¿Qué ha ocurrido con el hepatocarcinoma?

Javier SastreServicioi de Oncología Médica

HC San Carlos de Madrid

jsastrev@salud.madrid.org

2008

SORAFENIB

1ªL

2ªL

2017

REGORAFENIB

2018

LENVATINIB

CABOZANTINIB

RAMUCIRUMAB

PEMBROLIZUMAB + LENVATINIBATEZOLIZUMAB + BEVACIZUMAB

NIVOLUMAB

PEMBROLIZUMAB

Phase III REFLECT Trial design

Advanced

HCC 1:1

Sorafenib 400 mg/12h

Lenvatinib 12 mg/day

(8mg in < 60Kg)

Treatment until disease

Progression or

unaceptable toxicity

Stratification factors:

1. Region (Pacific Asia vs Non Pacific Asia)

2. Vascular invasion or extrahepatic disease

3. ECOG (0 vs 1)

4. Weight (< 60Kg vs > 60 Kg)

Primary objective:

Overall survival

Secondary objectives:

PFS

Response rate

Toxicity and Quality of Live

Lenvatinib pharmacokinetics

940 ptes

REFLECT: Assessments and Statistical analysis

• The primary end-point of OS was first tested for noninferiority then for superiority.– The required number of events for the primary analysis was 700 deaths.

• The HR and its 95% CI were estimated from a Cox proportional hazard model, withtreatment group as a factor and the analysis stratified according to randomizationfactors:

– The noninfeiority margin was set at 1.08 based on previous phase 3 trials of sorafenib.

– Noninferiority would be declared if the upper limit of the 2-sided 95% CI for HR was < 1.08.

• A fixed-sequence procidure was followed to control the overall type I error rate of analysis for efficacy endpoints at a = 0.05 (2-sided).

• After noninferiority was declared, secondary efficacy endpoints were tested:– Differences in PFS and TTP were tested using stratified log-rank test with randomization stratification factors

and the associated HR and its 95% CI were evaluated

– A difference in ORR was tested using the Cochran-Mantel-Haenszel chi-square test with randomizationstratification factors as strata, and the associated odds ratio and its 95% CI were evaluated.

• To assess futility, 2 interim analyses were performed using Bayesian predicitveprobability in a noninferiority design.

REFLECT: Primary end-point (OS)

Kuso M. Lancet 2018 Published online February 9, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30207-1

REFLECT: Secondary objective (PFS)

Kuso M. Lancet 2018 Published online February 9, 2018 http://dx.doi.org/10.1016/S0140-6736(18)30207-1

Presented By Ann-Lii Cheng at 2017 ASCO Annual Meeting

Presented By Ann-Lii Cheng at 2017 ASCO Annual Meeting

RESOURCE: Primary and Secondary end-points

10.6m vs 7.8m

3.1m vs 1.5m

RESOURCE: Subgroup analysis

Bruix et al. Lancet Oncol. 2016

Reducción de dosis: 54% (vs. 10% pbo.)

Interrupción tto: 10% (vs. 4% pbo.)

Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium

Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium

No. at Risk

Cabozantinib 470 382 281 206 159 116 93 63 44 31 22 12 4 1 0

Placebo 237 190 117 82 57 37 25 20 15 10 7 5 3 0 0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babilit

y o

f O

S

Time (months)

Abou-Alfa GK, et al. ASCO GI 2018;Poster presentation 207 (Board A4)

Median OS

mo (95% CI)

No. of

deaths

Cabozantinib (n=470) 10.2 (9.1-12.0) 317

Placebo (n=237) 8.0 (6.8-9.4) 167

HR=0.76 (95% CI 0.63–0.92), p=0.0049*

CELESTIAL: OS

Median PFSmo (95% CI)

No. ofevents

Cabozantinib(N=470)

5.2 (4.0–5.5) 349

Placebo (N=237) 1.9 (1.9–1.9) 205

Progression-free survival assessed per RECIST 1.1

0 3 6 9 12 15 18 21 24

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babilit

y o

f PFS

Time (months)

