ESMO SUMMIT LATIN AMERICA 2019Practice Changing Studies andCurrent Standards of Care ofHepatocellular Carcinoma

Arndt Vogel

CONFLICT OF INTEREST DISCLOSURESub-title

Honoraria from Roche, Bayer, MSD, BSM, Ipsen, Lilly, Amgen, BTG

TREATMENT OF HCC IN 2019

Vogel et al. ESMO CPG 2018, Annals of Oncology

LOCAL THERAPIES IN HCCMany options!

Nault et al. Journal of Hepatology 2018

TACE: MOST FREQUENTLY USED WORLD-WIDE

Lee et al., J Vasc Interv Radiol 2015

EVIDENCE FOR TACE

Llovet et al., Lancet 2002

950 patients screened, 70% ≥ 2 tumors, ∼5cm, Median: 2,8 treatmetns

17,9 (BSC!) vs. 28,7 months

Lencioni et al. Hepatology 2016

Real life

mOS: 19.4 months

Systematic review of 101 studies (n=10,108)Patients treated with lipiodol TACE

Freq

uenc

y (%

)

0

20

40

60

80

100

6 months

10

30

50

70

90

1 year

2 years

3 years

5 years

Phase-III Studie

PATIENT SELEKTION FORTACE IS KEY!HAP score to identify patients that benefit from TACE

0.00

0.25

0.50

0.75

1.00

0 20 40 60Survival (months)

HAP A HAP B HAP C HAP D

Derivation set

0.00

0.25

0.50

0.75

1.00

0 20 40 60Survival (months)

HAP A HAP B HAP C HAP D

Internal validation set

HAP score

Albumin < 36 g/dlBilirubin > 17 μmol/lAFP > 400 ng/mlMax. tumour > 7 cm

HAP PointsHAP A 0HAP B 1HAP C 2HAP D >2

N= 1714 N= 1714TACE

monthsA: 110B: 73C: 36D: 16

monthsA. 16B: 11C: 7D: 4

monthsA: 33B: 26C: 17D: 9

monthsA:33B: 21C: 13D: 7

Resection Sorafenib

T. Labeur/ Vogel/ Johnson; GO-TREAT HCC consortium @ILCA 2018

DEFINE THE TIME TO STOP TACEResponse matters!

0.00

0.25

0.50

0.75

1.00

0 20 40 60Overall survival (months)

18.4 months (95% C.I. 17.6, 19.2)ranging from 12.9 to 33.8

0.2

5.5

.75

10 20 40 60

Survival (months)

CR PR SD PD

Survival by mRECIST response

50836.02

(32.80, 40.33)

65321.32

(20.20, 22.96)

67413.88

(11.88, 15.00)

5046.97

(6.09, 7.93)

T. Labeur/ Vogel/ Johnson; GO-TREAT HCC consortium @ILCA 2018

DESPITE BEING “TACE-INELIGIBLE” ACCORDING TO GUIDELINES, A LARGE PROPORTION OF PATIENTS RECEIVE TACE

*Patients TACE-ineligible after inclusion, excluding those treated with sorafenib prior to TACE ineligibility

Received TACE (N=1,650)

39% (n=636) ineligible

61% (n=1,014) eligible

9% (n=47) started systemic therapy

at moment of ineligibility

91% (n=460) continued

TACE beyond point of

ineligibility

79% (n=363) never received

systemic therapy

Became TACE-ineligible (n=507)*

OPTIMIS, a global prospective observational study, examined the outcomes of patients with HCC treated with TACE, with or without subsequent sorafenib, in real-world practice

Adapted from Peck-Radosavljevic et al. ASCO 2018

EARLY SWITCH FROM TACE TO SYSTEMIC THERAPY

*Patients TACE-ineligible after inclusion, excluding those treated with sorafenib prior to TACE ineligibility

Received TACE (N=1,650)

39% (n=636) ineligible

61% (n=1,014) eligible

9% (n=47) started systemic therapy

at moment of ineligibility

91% (n=460) continued

TACE beyond point of

ineligibility

79% (n=363) never received

systemic therapy

Became TACE-ineligible (n=507)*

OPTIMIS, a global prospective observational study, examined the outcomes of patients with HCC treated with TACE, with or without subsequent sorafenib, in real-world practice

