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Recent Advances in ICPI: Hepatocellular CarcinomaESMO Preceptorship Program: Immuno-oncologySingapore20-21 November, 2019

Dr. CHEE Cheng Ean

Senior Consultant, Medical Oncology,

National University Cancer Institute, Singapore

Assistant Professor,

Yong Loo Lin School of Medicine, National University Singapore

Program Director,

Medical Oncology Senior Residency Program,

Advanced GI Fellowship Program,

National University Health System, Singapore

Disclosures

• Advisory boards: Bayer, Taiho

• Speaker engagement: Amgen

• Travel: Taiho

Overview

• HCC in 2019

• Immune checkpoint inhibitors (ICPI) in HCC – Approved indications

• Immune checkpoint inhibitors (ICPI) in HCC – Unapproved indications

Where are we in 2019?

Nov 2007

Sorafenib1

FDA

approved

Apr 2017

Regorafenib3

FDA approved

Sept 2017

Nivolumab

accelerated

approval

based on

CM-0406

May 2017

Lenvatinib2

non-inferior

to sorafenib

REFLECT

study

Jan 2018

Cabozantinib4

met OS

endpoint in

CELESTIAL

study

Jun 2018

Ramucirumab5

met OS

endpoint in

REACH-2

study

July 2018

Atezolizumab &

Bevacizumab

FDA breakthrough

designation after

Phase 1b study

Aug 2018

Lenvatinib2

FDA

approved

Nov 2018

Pembrolizumab

accelerated

approval based

on KN-2246

Jan 2019

Cabozantinib4

FDA

approved

May 2019

Ramucirumab5

FDA

approved

Jun 2019

Pembrolizumab

KN-240 8

phase III did not

meet primary

endpoint

Oct 2019

Nivolumab

CM-4599 did not

meet primary

endpoint

Nov 2019

Atezolizumab &

Bevacizumab

IMbrave150

meets primary

endpoint

First-line treatment

Second-line treatment

1. Llovet JM, et al. N Engl J Med 2008; 359(4): 378-90. 2. Kudo M et al. Lancet 2018; 391(10126): 1163-73. 3. Bruix J et al. Lancet 2017; 389(10064): 56-66. 4. Abou-Alfa GK et al. N Engl J Med 2018; 379(1): 54-63. 5. Zhu AX et al. Lancet Oncol 2019; 20(2): 282-96. 6. Zhu AX et al. Lancet Oncol2018; 19(7): 940-52. 7. El-Khoueiry AB et al. Lancet 2017; 389(10088): 2492-502. 8. Finn et al. ASCO (Abs). 2019. 9. Yau et al. ESMO (abs). 2019.

HCC treatment landscape in 2019

1st line Sorafenib Lenvatinib Atezolizumab//Bevacizumab?

2nd line Regorafenib

Cabozantinib

Ramucirumab (AFP>400)

Pembrolizumab

Nivolumab

3rd line Cabozantinib

Immunotherapy in HCC

• HCC develops in an inflammatory milieu, and various studies have revealed a role for immune tolerance in the development of this cancer.1

• Evidence for anti-tumor immunity in HCC:

• Reports of spontaneous HCC regression.2

• In liver transplant, HCC tumors with marked T-cell infiltrate, high CD4:CD8 ratio have reduced risk of tumor recurrence.3

• In resected HCC, low intratumoral Tregs and high activated CD8+ cytotoxic T cells had improved DFS and OS.4

• Anti-tumor immunity is suppressed by various mechanisms in HCC.

1Iñarrairaegui et al. Clin. Cancer Res. 2017; 2Parks et al. J Gastrointest Cancer. 2015; 3Unitt et al. J Hepatol. 2006; 4Gao et al. JCO. 2007


• In 2013: 1st checkpoint inhibitor, anti-CTLA4, tremelimumab, was evaluated in HCC in a phase II study.

