evolving treatment paradigm and future landscape in...

Evolving Treatment Paradigm

and Future Landscape in HCC

Tokyo Hepatitis Clinical Forum 29 Oct 2019

Masafumi Ikeda, MD, PhD.Department of Hepatobiliary & Pancreatic Oncology,

National Cancer Center Hospital East

Disclosure of COI

Presentator: Masafumi Ikeda, MD

My disclosure of COI are follows:

Employment/leadership position/Advisory role:

None

Stock ownership: None

Research fund: Bayer, Eisai, BMS,

Ono, Takeda, Roche, etc.

Honoraria (lecture, etc.): Bayer, Eisai, etc.

Others: None

Presentation overview

• Japanese practice and consensus

• Recent advances in systemic therapy


Lenvatinibvs. SorafenibREFLECT

Sunitinib vs. SorafenibSUN1170

Linifanib vs. Sorafenib

LiGHT

’07

Sorafenib vs. Placebo

SHARP


Asia-Pacific

Brivanib vs. Sorafenib

BRISK-FL

Sorafenib+Erlotinib vs. Sorafenib

SEARCH

Sora+FPiavs. Sorafenib

SILIUS

’08 ’12’11’10’09 ’13 ’17’16’15’14 ’19’18

Sora+DOXvs. Sorafenib

CALGB

Nivolumabvs. SorafenibCheckMate459

Development of newer agents for first-line treatments of advanced HCC

The results of phase III trials of newer agents

After the introduction of lenvatinib, our clinical

practice in HCC was dramatically changed.

Lenvatinib

RET, KIT, PDGFRα VEGFR1-3 FGFR, PDGFRβ FGFR1-4

➢ Lenvatinib is an oral

multikinase inhibitor targeting

VEGFR1-3, FGFR1-4,

PDGFRα, RET, and KIT.

Lenvatinib

Tumor growth

control

Inhibition of

neoangiogenesis

and

lymphangiogenesis

Inhibition of tumor

microenvironment

Reverse

resistance to

antiangiogenic

drugs

Lenvatinib was approved on March 2018 in Japan.

We can prescribe it in first, second or any lines.

Lenvatinib8 mg (BW<60 kg) or

12 mg (BW≥60 kg), qd

(n=478)

Sorafenib400 mg, bid

(n=476)n=954

Advanced HCC

・No prior Cx

・ECOG PS 0-1

・Child Pugh: A

Primary endpoint: OS

Secondary endpoints: TTP, PFS, ORR, safety

R

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REFLECT -First line-

Kudo M, et al. Lancet 2018

Lenvatinib vs. Sorafenib, Phase III:Study design

Lenvatinib vs. Sorafenib, Phase III:OS

Lenvatinib has demonstrated non-inferiority in OS

to sorafenib.

Best overall response, % mRECIST

Lenvatinib(n = 478)

Sorafenib(n = 476)

CR 2% 1%

PR 38% 12%

SD 33% 46%

SD (lasting ≥23 wks) 18% 19%

PD 17% 32%

ORR (CR+PR) 40.6% 12.4%

95% CI (36.2-45.0) (9.4-15.4)

P-value <0.0001

Lenvatinib vs. Sorafenib, Phase III:ORR -Independent review-

ORR by independent review was more favorable.

60 yrs, male, Child Pugh 5A, after resection for HCC.

Case: Extrahepatic metastases

S6 recurrent tumor Peritoneal metastases

AFP: 9,310 2.8

PIVKAII: 5,491 18

Before treatment

Lenvatinib 8 mg/day was initiated

After 3 years

After initiating lenvatinib, CR was obtained.

Lenvatinib was administered for a total of 3

years and discontinued because of sustained CR.

Currently, 1.5 year after the discontinuation of

lenvatinib, he is alive without recurrence.

70 yrs, female, Child Pugh 6A, no prior treatment.

