targeted therapy for advanced hepatocellular carcinoma...

Targeted Therapy for Advanced Hepatocellular Carcinoma (HCC)

Dr ZEE Ying Kiat

HASLD Conference

Ho Chi Minh City, 18 November 2018

Scope • Background

• Staging and treatment strategies

• Current systemic therapy

• Future perspectives

• Managing treatment-related toxicities

• Conclusions

Background

HCC: A Deadly Tumour on the Rise • HCC is the 7th most common cancer worldwide and is the 3rd leading cause of cancer-related

mortality1

• Most cases of HCC arise as a result of chronic liver inflammation or injury2

• The incidence of HCC is increasing due to the long-term consequences of chronic hepatitis C and hepatitis B viral infections3

• Most patients newly diagnosed with HCC are not candidates for curative treatment because of gross vascular invasion, extrahepatic metastases and/or poor liver function4

1. Ghouri YA et al. J Carcinog. 2017; 16:1. 2. Moradpour D et al. Eur J Gastroenterol Hepatol. 2005;17:477-483. 3. El-Serag HB, Mason AC. N Engl J Med. 1999;340(10):745-750. 4. Llovet JM et al. Hepatology. 1999;30:1434-1440.

Staging and treatment strategies

HCC: BCLC Staging and Treatment Strategy Barcelona Clinic Liver Cancer

1. Forner A et al. Lancet. 2018 ;391(10127):1301-1314.

Historically No Clear Benefit with Traditional Cytotoxic Therapies

No standard systemic therapy for advanced HCC prior to 2007

1. Abou-Alfa GK. J Clin Oncol. 2004.

Current systemic therapy

Systemic Targeted Therapy for Advanced Disease Sorafenib: Mechanism of action

Induces tumour cell apoptosis or inhibits tumour Exerts an anti-angiogenic effect by targeting the cell proliferation by targeting the RAF/MEK/ERK receptor tyrosine kinases VEGFR-2, VEGFR-3 and

PDGFR, and their associated signaling cascades8 pathway at the level of RAF kinase8

1. Strumberg D et al. Drugs Today. 2005;41(12): 773.

Systemic Targeted Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies

SHARP Clinical Trial Asia-Pacific Study

1. Llovet JM et al. N Engl J Med. 2008;359(4):378-390. 2. Cheng AL et al. Lancet Oncol. 2009;10(1):25-34.


Patients in the Asia-Pacific Study also had more prior locoregional therapies



One-third of patients required dose reductions due to toxicity


Systemic Targeted Therapy for Advanced Disease Failed Phase III studies

Indication / Target Population

Acronym Phase III Comparison (Active vs Control)

Primary Outcome

Child- Pugh

First line / Advanced HCC

BRISK-FL

-

-

SEARCH

-

SECOX

-

Brivanib vs Sorafenib

Linifanib vs Sorafenib

Sunitinib vs Sorafenib

Sorafenib + Erlotinib vs Sorafenib

Sorafenib + Cisplatin + 5FU vs Sorafenib

Sorafenib + Capecitabine + Oxaliplatin vs Sorafenib

Sorafenib + Doxorubicin vs Sorafenib

OS

OS

OS

OS

OS

OS

OS

A

A

A

A

A/B(7)

A

A

Second line / Advanced HCC

EVOLVE-1

BRISK

BRISK-APS

REACH

Everolimus vs Placebo

Brivanib vs Placebo

Brivanib vs Placebo

Ramucirumab vs Placebo

OS

OS

OS

OS

A

A/B(7)

A/B(7)

A/B(8) Adjuvant / Early HCC post resection or ablation

STORM Sorafenib vs Placebo RFS A

Systemic Targeted Therapy for Advanced Disease First-line lenvatinib vs sorafenib: Phase III Small molecule inhibitor of VEGFR1-3, PDGFR, FGFR, KIT and RET

REFLECT (non-inferiority) trial

Stratified by region (Asia-Pacific vs Western), MVI and/or EHS (yes vs no), ECOG PS (0 vs 1), body weight

(< 60 kg vs ≥ 60 kg)

Pts with unresectable, previously untreated HCC, Child-Pugh A, ECOG PS 0-1

(N = 954)

Treatment continued until PD, unacceptable toxicity, or

withdrawal of consent

*Body weight < 60 kg, 8 mg; body weight ≥ 60 kg, 12 mg.

