Ghassan Abou-Alfa, M.D., M.B.A.

Memorial Sloan-Kettering Cancer Center

ESMO 21st World Congress on Gastrointestinal Cancer

Barcelona

July 5, 2019

How to Integrate New Agents

in HCC (Sequence of Treatment)

The Role of TKIs

Ghassan Abou-Alfa, MD, MBA

Email: abou-alg@mskcc.org

Telephone: + 1 646 888 4184

Linkedin: Ghassan Abou-Alfa

Twitter: GABOUALFA

Disclosures➢ Research

ActaBiologica, Agios, Array, Astra Zeneca, Bayer, Beigene, BMS, Casi,

Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, Mabvax, Novartis,

OncoQuest, Polaris Puma, QED, Roche

➢ Consulting

3DMedcare, Agios, Alignmed, Amgen, Antengene, Aptus, Aslan, Astellas,

Astra Zeneca, Bayer, Beigene, Bioline, BMS, Boston Scientifc, Bridgebio,

Carsgen, Celgene, Casi, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis,

Flatiron, Genoscience, Halozyme, Hengrui, Incyte, Inovio, Ipsen, Jazz, Jansen,

Klus, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, Novella, Onxeo, PCI Biotech,

Pfizer, Pieris, QED, Redhill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax,

Tekmira, Twoxar, Vicus, Yakult, Yiviva

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

SHARP Overall Survival (ITT)

Llovet JM, et al. N Engl J Med. 2008;359: 378-390

SorafenibMedian: 46.3 weeks (10.7 months)

PlaceboMedian: 34.4 weeks (7.9 months)

Stable Disease and “Tumor Necrosis”Baseline Follow-up 1 Follow-up 2

Baseline Follow-up 1

2 months

Follow-up 2

4 months

Volume cm3 295 341 285

% Necrosis 2.09 53.07 51.03

Abou-Alfa, GK., et al. J Clin Oncol. 2006 Sep 10;24(26):4293-300

Abou-Alfa, GK. et al. ESMO, Stockholm , Sweden, October 2008

P value Volume Tumor Necrosis

(TN)

TN/ Volume

Ratio

AFP

Response 0.16 0.21 0.02 0.17

Survival 0.12 0.57 0.89 0.67

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

Regorafenib vs. Placebo Overall Survival

Bruix, J. et al. Lancet. Volume 389, No. 10064, p56–66, 7 January 2017

Median OS (95% CI)

Regorafenib: 10.6 months (9.1,

12.1)

Placebo: 7.8 months (6.3, 8.8

(hazard ratio [HR] 0.63; 95% CI

0.50, 0.79; P<0.001

Tovar V, et al. Gut 2017;66:530–540

Acquired Resistance to Sorafenib is Driven

by Activation of IGF and FGF Signaling

Exploratory Analysis of Survival

With the Sequence of

Sorafenib and Regorefanib

Finn R et al. GI Cancers Symposium 2017

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

Lenvatinib

1. LENVIMA Prescribing Information. Eisai Inc, Woodcliff Lake, NJ; May 2016.

2. Stjepanovic N, et al. Biologics. 2014;8:129-39.

FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; RET, rearranged during

transfection;

VEGFR, vascular endothelial growth factor receptor.

Lenvatinib

Tumor growth

control

Inhibition of

neoangiogenesis and

lymphangiogenesis

Inhibition of tumor

microenvironment

Reverse resistance to

antiangiogenic drugs

RET, KIT, PDGFR VEGFR1-3 FGFR, PDGFR FGFR1-4

Lenvatinib vs Sorafenib Primary Endpoint: OS

Kudo,M, et al. The Lancet 2018 391, 1163-1173DOI: (10.1016/S0140-6736(18)30207-1)

Lenvatinib vs Sorafenib PFS

Kudo,M, et al. The Lancet 2018 391, 1163-1173DOI: (10.1016/S0140-6736(18)30207-1)

Lenvatinib mRECIST Response

Kudo, M. et al. Lancet Volume 391, Issue 10126, 24–30 March 2018, Pages 1163-1173

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

CELESTIAL Overall SurvivalMedian 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

Hazard ratio 0.76 (95% CI 0.63-0.92), P=0.0049*

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

*Critical p-value ≤ 0.021 for second interim analysis

Months

Pro

babili

ty o

f O

S

0 3 6 9 12 15 18 21 24 27 30 33 36 39 420.0

0.2

0.4

0.6

0.8

1.0

Abou-Alfa, GK New England Journal of Medicine 379: 54-63

Second-Line Tivantinib vs Placebo

Rimassa, L, et al. Lancet Oncol. 2018 May;19(5):682-693.