Patient Characteristics (N=20)

Hepatitis C – related advanced HCC

Child Pugh A or B (CP B – 43%)

PV thrombosis 29%

Extrahepatic mets 10%

Prior sorafenib 24%

Treatment-related toxicities (G3 or higher)

AST elevation 45%

ALT elevation 25%

T Bil elevation 10%

Neutropenia 5%

Rash 5%

Diarrhea 5%

** Adverse events were manageable,

AST/ALT increase were transient and were

not associated with deterioration of liver

function. Sangro et al. J Hepatol. 2013


• In 2013: 1st checkpoint inhibitor, anti-CTLA4, tremelimumab, was evaluated in HCC in a phase II study.

Response (N=17)

PR 17.6%

(duration: 3.6, 9.2, 15.8 mo)

SD 58.8%

Sangro et al. J Hepatol. 2013

mTTP: 6.48 mo

(95% CI, 3.95-9.14)

mOS: 8.2 mo

(CI, 4.64-21.34)

Anti-viral response:

Decrease in HCV viral load in 11

pts at Day 120 & 6 pts at Day 210.

CheckMate 040/CA209-040: Non-randomized, Open-label Phase 1/2 Study of Nivolumab in Uninfected, HCV-infected, or HBV-infected Advanced HCC

1. Melero I, et al. Oral presentation at ASCO GI 2017; 2. Clinicaltrials.gov. NCT01658878.

a RECIST v1.1; b Baseline and every 6 weeks through week 25 using the EQ-5D utility index and visual analog scale (VAS).

Start Date: September 20122

Estimated Study Completion Date: July 2018Estimated Primary Completion Date: August 2017Study Locations: North America, Europe, Asia, Central America

Key Eligibility Criteria1

Inclusion• Histologically confirmed advanced HCC not amenable to curative resection• Child-Pugh scores ≤ 7 (escalation) or ≤ 6 (expansion)• Progression on 1 prior line of systemic therapy or intolerance or refusal of sorafenib• AST and ALT ≤ 5 × upper limit of normal; bilirubin ≤ 3 mg/dL• For HBV-infected patients, viral load < 100 IU/mL and concomitant effective antiviral therapy• ECOG PS 0 or 1

Exclusion• Any history of hepatic encephalopathy• Prior or current clinically significant ascites• Active HBV and HCV co-infection

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)

Sorafenib Naive (1L)(n = 11)

Sorafenib Experienced (2L)

(n = 37)

Uninfected (n = 113)

HCV infected (n = 50)

HBV infected (n = 51)

Sorafenib Naive (1L)(n = 69)

Sorafenib Experienced (2L)

(n = 145)

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

• 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

ALT, alanine transaminase; AST, aspartate transaminase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus.

https://clinicaltrials.gov/ct2/show/NCT01658878?term=NCT01658878&rank=1

CheckMate 040: Toxicities

El-Khoueiry et al. Lancet. 2017

Dose escalation cohort:

AEs consistent with toxicity profile

of Nivolumab in other tumor types.

CheckMate 040: Time to Response and Duration of Response


• Responses occurred early in

treatment:

CheckMate 040: Nivolumab Efficacy (Dose expansion cohort)


CheckMate 040: Nivolumab Efficacy (Dose expansion cohort)


Summary:

• Objective response rate: 20%

• 3 CRs, 39 PRs

• OS for uninfected sorafenib progressor cohort: 13.2 mo (95% CI, 8.6-NE)

• OS for other dose expansion cohorts: Not reached

CheckMate 040: Best Percentage Change in Tumor Burden


• Responses were

independent of etiology

• Responses were

independent of prior

sorafenib

CheckMate 040: PD-L1 expression on tumor cells and response


Responses were independent

of PD-L1 expression on tumor

cells.