Median OS: 12.1 months‡Median OS: 16.2 months‡

Adapted from Peck-Radosavljevic et al. ASCO 2018

EVIDENCE FOR SIRT3 negative trials: no rescue treatment after TACE failure/ advanced disease

SIRveNIB

Chow et al., ASCO 2017

SARAH

Vilgrain et al., EASL 2017

SORAMIC

Ricke et al., EASL 2018

per protocol population

100% previous TACE 18% previous TACE 25% previous TACE

SORAFENIBStandard of care in first line

10.5 months

14.8 months

12.7 months

12.7 months

SOFIA (2008 - 2010)n=296 from Italy

INSIGHT (2008 - 2014)n=782, Austria + Germany

GIDEON (2009 - 2012)n=3202 from 39 countries

BCLC Study (2008 - 2011)n=147 from Spain

Iavarone Hepatology 2011.Reig J Hepatol. 2014.

Geschwind. Radiology 2016.Ganten ESMO 2014.

Median Overall Survival

Target: VEGF-1-3, PDGFR-b, KIT, FLT-3, and RET

Firstline

2 Phase III Studies: SHARP, AP

8 Phase III Studies as control arm

4 Phase IV Studies

Data for CP B patients

LENVATINIBFirst alternative to Sorafenib in 1st line

Targets: VEGFR1-3, FGFR1-4, PDGFR α, RET and KIT.

1 Phase III study: RESOURCE

Non-inferioritysek. endpoints ++

No main portal vain infiltration (V1)

Tumor burden below 50%

No experience in CP B

Kudo et al. Lancet 2018

RESPONSE MATTERS! Increased OS for responders in the REFLECT study

Patients at risk:ResponseNon-response

This analysis was performed in the overall REFLECT population.REFLECT was a phase III study of lenvatinib vs sorafenib in patients with 1L unresectable HCC*Mantel-Byar test

Median OS, months (95% CI)Response: 22.4 (19.7–26.0)Non-response: 11.4 (10.3–12.3)

HR=0.61 (95% CI: 0.49–0.76)p<0.001*

1.0

0.8

0.6

0.4

0.2

0

OS

estim

ate

0 6 12 18 24 30 36 42Time (month)

3 9 15 21 27 33 39

159795

151571

121362

93241

56129

2251

610

00

155721

138441

108291

76180

4183

1126

15

11.4 22.4

Kudo et al. ASCO GI 2018

2ND LINE THERAPY IN HCCIncreasing options!

02468

1012141618

ORR

(%)

Objective response

0 5 10 15 20

Nivolumab¹⁻² (N=145)

Pembrolizumab³…

Camrelizumab⁴ (N=217)

Durvalumab⁵ (N=40)

Regorafenib⁶ (N=379)

Cabozantinib⁷ (N=470)

Ramucirumab⁸ (N=197)

Median OS (months)

Overall survival

Anti-PD(L)1 TKI Anti-VEGF

1. El-Khoueiry et al. Lancet 2017; 2. Crocenzi et al. ASCO 2017; 3. Zhu et al. ASCO 20184. Qin et al. ESMO 2018; 5. Wainberg et al. ASCO 2017; 6. Bruix et al. Lancet 20177. Abou-Alfa et al. N Engl J Med 2018; 8. Zhu et al. Lancet Oncol 2019

SYSTEMIC TREATMENT 2019

Sorafenibtolerability

Regorafenib NivolumabPembrolizumab

RamucirumabCabozantinib

FIR

ST L

INE

SEC

ON

D L

INE

AFP > 400 ng/ml

3rd

L

Cabozantinib

Sorafenib

Sorafenib Lenvatinib

EVOLUATION OF MOS IN ADVANCED HCCSequencing will improve survival

11 months

26 months

28 months

Sorafenib

Nivolumab (Ph2)

Sorafenib Regorafenib

Lenvatinib 12 months

26 monthsLenvatinib Sorafenib

FUTURE OF IMMUNOTHERPAY IN HCC?First negative phase-3!