Primary endpoint: OS (ITT) Secondary endpoints: PFS, TTP, RR, QoL MVI, macrovascular involvement; ECOG, Eastern Cooperative Oncology Group; PS, performance status; PD, progressive disease; OS, overall survival; ITT, intent to treat; PFS, progression free survival; TTP, time to progression, RR, response rate; QoL, quality of life

1. Kudo M et al. Lancet. 2018 Mar 24;391(10126):1163-1173

Sorafenib 400 mg BID (n = 476)

Lenvatinib PO daily* (n = 478)

Systemic Targeted Therapy for Advanced Disease First-line lenvatinib vs sorafenib: Phase III REFLECT (non-inferiority) trial

(n = 478) (n = 476)

*P < .00001 vs sorafenib

Conclusion: lenvatinib non-inferior to sorafenib in OS in first-line setting for unresectable HCC Statistically significant improvements in PFS, TTP, and RR for lenvatinib vs sorafenib

OS, overall survival; PFS, progression free survival; TTP, time to progression; RR, response rate.


Outcome Lenvatinib Sorafenib

mOS, mos (95% CI) 13.6 (12.1-14.9) 12.3 (10.4-13.9)

mPFS, mos (95% CI) 7.4 (6.9-8.8)* 3.7 (3.6-4.6)

mTTP, mos (95% CI) 8.9 (7.4-9.2)* 3.7 (3.6-5.4)

RR, n (%) 115 (24.1)* 44 (9.2)

Systemic Targeted Therapy for Advanced Disease First-line lenvatinib vs sorafenib: Phase III REFLECT (non-inferiority) trial

Grade 3/4

Grade 3/4 Any Any

count

128 (27) 14 (3) 249 (52) 54 (11) syndrome


Lenvatinib Sorafenib

TEAEs Occurring in (n = 476) (n = 475) ≥ 15% of Pts, n (%)

Decreased platelet 87 (18) 26 (6) 58 (12) 16 (3)

Abdominal pain 81 (17) 8 (2) 87 (18) 13 (3)

Hypothyroidism 78 (16) 0 8 (2) 0

Vomiting 77 (16) 6 (1) 36 (8) 5 (1)

Constipation 76 (16) 3 (1) 52 (11) 0

Elevated AST 65 (14) 24 (5) 80 (17) 38 (8)

Rash 46 (10) 0 76 (16) 2 (< 1)

Alopecia 14 (3) 0 119 (25) 0

Lenvatinib Sorafenib

TEAEs Occurring in (n = 476) (n = 475) ≥ 15% of Pts, n (%)

Any Grade Grade 3/4 Any 3/4

Hypertension 201 (42) 111 (23) 144 (30) 68 (14)

Diarrhea 184 (39) 20 (4) 220 (46) 20 (4)

Decreased appetite 162 (34) 22 (5) 127 (27) 6 (1)

Decreased weight 147 (31) 36 (8) 106 (22) 14 (3)

Fatigue 141 (30) 18 (4) 119 (25) 17 (4)

Hand-foot

Proteinuria 117 (25) 27 (6) 54 (11) 8 (2)

Dysphonia 113 (24) 1 (< 1) 57 (12) 0

Nausea 93 (20) 4 (1) 68 (14) 4 (1)

Systemic Targeted Therapy for Advanced Second-line regorafenib: Phase III RESORCE study Small molecule inhibitor of VEGFR1-3, TIE2, PDGFR, FGFR, KIT, RET and RAF

4-wk cycles

Disease

Randomized 2:1

Pts with BCLC stage B or C HCC; documented PD on sorafenib ≥ 20

days at ≥ 400 mg/day; Child-Pugh A liver

function; ECOG PS 0-1

(N = 573)

All pts treated until PD, death, or unacceptable

toxicity

Primary endpoint: OS (ITT) Secondary endpoints: PFS, TTP, RR, DCR BSC, best supportive care; DCR, disease control rate; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; ITT, intent to treat; PD, progressive disease; PS, performance status; TTP,

time to progression, RR, response rate.