KEYNOTE-224: A Non-Randomised, Open-label, Phase 2 Trial of Pembrolizumab in Patients with Advanced HCC Previously Treated with Sorafenib

Zhu. ASCO GI. 2018

• N=104

• All patients had sorafenib as 1st line therapy


* At last disease measurement

Zhu et al. Lancet Oncol. 2018

• Median time to response: 2·1 months (IQR, 2·1–4·1)

• Median duration of response: Not reached (range: 3·1–14·6+*)

• Duration of response ≥9 months: 12 (77%)

ORR: 18%, (1 CR and 17 PRs)



Response was independent of etiology or intolerance/progressing on sorafenib



• TRAEs in more than 10% of participants were fatigue, diarrhea, pruritis, and rashes, which are

events that are typically observed following pembrolizumab treatment.

• Immune-mediated adverse events of any attribution in all treated patients (n=104) were

observed in 14% of patients (see Table).

* No HBV or HCV flare.



• Exploratory correlation of biomarker and outcome was performed.

• The combined positive score, was associated with response to anti-PD-1 therapy with

pembrolizumab in a subset of patients.

• The association with tumour proportion score was not significant.

• Limitations: Retrospective evaluation of PD-L1 expression, small sample size.

Combined positive score: the number of PD-L1-positive cells (tumor cells, lymphocytes, and macrophages)/total number of

viable tumor cells ×100.

Tumor proportion score: the percentage of viable tumor cells with partial or complete membrane staining of PD-L1 (≥1%)

relative to all viable tumor cells present in the sample.

KEYNOTE-240: Phase 3 Study of Pembrolizumab vs Best Supportive Care for Second-Line Therapy in Advanced HCC

Key Eligibility Criteria

− Pathologically/radiographically confirmed HCC

− Progression on/intolerance to sorafenib

− Child Pugh class A

− BCLC stage B/C

− ECOG PS 0-1

− Measurable disease per RECIST v1.1

− Main portal vein invasion was excluded

Pembrolizumab

200 mg Q3W + BSC

Saline-placebo Q3W + BSC

Stratification Factors

− Geographic region (Asia w/o Japan vs non-Asia w/Japan)

− Macrovascular invasion (Y vs N)

− AFP level (≥200 vs

KEYNOTE-240: Study Endpoints

• Primary

– OS

– PFS (RECIST v1.1, central review)

• Secondary

– ORR, DOR, DCR and TTP (all RECIST v1.1, central review)

– Safety and tolerability

• Response was assessed Q6W

Dual primary endpoints

KEYNOTE-240: Comments

• Results are similar to phase 2 KEYNOTE-224 (which lead to accelerated approval)

• Safety similar to anti-PD1 trials in HCC

• Validates that ORR with anti-PD1 in the 2nd-line setting is ~20%

• More Asian patients in KEYNOTE-240 (38%) vs. KN-224 (13%).

• Await KN-394.


Statistics of the study:

• OS: HR=0.781 (P=0.0238) (prespecified P=0.0174) – endpoint not met

• PFS (1st interim): HR=0.718 (P=0.0022) (prespecified P=0.0020) – endpoint almost met

• Overall, statistically - not met This is the problem with dual primary end points and multiple interim analyses (but it was pre-specified!).

• Placebo group did remarkably well!

• Main portal vein was excluded

• 47% went onto further lines of therapy (including 10% of anti-PD1/PDL1)


0 4 8 1 2 1 6 2 0 2 4 2 8 3 2

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T i m e ( m o n t h s )

Ov

er

all S

ur

viv

al (

%)

N o . a t r i s k

2 7 8 2 3 7 1 9 0 1 5 2 1 1 0 5 7 1 6 1 0

1 3 5 1 1 3 8 4 6 5 4 2 2 3 8 1 0

M e d i a n ( 9 5 % C I )

1 3 . 9 m o ( 1 1 . 6 - 1 6 . 0 )

1 0 . 6 m o ( 8 . 3 - 1 3 . 5 )

Events HR (95% CI) P

Pembrolizumab 183 0.781 (0.611-0.998) 0.0238

Placebo 101

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T i m e ( m o n t h s )

P

ro

gr

es

sio

n-

fr

ee

S

ur

viv

al (

%)

N o . a t r i s k

2 7 8 1 1 4 6 4 3 8 2 4 1 1 3 0

1 3 5 4 6 1 6 7 3 1 1 0

M e d i a n ( 9 5 % C I )

3 . 0 m o ( 2 . 8 - 4 . 1 )

2 . 8 m o ( 1 . 6 - 3 . 0 )

Events HR (95% CI) P

Pembrolizumab 214 0.718 (0.570-0.904) 0.0022 Placebo 118

1 9 . 4 %

6 . 7 %

Final Analysis - PFSOS

• Anti-PD1 in the second line setting does offer benefit (and durable one!) in a selected group of

patients.