MET as a Prognostic Factor

Median OS Patients Events

MET Dx Low 9.0 13 9

MET Dx High 3.8 15 15HR: 2.94 (95% CI: 1.16-7.43) Log Rank: P=0.02

Rimassa, L, et al. Abstract 4006. ASCO 2012

Pro

po

rtio

n o

f P

atie

nts

Su

rviv

ing

M o n th s

Pro

ba

bil

ity

of

OS

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6 3 9 4 2

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

A E = n o

A E = y e s

M o n th s

Pro

ba

bil

ity

of

OS

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6 3 9 4 2

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0A E = y e s

A E = n o

M o n th s

Pro

ba

bil

ity

of

PF

S

0 3 6 9 1 2 1 5 1 8 2 1 2 4

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0A E = y e s

A E = n o

M o n th s

Pro

ba

bil

ity

of

PF

S

0 3 6 9 1 2 1 5 1 8 2 1 2 4

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0A E = y e s

A E = n o

Cabozantinib Outcome Correlation with Adverse Events

PPE (any grade, first 8 wks) Hypertension (SBP ≥150, first 8 wks)

Abou-Alfa, GK, et al. J Clin Oncol 37, 2019 (suppl; abstr 4088)

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

Ramucirumab vs Placebo in Patients

with Baseline AFP > 400ng/mL

Zhu A et al. The Lancet Oncology, Vol. 20, No. 2, p282–296

Abou-Alfa, GK, The Lancet Oncology, Vol. 20, No. 2, p177–179

Ramucirumab : 8·5 months [95% CI

7·0–10·6]

Placebo: 7·3 months [5·4–9·1]

HR 0·710 [95% CI 0·531–0·949];

p=0·0199

Reach + Reach-2 AFP Marker

Pooled Analysis

Llovet, J. et al. J Clin Oncol 37, 2019 (suppl; abstr 4073)

Agenda

⚫ Sorafenib

⚫ Regorafenib

⚫ Lenvatinib

⚫ Cabozantinib

⚫ Ramicirumab

⚫ What to make of TKIs versus IOs?

TKIs First .. So FarFirst Line Second Line Third Line

Classic Sorafenib Regorafenib Checkpoint inhibitor

Novel Lenvatinib Cabozantinib Checkpoint inhibitor

Nivolumab Before

Classic First Line

Nivolumab Sorafenib Regorafenib

Nivolumab Before

Novel First Line

Nivolumab Lenvatinib Cabozantinib

Nivolumb as First Line Nivolumab Cabozantinib

Pembrolizumab

after TKI

Sorafenib Regorafenib Pembrolizumab

Pembrolizumab

in the midst of TKI

Lenvatinib Pembrolizumab Cabozantinib

AFP > 400 Ramucirumab

… and still TKIs FirstFirst Line Second Line Third Line

ClassicSorafenib Regorafenib Nivolumab

Pembrolizaumab

NovelLenvatinib Cabozantinib

Nivolumab

Pembrolizaumab

Pembrolizumab

after TKISorafenib Regorafenib

Nivolumab

Pembrolizaumab

Pembrolizumab

in the midst of TKILenvatinib

Nivolumab

PembrolizaumabCabozantinib

AFP > 400 Ramucirumab

Atezolizumab plus Bevacizumab

Stein S. et al J Clin Oncol 36, 2018 (suppl; abstr 4074)

The Cancer–Immunity Cycle

HIMALAYA: Durvalumab +

Tremelimumab vs SorafenibKey Eligibility Criteria

• Unresectable HCC not eligible for locoregional

therapies

• BCLC B or C

• Child–Pugh A

• No prior systemic

therapy

N ~ 1200

R

Durvalumab

Sorafenib

Durvalumab +

Tremelimumab

Endpoints

• Primary endpoints: OS

• Other endpoints: TTP, PFS, ORR, DCR, DoR, QoL

.

clinicaltrials.gov NCT03298451

Conclusions

➢ Sorafenib and levantinib are approved first line of therapy

➢ Regorafenib, cabozantinib, ramicirumab, are approved second line of therapy

➢ Checkpoint inhibitors so far have not shown an OS improvement in first or second line treatment