No. at RiskCabozantinib

Placebo

470

237

266

70

131

21

80

13

39

5

15

2

10

2

3

2

3

1

HR=0.44 (95% CI 0.36–0.52), P<0.0001

Abou-Alfa GK, et al. ASCO GI 2018;Poster presentation 207 (Board A4)

Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium

Presented By Ghassan Abou-Alfa at 2018 Gastrointestinal Cancers Symposium

REACH 2: Study Design

R

A

N

D

O

M

I

Z

E

2:1

Stratification factors

• Macrovascular invasion

(yes vs. no)

• ECOG PS (0 vs. 1)

• Geographic region

• Americas, Europe,

Israel and Australia

• Asia (except Japan)

• Japan

Primary endpoint: Overall survival

Secondary endpoints:

• PFS, TTP, ORR

• Time to deterioration in FACT

Hepatobiliary Symptom Index-8

(FHSI-8)

• Time to deterioration in ECOG PS

• Safety, PK, Immunogenicity

• Baseline AFP ≥400

ng/mL

• BCLC stage B/C

• Child Pugh A

• ECOG PS 0/1

• Prior sorafenibPlacebo + BSC

Q2W

Ramucirumab + BSC

8 mg/kg IV Q2W

Statistical assumptions and analysis

• 80% power, alpha 0.05

• HR 0.67

• mOS 6.7 months ramucirumab vs. 4.5 months placebo

• N=279 (2:1 randomization, ramucirumab vs placebo)

• 221 events

ClinicalTrials.gov NCT02435433

REACH 2: Overall Survival

Ramucirumab Placebo Difference P-value

Patients / Events 197/147 95/74

Median, months 8.5 7.3 1.2

HR (95% CI) 0.710 (0.531, 0.949) 0.0199

Survival rate (%)

12 months 36.8 30.3 6.5 0.2930

18 months 24.5 11.3 13.2 0.0187

Adverse EventsRamucirumab Placebo

n (%) n=197 n = 95

Discontinuation due to treatment-related AEa 21 (10.7) 3 (3.2)

Dose adjustmentb due to AE 68 (34.5) 13 (13.7)

Deaths due to treatment-related AEa 3 (1.5)

TEAEs in ≥ 15% Patients in Ramucirumab arm Any Grade Grade ≥3 Any Grade Grade ≥3

Patients with ≥ 1 TEAE 191 (97.0) 116 (58.9) 82 (86.3) 42 (44.2)

Fatigue 54 (27.4) 7 (3.6) 16 (16.8) 3 (3.2)

Peripheral edema 50 (25.4) 3 (1.5) 13 (13.7) 0

Hypertension 48 (24.4) 24 (12.2) 12 (12.6) 5 (5.3)

Decreased appetite 46 (23.4) 3 (1.5) 19 (20.0) 1 (1.1)

Proteinuria 40 (20.3) 4 (2.0) 4 (4.2) 0

Abdominal pain 39 (19.8) 3 (1.5) 12 (12.6) 2 (2.1)

Nausea 37 (18.8) 0 11 (11.6) 0

Ascites 35 (17.8) 8 (4.1) 7 (7.4) 2 (2.1)

Diarrhea 32 (16.2) 0 14 (14.7) 1 (1.1)

AE = Adverse Events aRelated per investigator judgement; bDose adjustment = dose delay, dose reduction and dose omission

• There are a number of approaches to immunotherapy for HCC:1,2

1. Feun LG et al. Hepatoma Res 2017;3:43–51.2. Greten TF, et al. Clin Cancer Res. 2013;19:6678–6685.

Antibody

CTL mediated lysisTumor cell

death

Peptides

Cytokines

Enhanced

T-cell function

Foxp3+ Treg

IL-10, TGF-β

MDSC

T-cell

activation

T-cell

T-cell activation

& priming

Antibody

Oncolytic

virusTumor

ablation

Checkpoint

blockadeCytokines (GM-

CSF,

IL-2, IFN-y, etc)