Pembrolizumab

13.9 mo (11.6 – 16.0)

Placebo

10.6 mo (8.3 – 13.5)

Pembrolizumab

3.0 mo (2.8 – 4.1)

Placebo

2.8 mo (1.8 – 3.0)

Would I consider anti-PD1 therapy as 2nd-line treatment and

beyond in advanced HCC?

Yes… for patients who are TKI intolerant / ineligible


• Await further analyses eg. stratification with AFP (pre-specified)

Events/ HR Patients (95% CI)

Viral Status HBV 76/101

HCV 41/64 Uninfected 167/248

AFP (ng/mL)

CheckMate-040: Phase 1/2 study of Nivolumab + Ipilimumab combination in advanced HCC (2nd line)

Yao et al. ASCO. 2019

CheckMate-040: Baseline characteristics


2nd line and

beyond

CheckMate-040: Patient exposure and disposition


CheckMate-040: Response


ORR >30%

across all groups

CheckMate-040: Overall survival


Arm A

had best OS

CheckMate-040: Treatment-Related Adverse Events


Higher G3/4

toxicities in Arm A

CheckMate-040: Comments


• Phase 1/2 study (not a phase 3 study)

• Acceptable safety profile of dual agent IO in advanced HCC

• ORR >30% with dual agent IO

• But, comes at a price of increased toxicities (patient and financial)!

Would I consider Nivolumab + Ipilimumab as 2nd-line treatment

and beyond in advanced HCC?

Not yet…Await larger studies to confirm efficacy

CheckMate-459: Randomized open-label phase 3 study of Nivolumab vs Sorafenib as first-line treatment in advanced HCC

Yao et al. ESMO. 2019

CheckMate-459: No significant difference in overall survival (primary endpoint)

Some may have clinical

benefit (durable response)


CheckMate-459: Similar outcomes regardless of PD-L1 expression


CheckMate-459: Nivolumab had less toxicities


CheckMate-459: Better QoL with Nivolumab


CheckMate-459: Comments

• Primary endpoint (OS): HR=0.85 (P=0.0752) (prespecified P=0.0419) – not met

• PD-L1 not a predictive biomarker

• Sorafenib group did remarkably well! • Subsequent 20% IO, 23% another TKI

• Results confirms findings of CM-040 (Nivolumab 2nd-line study)• Response rate ~20%

• Safety favorable

• Improved QoL compared to Sorafenib

Would I consider Nivolumab as 1st-line treatment in advanced HCC?

Yes…For those who are TKI-ineligible upfront

Atezolizumab + Bevacizumab in HCC

1Stein et al. ASCO 2018. Abstract. 2Pishvaian et al. ESMO Congress 2018. Abstract. 3Lee et al. ESMO (Abs.) 2019

GO30140: Phase Ib results (Arm A)Drug Pts ORR DCR Safety

ASCO 20181 N=26 62%

(no CR)

All grade TRAE 21/26 (81%)

Grade 3/4 TRAE 9/26 (35%)

No Gr 5 TRAEs

Serious events: autoimmune encephalitis, mental

status change, intra-abdominal hemorrhage.