1. Bruix J et al. Lancet. 2017; 389(10064):56-663.

Placebo + BSC PO daily Wks 1-3

(n = 194)

Regorafenib + BSC 160 mg PO daily Wks 1-3

(n = 379)

Systemic Targeted Therapy for Advanced study

Disease Second-line regorafenib: Phase III RESORCE

*HR 0.44; 95% CI: 0.36-0.55; P < .001; †P = .005

38% reduction in risk of death (HR: 0.62; 95% CI: 0.50-0.78; P < .001) 54% reduction in risk of progression or death (HR: 0.46; 95% CI: 0.37-0.56; P < .001)

DCR (CR + PR + SD): 65.2% vs 36.1% (P < .001)

DCR, disease control rate; SD, stable disease; TTP, time to progression.


Endpoint Regorafenib Placebo (n = 379) (n = 194)

Median OS, mos 10.6 7.8

Median PFS, mos 3.1 1.5

Median TTP 3.2* 1.5*

RR, % 10.6† 4.1†

Systemic Targeted Therapy for Advanced study

Disease Second-line regorafenib: Phase III RESORCE


Adverse Events, % Regorafenib Placebo (n = 379) (n = 194)

Any ≥ grade 3 adverse events 79.7 58.5

Hypertension 15.2

4.7

Hand–foot syndrome 12.6

0.5

Fatigue 9.1

4.7

Diarrhea 3.2

0

Dose modifications due to 68.2 31.1 adverse events Deaths occurring ≤ 30 days 13.4 19.7 after last dose

Systemic Targeted Therapy for Advanced Second-line cabozantinib: Phase III CELESTIAL study Small molecule inhibitor of MET, VEGF and AXL

Disease

Stratified by region (Asia-Pacific vs other), etiology (HBV, HCV, or other), and

EHS and/or vascular invasion (Yes or No)

Patients with unresectable HCC following failure of previous

sorafenib therapy; stage B/C BCLC;

≥ 1 target lesion per mRECIST; Child-Pugh A; ECOG PS 0 or 1

(n = 607)

Primary endpoint: OS Secondary endpoints: PFS, RR ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; PS, performance status; OS, overall survival; PFS, progression free survival, RR, response rate.

1. Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63.

Placebo daily (n = 237)

Cabozantinib 60 mg daily (n = 470)

Systemic Targeted Therapy for Advanced Disease Second-line cabozantinib: Phase III CELESTIAL study

OS, overall survival; PFS, progression free survival; RR, response rate


Endpoint Cabozantinib Placebo P value (n = 470) (n = 237)

Median OS, mos 10.2 8.0 P = .005

Median PFS, mos 5.2 1.9 P < .001

RR, % 4 < 1 P = .009

Systemic Targeted Therapy for Advanced Disease Second-line cabozantinib: Phase III CELESTIAL study


Systemic Targeted Therapy for Advanced Second-line ramucirumab: Phase III REACH-2 study Monoclonal VEGFR2 antibody

Stratified by macrovascular invasion, ECOG PS (0 vs 1), geographic region (Japan vs rest of Asia vs other regions)

Disease

Advanced HCC patients with baseline AFP ≥ 400 ng/mL, BCLC

stage B/C, Child-Pugh A, ECOG PS 0/1 with prior sorafenib

(N = 292)

Until PD or unacceptable

toxicity

Primary: OS Secondary: PFS, TTP, ORR

OS, overall survival; PFS, progression free survival; TTP, time to progression; ORR, overall response rate

1. Zhu AX, et al. ASCO 2018. Abstract 4003.

Placebo Q2W +

Best supportive care (n = 95)

