

7 Release of cancer cell antigens

Immunogenic cell death

Tolerogenic cell death

1

2

CTLA-4 and PD-1/PD-L1 Blockade for Cancer Therapy

Ribas A. N Engl J Med. 2012;366:2517-9.

istory of Immotherapy

and ICPIs

Cancer Immunotherapy

Mellman I et al. Nature 2011;480:480-9.

Active immunotherapy

Adoptive cell transfer

immunotherapy

IL-2

IFN

IL-15

IL-21

Peptide vaccine

DC vaccine

Genetic vaccine

OX40

CD137

CD40

PD-1

CTLA-4

T-cell cloning

CIK cell

TCR or CAR

genetic engineering

Immune checkpoint

inhibitors

Immune agonists

Milestones of Cancer Immunotherapy

Steinman RM, et al. J Exp Med. 1973;137:1142-62. Kirkwood JM, et al. J Clin Oncol. 1996;14:7-17. Fyfe G, et al. J Clin Oncol. 1995;13:688-96.

Atkins M. et al. J Clin Oncol. 1999;17:2105-16. Ishida Y, et al. EMBO J. 1992;11:3887-95. Nishimura H, et al. Immunity. 1999;11:141-51.

Freeman GJ, et al. J Exp Med. 2000;192:1027-34. Higano CS, et al. Cancer. 2009;115:3670-9. Hodi FS, et al. N Engl J Med. 2010;363:711-23.

Robert C, et al. Lancet. 2014;384:1109-17. Weber JS, et al. Lancet Oncol. 2015;16:375-84. Rizvi N, et al. Lancet Oncol. 2015;16:257-65.

Borghaei H, et al. N Engl J Med. 2015;373:1627-39. Garon EB, et al. N Engl J Med. 2015;372:2018-28. Motzer RJ, et al. N Engl J Med. 2015;373:1803-13.

First Achievement: Ipilimumab (anti-CTLA-4) for Melanoma

Hodi FS et al. N Engl J Med. 2010;363:711-23.

Ipilimumab

Ipilimumab + gp100

gp100

Characteristic

Ipilimumab + gp100

(n = 403)

Ipilimumab Alone (n = 137)

gp100 Alone (n = 136)

Median OS, mos 10 10.1 6.4

HR (vs gp100 alone) 0.68 0.66 --

P value < .001 .003 --

Anti-PD-1 inhibitors for Various Cancers

Hamid O, et al. N Engl J Med. 2013;369:134-44.

Nivolumab

ORR Melanoma: 28% NSCLC: 18% Renal cell cancer: 27%

Topalian SL et al. N Engl J Med. 2012;366:2443-54.

Pembrolizumab

Confirmed ORR Melanoma: 38% (comparable ± previous ipilimumab)

Immune Checkpoint Inhibitors (ICPIs) for Various Cancers

Gentzler R, et al. Immunotherapy. 2016;8:583-600.

ORR

ORR

mmune Checkpoint Inhibitors

for HCC

Rationale: PD-1/PD-L1 axis (+) in HCC

Gao Q et al. Clin Cancer Res. 2009;15:971-79.

Kuang DM et al. J Exp Med. 2009;206:1327-37.

HCC cell lines Tumor tissues

• Expression level: 45-100%

• Expression location: HCC microenvironment

(e.g. Kupffer cells, tumor-associated monocytes)

• Expression correlated with HCC stage,

HBV infection,

and inflammation.

• Clinical outcome of elevated expression: ↓ DFS

Tremelimumab (anti-CTLA-4 Ab) for HCV-related HCC

Phase II open-label trial. N=21. BCLC A 14%/B 29%/C 57%, Child class B 43%

Sangro B et al. J Hepatol. 2013;59:81-8.