July 2018: FDA Granted Atezolizumab Combo Breakthrough Designation for Frontline HCC

ESMO 20182 N=68 34%

1 CR

22 PRs

78% All grade TRAE 49/68 (72%)

Grade 3/4 TRAE 17/68 (25%)

No Gr 5 TRAEs

Immune-related AEs requiring systemic

corticosteroid tx = 4 pts (6%)

ESMO 20193 N=104 36% 71% All grade TRAE 91/104 (88%)

Grade 3/4 TRAE 41/104 (39%)

Gr 5 TRAEs 3/104 (3%)


GO30140: Phase Ib results (Arm F)


Primary Endpoint: PFS metHR = 0.55 (0.4 – 0.74)

P = 0.00108

5.6 mo

3.4 mo

Awaiting results – ESMO ASIA 2019

Advanced HCC with Child-Pugh B Liver Function

Approved indication

1st line: Sorafenib (GIDEON)

1st or 2nd line: Limited data with ICPI.

• CheckMate-040 (Nivolumab)1: 4 patients (2%) with CP B

• KEYNOTE-224 (Pembrolizumab)2: 6 patients (6%) with CP B

• Tremelimumab (Hep C, phase 2 study, Sangro et al.)3: 9 patients (43%) with CP B

• 2019: CheckMate-040 (Nivolumab, Child-Pugh B cohort)4

Unapproved indication

1El-Khoueiry et al. Lancet. 2017; 2Zhu et al. Lancet Oncol. 2018; 3Sangro et al. J Hepatol. 2013; 4Kudo et al. ASCO GI (abs) 2019.

CheckMate-040 (Nivolumab, Child-Pugh B7/8 cohort)

Kudo et al. ASCO GI (abs) 2019.

• Prospective cohort (N=49)

• Sorafenib-naïve (n = 25) or -experienced (n = 24)

• 28 (57.1%) had vascular invasion or extrahepatic spread

• Treatment-related adverse events (TRAEs) were reported in 25 (51%) pts

• 4 (8.2%) pts had select hepatic TRAEs

• TRAEs led to discontinuation in 2 pts (4.1%)

ORR DCR mTTR mDOR mOS

10.2% 55.1% 2.7 mo 9.9 mo 7.6 mo

9.8 mo (sorafenib-naïve)

7.3 mo (sorafenib-treated)

Summary: 1st Line Therapies in Advanced HCC

Study Phase LineChild

PughControl arm Specifics

ORR,

%

DCR,

%

PFS,

month

s

OS,

mon

ths

Sorafenib

(SHARP)13 1st A Placebo 2 43 - 10.7*

Lenvatinib

(REFLECT)23 1st A Sorafenib No portal vein thrombosis 40 74 7.3 13.6*

Nivolumab

(CheckMate 459)33 1st A Sorafenib 15 55 3.7 16.4

Atezolizumab +

Bevacizumab

GO3014042 1st A Atezolizumab ~37-45% PV invasion 20 67 5.6* -

1. Llovet JM, et al. N Engl J Med 2008; 359(4): 378-90. 2. Kudo M et al. Lancet 2018; 391(10126): 1163-73. 3. Yau et al. ESMO (abs). 2019. 4. Lee et al. ESMO (Abs) 2019.