Case: Vascular invasion

S7 Vv3(Delayed phase)

S7 Vv3(Arterial phase) Left pulmonary metastases

Right pulmonary metastases

Lenvatinib 8 mg/day was initiated

Before treatment

AFP: 71,905 10

PIVKAII: 62,926 30

After lenvatinib initiated, 13 months

ongoing in the CR.

After 10 mo

2%

50%

66%

85%

76%

81% 79%83%

76%

85%

90%85%

78%83%

98%

50%

34%

15%

24%

19% 21%17%

24%

15%

10%15%

22%17%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Japanese market research of1st line systemic therapy in HCC

Prescription share of lenvatinib has reached 80%

or more of 1st line systemic therapy.

Lenvatinib

Sorafenib

Number of prescription of lenvatinib exceeded that of

sorafenib immediately after the approval for HCC

The efficacy of real world data in Japan was

comparable to that of REFLECT trial.

Efficacy of lenvatinib in clinical practice in Japan: RELPEC group

-Real-life Practice Experts for HCC (RELPEC)-

Subjects: 152 patients, 13 centers in Japan

-TTP- -OS-

Median: 7.0 mo Median: Not reached

mRECIST

ORR: 38.7%

DCR: 86.0%

Hiraoka A, et al. 2019

Hospital Author n ORR DCR

Red Cross Hosp Sakamoto A 203 39% 83%

RELPEC Hiraoka A 152 38.7% 86.0%

Kurume Univ Nakano M 127 28% 62%

Yokohama City Univ Ogushi K 111 36% 77%

Gunma Univ Hatanaka T 94 30.4% 78.5%

Kyushu cancer center Sugimoto R 92 47% 75%

Hokkaido Univ Sho T 87 55.3% 91.5%

Yamaguchi Univ Saeki I 66 36.1% 55.7%

Chiba Univ Maruta S 62 40% ND

Saitama Univ Imai Y 62 51% 84%

Osaka City Univ Suou M 52 55% 64%

Musashino Red Cross Kaneko S 45 35.7% 69.0%

Kanagawa Cancer Center Morimoto M 41 80% 80%

Hiroshima Univ Aikata H 39 59.0% 82.1%

Tokushima Univ Tomonari T 38 57.6% 96.1%

Kyushu Medical Center Wada Y 37 32.4% 62.1%

Osaka Red Cross Hosp Nakanishi R 37 43.3% 83.3%

Osaka Univ Maesak K 35 30.0% 83.3%

Kanagawa Cancer Center Fukushima T 34 38% 79%

Toho Univ Mukoudu T 31 67.9% 92.9%

Osaka Medical Univ Yokohama K 24 25.0% 68.8%

Nagasaki Univ Sasaki R 23 43.5% 82.6%

Iwate Medical Univ Kuroda H 23 45.0% 85.0%

Kyushu Univ Ito S 22 20% 46.70%

Initial experience of lenvatinibAnnual meeting of Japan Association of Molecular Targeted Therapy for HCC 2019

ORR median (min-max): 36% (20-80%)

DCR median (min-max): 78% (47-96%)

Ref) REFLECT trial: ORR 41%, DCR 74%

The efficacy of lenvatinib in clinical practice

was comparable to that of REFLECT trial.

Japanese practice and consensus

-Summary-

• After the introduction of lenvatinib, Japanese

HCC practice was dramatically changed.

• In clinical practice, lenvatinib demonstrated

the comparable ORR to REFLECT trial.

Presentation overview

• Japanese practice and consensus

• Recent advances in systemic therapy


Lenvatinibvs. SorafenibREFLECT

Although nivolumab was extremely promising in phase I,

it was the negative result in the phase III trial.