Dendritic

cells

Cancer Vaccines

Elimination of

suppressor cells

Blockade of

immunosuppressive

cytokines

There are a number of ongoing checkpoint inhibitor studies in HCC

Tumour entity Investigated regimen Trial identifier

HCC Nivolumab (anti PD-1 Ab) NCT02576509

HCC Nivolumab (anti PD-1 Ab) plus CC-122 (immunostimulatorypathway modifier)

NCT02859324

HCC Nivolumab (anti PD-1 Ab) plus LRT (Yttrium 90Y glass microspheres)

NCT02837029

HCC Nivolumab (anti PD-1 Ab) plus ipilimumab (anti CTLA-4 Ab) NCT01658878

HCC PDR001 (anti PD-1 Ab) plus INC280 (c-Met inhibitor) NCT02795429

HCC Pembrolizumab (anti PD-1 Ab) NCT02702401

HCC Pembrolizumab (anti PD-1 Ab) NCT02940496

HCC Pembrolizumab (anti PD-1 Ab) plus dendritic cells, cytokine-induced killer cells

NCT02886897

HCC Atezolizumab + bevacizumab vs sorafenib

HCC Tremelimumab (anti CTLA-4 Ab) NCT01853618

HCC Tremelimumab (anti CTLA-4 Ab) plus durvalumab (anti PD-1L Ab) NCT02519348

HCC Tremelimumab (anti CTLA-4 Ab), durvalumab (anti PD-1L Ab) plus LRT

NCT02821754

Phase 1/2 Study of Nivolumab ± Other Agents in HCC (CheckMate040)1

1. CheckMate 040 (NCT01658878). Available at: https://clinicaltrials.gov/ct2/show/NCT01658878?term=checkmate+040&rank=1 (Accessed January 2018).

2. El-Khoueiry AB et al. The Lancet 2017:389:2492–2502.

Cabo, cabozantinib; Ipi, ipilimumab; Nivo, nivolumab.

Cohort 1: NivoDose

EscalationUninfected HCC

HCV-infected HCCHBV-infected HCC

Patients with advanced HCC (N=620)

Inclusion criteria (cohort non-specific*):1

• Advanced HCC ineligible for, or progressive disease after, surgical and/or locoregionaltherapies

• ECOG PS 0 or 1

Exclusion criteria (cohort non-specific*):

• Prior or current clinically significant ascites

• History of hepatic encephalopathy

• Prior anti-PD-1/PD-L1/PD-L2 or other antibody therapy2

Cohort 3: 1L Nivo vs Sorafenib

Cohort 4: Nivo + Ipi

Cohort 6: Nivo + Cabo vs Nivo + Cabo + Ipi

Study Endpoints

• Primary:

• Safety, tolerability

• ORR

• Secondary:

• CR

• DCR

• DOR

• TTR

• TTP

• PFS

• OS

Enrollment is ongoing

Cohort 2: Nivo

Dose ExpansionUninfected sorafenib

naïve/intolerantUninfected sorafenib

progressorsHCV-infected HCCHBV-infected HCC

Cohort 5: Nivo in Child-Pugh B7 to B8

*Cohort specific inclusion/exclusion criteria not listed here

Data

available2

CheckMate 040: Overall survival

Study Design

Presented By Andrew Zhu at 2018 Gastrointestinal Cancers Symposium

KEYNOTE-224: Pembrolizumab in HCC previouslytreated with Sorafenib

Presented By Andrew Zhu at 2018 Gastrointestinal Cancers Symposium

Slide 6

Presented By Andrew Zhu at 2018 Gastrointestinal Cancers Symposium

Ikeda et al. @ASCO 2018

A Phase 1b Trial of Lenvatinib (LEN) Plus Pembrolizumab

in Patients With Unresectable HCC

ORR: 42%

2008

SORAFENIB

1ªL

2ªL

2017

REGORAFENIB

2018

LENVATINIB

CABOZANTINIB

RAMUCIRUMAB

PEMBROLIZUMAB + LENVATINIBATEZOLIZUMAB + BEVACIZUMAB

NIVOLUMAB

PEMBROLIZUMAB

Conclusiones