MANY IMMUNOTHERAPY COMBINATIONS ARE UNDER INVESTIGATION

Combinations of checkpoint inhibitors + anti-VEGF

Combinations of two checkpoint inhibitors

Pembrolizumab + regorafenib (phase Ib)Anti-PD1 + TKI

Durvalumab + tremelimumab (phase III)Anti-PDL1 + anti-CTLA4

Pembrolizumab (phase I/II)Anti-PD1

Durvalumab (phase I/II)Anti-PDL1

Avelumab▼ (phase II) Anti-PDL1

Camrelizumab + apatinib (phase II) Anti-PD1 + TKI

Atezolizumab + bevacizumab (phase III)Anti-PDL1 + anti-VEGF

Nivolumab + bevacizumab (phase I)Anti-PD1 + anti-VEGF

Nivolumab (phase III)Anti-PD1

Atezolizumab▼ (phase Ib)Anti-PDL1

Camrelizumab (phase II)Anti-PD1

Nivolumab + relatlimab (phase I/II)Anti-PD1 + anti-LAG3

Nivolumab + ipilimumab (phase II)Anti-PD1 + anti-CTLA4

Pembrolizumab + lenvatinib (phase III)Anti-PD1 + TKI

Nivolumab + lenvatinib (phase Ib) Anti-PD1 + TKI

Spartalizumab + sorafenib (phase II)Anti-PD1 + TKI

Tislelizumab (phase III)Anti-PD1

Spartalizumab (phase Ib/II)Anti-PD1

Cemiplimab (phase I)Anti-PD1

Monotherapy (checkpoint inhibitors – mostly in 2L)

Atezolizumab + cabozantinib (phase III)Anti-PDL1 + TKI

Avelumab + axitinib (phase Ib)Anti-PDL1 + TKI

Nivolumab + sorafenib (phase III)Anti-PD1 + TKI

PHASE IB DATA: PEMBROLIZUMAB + LENVATINIB

BOR (INV-mRECIST)(n=26)

Confirmedresponses only

Includingunconfirmedresponses

ORR, n (%) 7 (27) 11 (42)

CR – 1 (4)

PR – 10 (39)

SD – 15 (58)

PD – 0

Median PFS, months 9.7

Cha

nge

from

bas

elin

e (%

)

40

20

0

–20

–40

–60

–80

–100

HBV+ (n=6)

HCV+ (n=10)

Alcohol (n=6)

Unknown (n=3)

Other (n=1)

Part 1 (n=6)

Part 2 (n=20)

Best change in tumour size

BOR, best overall response; HCV, hepatitis C virus; INV, investigator assessed1. Adapted from Ikeda et al. ASCO 2018

-100-80-60-40-20

020406080

100

Max

imum

SLD

redu

ctio

n fr

om b

asel

ine

(%)

Response by INV-RECIST v1.1

Data cut-off: 26 July 2018*Data from four patients (6%) not evaluable or missing §Baseline EHS/MVI data from one patient missingEHS, extrahepatic spread; MVI, macrovascular invasionNE, not evaluable or missing; SLD, sum of longest diameter 1. Adapted from Pishvaian et al. ESMO 2018

CR

PR

SD

PD

NE

BOR (INV-RECIST v1.1) (n=73)ORR, n (%)* 23 (32)

CR 1 (1)PR 22 (30)SD 33 (45)PD 13 (18)

By aetiology, n/n (%)HBV 11/36 (31)HCV 10/23 (43)Non-viral 2/14 (14)

By EHS/MVI, n/n (%)§

EHS and/or MVI 18/64 (28)MVI negative 13/32 (41)EHS negative 9/22 (41)Neither EHS nor MVI 5/8 (63)

–20

–40

–60

–80

–100

PHASE IB DATA: ATEZOLIZUMAB + BEVACIZUMAB

TAKE HOME

Multidisciplinary evaluation is key!

Patients for potentially curative therapies (liver transplantation,

resection, RFA) need to be identified

TACE is the current standard of care for intermediate stage HCC, but we

need to better define the time point to switch to systemic therapies

SIRT is no rescue treatment after TACE, maybe alternative to TACE

TKIs (Sorafenib, Lenvatinib, Regorafenib, Cabozantinib) are currently

standard of care in 1st and 2nd line

Ramucirumab first non-TKI in 2nd line

IO therapy looks promising, but so far no positive phase-3