TTP: median 6.5 mo OS: median 8.2 mo

• Objective response rate: 17.6% (all PR)

• Disease-control rate: 76.4% (PR 17.6%, SD 58.8%)

Nivolumab (anti-PD1): CheckMate 040 trial

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

• Interim analysis data cutoff date: August 8, 2016

– Median follow-up was 13.3 months in the dose-escalation phase and 10.5 months in the dose-expansion phase

Dose Escalation

0.1–10 mg/kg

N = 48

Dose Expansion

3 mg/kg

N = 214

Uninfected (n = 23)

HCV infected (n = 10)

HBV infected (n = 15)

Uninfected (n = 113)

HCV infected (n = 50)

HBV infected (n = 51)

Sorafenib Experienced (2L)

(n = 37)

Sorafenib Naive (1L)

(n = 11)


(n = 145)

Sorafenib Naive (1L)

(n = 69)

Study Endpoints

Primary

• Safety and tolerability (escalation)

• Objective response ratea (expansion)

Secondary

• Objective response ratea (escalation)

• Disease control rate

• Time to response

• Duration of response

• Overall survival

Other

• Biomarker assessments

• Patient-reported outcomesb

All

Pati

en

ts (

N =

262)

Melero I et al. J Clin Oncol. 2017;35 (suppl 4S; abstract #226)

Phase I/II study (interim analysis), N=262

Baseline Characteristics


Melero I et al. ESMO 2016.

Phase II dose-expansion study (interim analysis), N=214

Safety



Best Overall Response



Response: Waterfall Plots

Dose-Escalation Cohort Dose-Expansion Cohort


Time-to-Response / Duration of Response

Dose-Escalation Cohort

• Median DOR: 17 months

• Ongoing responses: 1 patient

Dose-Expansion Cohort

• Median DOR: 9.9 months

• Ongoing responses: 30 patients


El-Khoueiry AB et al. J Clin Oncol. 2016;34 (suppl; abstract #4012)

Phase I dose-escalation study (interim analysis), N=48

EHM (+), 76%; Prior SRB treatment, 70%

Overall Survival

* Median OS: 15.1 mo (similar between Sorafenib-naïve or –treated groups)

Exploratory Biomarkers



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

Effect of ICPIs on HBV/HCV


Viral Kinetics: HCV RNA and qHBsAg

* Limited antiviral activity

Nivolumab

Tremelimumab

Sangro B et al. J Hepatol. 2013;59:81-8.

Nivolumab (anti-PD1): CheckMate 459 trial

• Primary Endpoints: TTP, OS

• Secondary Endpoints: ORR, PFS, PD-L1 expression,

tumor efficacy

Sangro B et al. ASCO 2016. Abstract TPS4147. ClinicalTrials.gov: NCT02576509.

Phase III open-label study (vs Sorafenib as first-line treatment), planned N=726

Combination Therapies in the Era of anti-PD-1/PD-L1

Immunogenic

tumors

Non-immunogenic

tumors

Anti-PD-1 + Anti-CTLA-4 Combination Therapies Nivolumab and/or Ipilimumab for melanoma

Larkin J et al. N Engl J Med. 2015;373:23-34.

uestion about

Immune Checkpoint Inhibitors

Garon EB et al. N Engl J Med. 2015;372:2018-28.

Herbst RS et al. Lancet 2016;387:1540-50.

KEYNOTE-001/010 studies, Pembrolizumab for advanced NSCLC

1. Absence of Reliable Biomarker

45.4%

8.1%


CheckMate 040 – Nivolumab for HCC

PD-L1 expression of Tumor Cells (≥ 1%)

* Irrespective of PD-L1 expression

Biomarker: PD-L1 expression and anti-PD-1 response

Grigg C, Rizvi NA. J Immunother Cancer. 2016;4:48-57.

“ Quantifiable, reproducible IHC-based PD-L1 testing ? “

Reliable Biomarker ?

1) Cut-off value of positivity

- Dichotomous value ?

- 1% in CheckMate 010, CheckMate 459 trials

- 50% in KEYNOTE 010 study

- Continuous variable ?