Sunitinib vs. SorafenibSUN1170

Linifanib vs. Sorafenib

LiGHT

’07


SHARP


Asia-Pacific

Brivanib vs. Sorafenib

BRISK-FL

Sorafenib+Erlotinib vs. Sorafenib

SEARCH

Sora+FPiavs. Sorafenib

SILIUS

’08 ’12’11’10’09 ’13 ’17’16’15’14 ’19’18

Sora+DOXvs. Sorafenib

CALGB

Nivolumabvs. SorafenibCheckMate459

Development of newer agents for first-line treatments of advanced HCC


Nivolumab iv,240 mg, q2wAdvanced HCC

・No prior systemic Tx

・ECOG PS 0-1

・Child Pugh A Sorafenib, 400mg, bid

R

an

do

mi

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n=743

Nivolumab vs. Sorafenib, Phase III: Study design

Checkmate 459

NCT02576509

-First line-

Primary endpoint: OS

Secondary endpoints: ORR, TTP, PFS, etc.

Nivolumab vs. Sorafenib, Phase III: Overall survival

-Overall survival-

The result was no significant difference, but the authors

have been reported to be clinically meaningful results.Yau T, et al. ESMO 2019

Hazard ratio of each agents in comparison to sorafenib

The hazard ratio of nivolumab was lowest.

Hazard ratio 95%CI p-value

Sunitinib 1.30 1.13-1.50 0.0014

Brivanib 1.06 0.93-1.22 0.3730

Linifanib 1.046 0.896-1.221 ND

Sorafenib+Erlotinib 0.929 0.781-1.106 0.408

Sorafenib+Doxorubicin 1.06 0.80-1.40 0.24

Sorafenib+intra-arterial FP 1.009 0.743-1.371 0.955

SIRT(SARAH) 1.15 0.94-1.41 0.18

SIRT(SIRveNIB) 1.1 0.9-1.4 0.36

Lenvatinib 0.92 0.79-1.06 ND

Nivolumab 0.85 0.72-1.02 0.0752ND, no data.

Pembrolizumab demonstrated the negative result.

Brivanib vs. PlaceboBRISK-PS

Everolimus vs. PlaceboEVOLVE-1

Ramucirumabvs. Placebo

REACH

Regorafenib vs. PlaceboRESORCE

ADI-PEG20

vs. Placebo

’14 ’17 ’18’15’12 ’13 ’19’16

Tivantinib vs. Placebo

METIV-HCC

Cabozantinib vs. Placebo

CELESTIAL

Ramucirumabvs. PlaceboREACH2

S-1 vs. PlaceboS-CUBE

Pembrolizumab

vs. Placebo

KEYNOTE-240

Development of newer agents for second-line treatments of advanced HCC


Pembrolizumab200 mg, q3w

+BSCAdvanced HCC

・Refractory or

intolerant to sorafenib

・ECOG PS 0-1

・Child Pugh APlacebo+BSC

Co-primary endpoints: PFS, OS

Secondary endpoints: ORR, DCR, TTP,

duration of response, safety

R

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n=413

Pembrolizumab vs. Placebo, Phase III: Study design

Fin RS, et al. ASCO 2019

KEYNOTE-240

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

su

rv

iv

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

-Overall survival-

Because Efficacy boundary for OS was p<0.0174

(Hazard ratio=0.65), this result was negative.Fin RS, et al. ASCO 2019

Pembrolizumab vs. Placebo, Phase III: OS

Comparison of Pembrolizumab vs. other agents

RegorafenibCabozantinib Ramucirumab Pembrolizumab

PFS

HR (95%CI)

0.46

(0.37-0.56)

0.44

(0.36-0.52)

0.452

(0.339-0.603)

0.718

(0.570-0.904)

p-value <0.0001 <0.0001 <0.0001 0.00007

OS

HR (95%CI)

0.63

(0.50-0.79)

0.76

(0.63-0.92)

0.710

(0.531-0.949）0.781

(0.611-0.998)

p-value <0.0001 0.0049 0.019 0.0238

Pembrolizumab was inferior to the other agents.

Lenvatinib reduces TAM and induced activated cytotoxic

T cells, promoting antitumor activity of PD-1 inhibitors.

Ikeda M, et al.