Summary: 2nd Line Therapies in Advanced HCC

Study Phase Line PtsPrior 1st

line

Child

PughSpecifics

ORR,

%

DCR,

%

PFS,

month

s

OS,

month

s

Regorafenib

(RESORCE)13 2nd 573 Sorafenib A

Radiographic progression on sorafenib,

Tolerated =/> 400 mg/day sorafenib for 20/28 days11 65 3.1 10.6

Cabozantinib

(CELESTIAL)23 2nd/3rd 707 Sorafenib A

After 1-2 prior therapies, inc. sorafenib

(27% received 2 prior systemic therapies)4 64 5.2 10.2

Ramucirumab

(REACH-2)33 2nd 292 Sorafenib A AFP =/>400 5 59.9 2.8 8.5

Nivolumab

(CM-040)41/2 2nd 214 Sorafenib A-B7

Progressed on =/> 1 prior therapy that inc. sorafenib

or intolerant / refused sorafenib20 64 4 NR

Nivolumab

(CM 040)51/2 2nd 49 Sorafenib B7-8


or intolerant / refused sorafenib10.2 55 - 7.6

Pembrolizumab

(KN-224)62 2nd 104 Sorafenib A 17 62 4.9 12.9

Pembrolizumab

(KN-240)73 2nd 413 Sorafenib A 18.4 62 3.0 13.9

Nivo 1 + Ipi 3

(CM 040)81/2 2nd 50 Sorafenib A


or intolerant / refused sorafenib32 54 - 22.8

1. Bruix J et al. Lancet 2017; 389(10064): 56-66. 2. Abou-Alfa GK et al. N Engl J Med 2018; 379(1): 54-63. 3. Zhu AX et al. Lancet Oncol 2019; 20(2): 282-96. 4. El-Khoueiry AB et al. Lancet 2017; 389(10088): 2492-502. 5. Kudo et al. ASCO GI (Abs). 2019. 6. Zhu AX et al. Lancet Oncol 2018; 19(7): 940-52. 7. Finn et al. ASCO (Abs). 2019. 8. Yau et al. ESMO (abs). 2019.

AA

AA

Summary: IO Therapies in Advanced HCC

1. Yau et al. ESMO (abs). 2019. 2. Lee et al. ESMO (Abs). 2019. 3. El-Khoueiry AB et al. Lancet 2017; 389(10088): 2492-502. 4. Kudo et al. ASCO GI (Abs.). 2019. 5. Zhu AX et al. Lancet Oncol 2018; 19(7): 940-52. 6. Finn et al. ASCO (Abs). 2019. 7. Yau et al. ASCO (Abs). 2019. 8. Ikeda et al. JCO. 2018;36:4076. 9. Lee et al. ESMO (Abs). 2019. 10. Kelley et al. JCO. 2017;35:4073. 11. Xu et al. JCO. 2018;36:4075.

Study Phase Line Pts Prior 1st lineChild

PughSpecifics ORR, %

DCR,

%

PFS,

months

OS,

months

Nivolumab

(CheckMate 459)13 1st 743 - A Vs. Sorafenib 15 55 3.7 16.4

Atezolizumab +

Bevacizumab

GO3014022 1st 119 - A

Vs. Atezolizumab

~37-45% PV invasion 20 67 5.6* -

Nivolumab

(CM-040)31/2 2nd 214 Sorafenib A-B7

Progressed on =/> 1 prior therapy that inc. sorafenib or

intolerant / refused sorafenib20 64 4 NR

Nivolumab

(CM-040)41/2 2nd 49 Sorafenib B7-8


intolerant / refused sorafenib10.2 55 - 7.6

Pembrolizumab

(KN-224)52 2nd 104 Sorafenib A 17 62 4.9 12.9

Pembrolizumab

(KN-240)63 2nd 413 Sorafenib A 18.4 62 3.0 13.9

Nivo 1 + Ipi 3

(CM 040)71/2 2nd 50 Sorafenib A


intolerant / refused sorafenib32 54 - 22.8

Pembrolizumab +

Lenvatinib81b 1st/2nd 26

None/

SorafenibA 42.3 100 9.7 NR

Atezolizumab +

Bevacizumab91b 1st 104 None A 36 71 - NR

Durvalumab +

Tremelimumab101/2 1st 40 None A 25 57.5 NA NA

SHR-1210 +

Apatinib111 2nd 18 None A 50 85.7 7.2 NR

AA

AA

BT

Conclusions

• HCC is an immunogenic disease.

• Treatment with ICPI provides durable response.

• Tumor responses occur early.

• Poor ECOG PS or poor liver function is not an excuse to give ICPI, but can be used cautiously.

• Refer for systemic therapy early to prevent deterioration of liver function.

• Important to work closely with Hepatologist to manage liver disease.

• Most experience with ICPI used is in advanced disease. ICPI in early and intermediate stage HCC – in clinical trials.

• Still in need of biomarker to identify subgroups who will benefit most from ICPI.

Thank you

[email protected]

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