2) Location of expression

- in tumor ?

- in inflammatory cells within microenvironment?

3) Quality of commercially available antibodies

4) Protein ? mRNA ?

Grigg C, Rizvi NA. J Immunother Cancer. 2016;4:48-57.

2. Immune-related Adverse Events (irAEs)

“ Archiles heel of ICPIs ”

Weber JS et al. J Clin Oncol. 2012;30:2691-7.

irAE: Kinetics

Kinetics of irAEs with Ipilimumab

Lee JH et al. Hepatol Res. 2011;41(1):79-86.

irAE: PD-L1 and hepatitis

PD-L1 (B7-H1) expression

Mesalamine (+)

Mesalamine (-)

Interferon-γ

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

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)


CheckMate 040 trial. Nivolumab for HCC

irAE in HCC patients

Michot JM et al. Eur J Cancer. 2016;54:139-48.

Frequencies of irAEs: CTLA-4 > PD-1/PD-L1

Distribution of irAEs with respective ICPIs Grade 1/2 irAEs Grade 3-5 irAEs

http://www.clinicaloptions.com/immuneAEtool

irAEs: Management

Utilize Online Interactive Tools

Grade 3/4 pneumonitis, nephritis, enterocol

itis, hepatitis, or infusion-related reaction

New or worsening neuropathy

Any life-threatening or grade 4 AE

Any severe or grade 3 recurrent AE

Hepatitis associated with AST/ALT > 5 x ULN

AST/ALT ≥ 50% ↑ from baseline lasting

≥ 1 wk*

Total bilirubin > 3 x ULN

*In pts with liver metastasis who begin treatment with grade 2 elevation of AST/ALT. †Pts receiving ipilimumab may tolerate treatment with PD-1/PD-L1 inhibitor alone. ‡Steroids do not appear to accelerate the rate of improvement.

Initiate steroid therapy

Permanently

discontinue ICPIs

Pembrolizumab adverse reaction management guide. Nivolumab adverse reaction management guide.

Ipilimumab adverse reaction management guide.

If improvement (-) in colitis or

pneumonitis

infliximab

or mycophenolate†

If no improvement in hepatitis,

consider mycophenolate

(infliximab contraindicated)

Grade 4 elevation of pancreatic enzymes Usually resolves with Tx

interruption‡

ummary

Summary

1. Inhibition of inhibitory immune checkpoints (CTLA-4,

PD-1/PD-L1): good targets of cancer immunotherapy

2. Despite short history, ICPIs demonstrated

a huge breakthrough in cancer therapy

- approved for melanoma, NSCLC, RCC, HL, and HNSCC.

3. For HCC (interim analysis)

- Showed promising results with 16% of ORR and 68% of DCR

- On-going trial: first-line nivolumab vs sorafenib

- Combination therapy with other ICPIs, LRT, or sorafenib?

4. Remained problems

- Reliable biomarker - Immune-related AEs

hank you for your attention

Immune Checkpoint Inhibitors

for HCC

Jeong-Hoon Lee, M.D., Ph.D.

Department of Internal Medicine and Liver Research Institute

Seoul National University College of Medicine

IL-12

Immune Escape of Tumor Cells: Three Phases

Vesely MD, et al. Annu Rev Immunol. 2011;29:235-271.

Elimination (cancer immunosurveillance)

Equilibrium (cancer persistence/dormancy)

Escape (cancer progression)

Chronic inflammation

Genetic instability and

immunoselection (ie, editing) VEGF

CD8+

T-cell

CD8+

T-cell CD8+

T-cell NKT

cell NK

CD4+

T-cell CD4+

T-cell

CD8+

T cell

γδ

T cell MΦ

CD4+

T-cell

CD8+

T-cell

NK MΦ

CD8+

T-cell M2

MΦ

PD-L1

CTLA-4

IFN-γ

TGF-β

IDO

IL-10

Galectin-1

CTLA-4

Treg MDSC

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