ASCO 2018

Lenvatinib+Pembrolizumab: Mechanisms

Parameter, n (%)

mRECIST

Investigator

mRECIST

Central

RECIST1.1

Central

CR* 3.3% 10.0% 0%

PR* 40.0% 50.0% 53.3%

SD 53.3% 33.3% 36.7%

PD 0% 3.3% 6.7%

ORR* 43.3% 60.0% 53.3%

DCR 96.7% 93.3% 90.0%

ORR(Excluding confirmation)

36.7% 50.0% 36.7%

Extremely favorable responses were obtained.

n=30 (Phase I: n=6, Phase II: n=24)

Lenvatinib+Pembrolizumab, Phase Ib: ORR

Ikeda M, et al. AACR2019

All patients demonstrated tumor shrinkage effect.

Lenvatinib+Pembrolizumab, Phase Ib: Waterfall plots


Also, durable responses were seen.

Lenvatinib+Pembrolizumab, Phase Ib: Spider plots


Lenvatinib+PembrolizumabAdvanced HCC


・ECOG PS 0-1

・Child Pugh ALenvatinib+

Placebo

Co-primary endpoints: PFS, OS

Secondary endpoints: ORR, duration of response,

DCR, PFS, adverse events

R

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n=750NCT03713593

Lenvatinib+Pembrolizumab vs. Lenvatinib+Placebo, Phase III, LEAP-002

-First line-

Lee MS, et al. APPLE 2019

Favorable tumor shrinkage effect was reported

by atezolizumab plus bevacizumab.

ORR

RECIST1.1 (Central) 36%

mRECIST (Central) 39%

RECIST1.1 (Investigator ) 33%

Bevacizumab plus atezolizumab, Phase Ib: Waterfall plot

-Independent review facility (RECIST v1.1)-

APPLE2019 (Update)

Bevacizumab plus atezolizumab, Phase Ib: PFS and OS

Favorable PFS and OS were reported.

APPLE2019 (Update)

RECIST1.1

(Central)

mRECIST1.1

(Central)

RECIST1.1

(investigator)

PFS (median) 7.3 months 7.3 months 7.4 months

PFS at 6 months 54% 55% 56%

PFS at 12 months 35% 35% 38%

OS (median) 17.1 months

OS at 6 months 82%

OS at 12 months 63%

Lee MS, et al. APPLE 2019

Bevacizumab+AtezolizumabAdvanced HCC


・ECOG PS 0-1

・Child Pugh A Sorafenib

R

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n=480NCT03434379

Bevacizumab plus Atezolizumab vs. Sorafenib, Phase III, IMbrave 150

-First line-

Primary endpoint: OS, ORR

Secondary endpoints: PFS, TTP, duration of response,

adverse eventsFinn RS, et al. ASCO2018 TPS4141

2,3%6,6%

4,0% 4,6%

18,8%20,0%18,3%

25,0%

32,0%36.0%

53,0%

0,0%

10,0%

20,0%

30,0%

40,0%

50,0%

60,0%

Overa

ll r

esp

on

se r

ate

(%

)Comparison of ORR by RECIST 1.0 or 1.1

In the recent results of systemic therapy,

the encouraging ORRs were reported.

Intermediate stage Advanced stage

Paradigm shift by new agents

Present

TACESorafenib or

Lenvatinib

Regorafenib

Ramucirumab

T

A

C

E

Atezo+Beva or

Sorafenib or

Lenvatinib or

combo

Regorafenib or

Ramucirumab or

Cabozantinib or

combo

A few years later

The other

single or

combo

Japan Odds Ratio (95% CI)

Characteristic CategoryLenvatinib Sorafenib

Lenvatinib vs Sorafenibn % n n (%)

Overall 81 46.9 % 87 12.6 % 5.31 (2.54,11.11)

Age

<65 years

65-74 years

≥75 years

18

42

21

50.0 %

42.9 %

52.4 %

30

31

26

13.3 %

12.9 %

11.5 %

3.58 (0.81,15.77))