Ramucirumab 8 mg/kg IV Q2W +

Best supportive care (n = 197)

Systemic Targeted Therapy for Advanced Disease Second-line ramucirumab: Phase III REACH-2 study

(n = 197) (n = 95) P value

P = .0199

P < .0001

OS benefit favoured ramucirumab in all subgroups except females (possibly due to small n) Ramucirumab shows PFS benefit in all pre-specified subgroups

OS, overall survival; PFS, progression free survival; ORR, overall response rate; DCR, disease control rate

1. Zhu AX, et al. ASCO 2018. Abstract 4003.

Outcome Ramucirumab Placebo HR (95% CI)

Median OS, mos 8.5 7.3 0.71 (0.531-0.949)

Median PFS, mos 2.8 1.6 0.452 (0.339-0.603)

ORR, % (95% CI) 4.6 (1.7-7.5) 1.1 (0-3.1) P = .1697

DCR, % (95% CI) 59.9 (53.1-66.7) 38.9 (29.1-48.8) P = .0006

Median follow-up, mos 7.9 6.6

Systemic Targeted Therapy for Advanced Disease Second-line ramucirumab: Phase III REACH-2 study

*TEAEs in ≥ 15% patients in ramucirumab arm. 1. Zhu AX, et al. ASCO 2018. Abstract 4003.

TEAE in ≥ 15% of Patients in Ramucirumab Arm, n Ramucirumab (n = 197) Placebo (n = 95) (%) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Patients with ≥ 1 TEAE* 191 (97) 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

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

(5.3) Decreased appetite 46 (23.4) 3 (1.5) 19 (20) 1

(1.1) Proteinuria 40 (20.3) 4 (2) 4 (4.2) 0

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

(2.1) Nausea 37 (18.8 0 (0) 11 (11.6) 0

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

(2.1) Diarrhea 32 (16.2) 0 (0) 12 (14.7) 1

(1.1)

Discontinuation due to TRAE 21 (10.7) 3 (3.2)

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

Deaths due to TRAE 3 (1.5) 0 (0)

Systemic Targeted Therapy for Advanced Disease Summary of first- and second-/third-line studies

Cancer Immunotherapy destruction via several mechanisms1-5 Cancer evades immune cell recognition and

A Reduced presentation of tumour antigens to the

immune system

B Release of immunosuppressive factors

Factors/enzymes directly

or indirectly suppress

immune response Downregulation of MHC expression

Suppression of APC

Tumour cell APC

C Recruitment of immunosuppressive cells

Tumour microenvironment

Tregs MDSCs

Images adapted from Davies M. Cancer Manag Res. 2014;6:63-75 and reprinted from Mellman I et al. Nature. 2011;480(7378):480-489.

BTLA = B- and T-lymphocyte attenuator; GITR = glucocorticoid induced tumour necrosis factor-related protein; HVEM = herpes virus entry mediator; LAG-3 = lymphocyte-activation gene 3;

MDSC = myeloid-derived suppressor cell; TIM-3 = T-cell immunoglobulin domain and mucin domain-3; VISTA = V-domain immunoglobulin-containing suppressor of T-cell activation.

1. Mellman I et al. Nature. 2011;480(7378):480-489. 2. Spranger S et al. J Immunother Cancer. 2013;1:16. 3. Töpfer K, Kempe S, Müller N, et al. J Biomed Biotechnol. 2011;918471:1-19. 4. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264. 5. Ma Y et al. J Cancer. 2013; 4(1): 36-44.

D T-cell immune checkpoint

modulation

Cancer Immunotherapy Immune checkpoint inhibition: CTLA-4 and PD-1/PD-L1

T-cell migration Priming phase (lymph node)

Effector phase (peripheral tissue)

Dendritic cell

Cancer cell

T cell T cell

MHC MHC TCR TCR

CD28 Dendritic

cell T cell PD-1

T cell Cancer cell PD-L1

B7 CTLA-4

Atezolizumab (Tecentriq®) Ipilimumab (Yervoy®) Pembrolizumab (Keytruda®) Nivolumab (Opdivo®)

MHC = major histocompatibility complex; TCR = T-cell receptors; CTLA-4 = cytotoxic T-lymphocyte associated protein 4; PD-1 = programmed death protein 1; PD-L1 = programmed death protein ligand 1.