4.04 (1.24,13.2)

5.57 (1.40,22.15)

Body weight < 60 kg

≥ 60 kg

41

40

56.1 %

37.5 %

46

41

8.7 %

17.1 %

11.38 (3.35,38.64)

2.79 (1.03,7.53)

ECOG PS0

1

76

5

46.1 %

60.0 %

75

12

12.0 %

16.7 %

5.69 (2.54,12.74)

3.50 (0.57,21.48)

BCLC stageB

C

31

50

61.3 %

38.0 %

34

53

11.8 %

13.2 %

10.23 (2.99,35.01)

3.57(1.41,9.06)

Etiology

HBV

HCV

Alcohol

25

38

7

40.0 %

57.9 %

57.1%

22

51

3

13.6 %

11.8 %

33.3%

2.89 (0.67,12.53)

7.11 (1.41,9.06)

2.00 (0.21,19.23)

Lenvatinib vs. Sorafenib, Phase III:Japanese subgroup: subgroup of ORR

The ORR in BCLC-B was highest (61.3%) among all subgroups,

so, this population might be good candidate for lenvatinib.

Propensity score matched

*Clinical trial 14 pts, expanded access 1pt, real world data 15 pts

Up-to-7 Criteria Out

Child-Pugh A

Intermediate stage HCC patients who received

lenvatinib or TACE as an initial treatment

(n=642) 2006-2018

Lenvatinib

(n=37)

Excluded (n=466)

• Up to 7 criteria in (n=424)

• Child Pugh B or C (n=42)

TACE

(n=139)

Lenvatinib*

(n=30)

TACE

(n=60)

Kudo M, et al. 2019

Lenvatinib vs. TACE for intermediatestage HCC: Patients flows

Lenvatinib

n=30

TACE

n=60 Odds ratio (95%CI)

p-value

ORR 73.3% 33.3% 5.39 (1.90 – 16.67) <0.001

CR+PR+SD≥24w 96.7% 36.7% 48.1 (7.01 –2073.85) <0.001

DCR 100% 55.0%

CR 2 4

PR 20 16

SD 7 12

PD 0 26

NE 0 2

-Propensity matched analysis-

Kudo M, et al. 2019

The response rate was higher in the lenvatinib group.

Lenvatinib vs. TACE for intermediatestage HCC: Response rate

MedianHR

(95%CI)p-value

Lenvatinib 16.0 mo 0.19 <0.001

TACE 3.0 mo (0.10-0.35)

PFS was significantly better in the lenvatinib group.Kudo M, et al. 2019


Lenvatinib vs. TACE for intermediatestage HCC: PFS


MedianHR

(95%CI)p-value

Lenvatinib 37.9 mo 0.48 <0.01

TACE 21.3 mo (0.16-0.79)

Kudo M, et al. 2019

Lenvatinib vs. TACE for intermediatestage HCC: OS

OS was significantly better in the lenvatinib group.

TACEIntermediate stage HCC

・No prior TACE or

systemic Tx

・ECOG PS 0-1

・Child Pugh ASystemictherapy

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TACE vs. Systemic therapy for intermediate stage HCC

Primary endpoint: PFS

Secondary endpoints: OS, Adverse events, QOL

Recent advances in systemic therapy

as of Apr. 2013

• I-O monotherapy for advanced HCC have disappointing results.

• However, in the combination therapy of VEGF inhibitors and I-O agents, favorable tumor shrinkage effects have been reported, and will be a new standard treatment.

• Recently, lenvatinib has been reported to be favorable efficacy for intermediate stage HCC.

• In patients with intermediate stage HCC, it is necessary to elucidate which treatment is better, TACE or systemic therapy.

-Summary-

•Lenvatinib: new standard treatment

•VEGF inhibitor+I-O agent: new hope

•TACE: may be replaced by systemic therapy

-Take home messages-

Evolving treatment paradigm and future landscape in HCC

evolving treatment paradigm and future landscape in...

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