1. Ribas A. N Engl J Med. 2012;366:2517-2519.

Renal

Nephritis1

Type 1 diabetes

Respiratory

Pneumonitis1,3

Gast

Cancer Immunotherapy Potential treatment-related toxicities

Endocrine Hepatic

Autoimmune hepatitis1,3 ALT/AST

increases1,2

Hypophysitis1–3 Thyroiditis1,3

4

Renal failure5

rointestinal

iarrhoea1,2

Skin

Maculopapular rash1

Pruritus1,2

Neuromuscular

Peripheral sensory

neuropathy1

The treatment-related toxicities described here represent some but not all toxicities that may occur with immune checkpoint inhibitor therapies. 1. Teply BA et al. Oncology (Williston Park). 2014;28 Suppl 3:30–38. 2. Hodi FS et al. N Engl J Med. 2010;363(8):711–723. 3. Topalian SL et al. N Engl J Med. 2012;366(26):2443–2454. 4. Mellati M et al. Diabetes Care. 2015;38(9):e137–e138. 5. Forde PM et al. Anticancer Res. 2012;32(10):4607–4608.

Immunotherapy for Advanced Disease Immune checkpoint inhibition with PD-1 antibodies

Without

hepatitis

1. El-Khoueiry AB et al. Lancet 2017.

Phase I/II Nivolumab Dose Escalation (n = 48) CheckMate 040 3 + 3 design

n = 6 n = 9 n = 10 n = 10 n = 13

viral

Dose Expansion (n = 214) 3 mg/kg

HCV 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg infected (n = 3) (n = 4) (n = 3)

HCV infected (n = 50)

HBV 0.1 mg/kg 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg infected (n = 5) (n = 3) (n = 3) (n = 4)

HBV infected (n = 51)

Sorafenib progressor (n = 57)

10 mg/kg (n = 13)

3.0 mg/kg (n = 3)

1.0 mg/kg (n = 3)

0.3 mg/kg (n = 3)

0.1 mg/kg (n = 1)

Sorafenib untreated or intolerant (n = 56)



Outcome Uninfected Untreated/in tolerant (n =

56)

Uninfected Progressor

(n = 57)

HCV Infected (n = 50)

HBV Infected (n = 51)

All Pts (n = 214)

ORR, % 23 21 20 14 20

CR 0 4 0 2 1

PR 23 18 20 12 18

SD 52 40 46 41 45

PD 23 32 28 45 32

Median OS, mos NR 13.2 NR NR NR

OS at 6/9 mos, % 89/82 75/63 85/81 84/70 83/74

Median PFS, mos 5.4 4.0 4.0 4.0 4.0

Immunotherapy for Advanced Disease Immune checkpoint inhibition with

Dose Escalation

PD-1 antibodies Dose Expansion

≥ 1% ≥ 1% < 1% NA < 1% NA PD-L1: PD-L1: 100

50

0

-50

-100 Pts Pts


Ch

ange

in T

arge

t Le

sio

n S

ize

Fro

m

Bas

elin

e (%

)

PD-L1 < 1% PD-L1 ≥ 1%

ORR, n/N (%) 4/26 (15.4) 2/9 (22.2)

PD-L1 < 1% PD-L1 ≥ 1% ORR, n/N (%) 17/99 (17.2) 8/25 (32.0)


Randomized, open-label, multicenter phase III trial

Stratified by etiology, vascular invasion and/or extrahepatic spread, and geography

Advanced HCC; no prior systemic

therapy; not eligible for/progressed after locoregional therapy; C-P A; ECOG PS 0-1 (planned N = 726)

All pts treated until PD, unacceptable

toxicity, or withdrawal of

consent

*Nonviral HCC, HBV-HCC (HBV infection resolved or controlled), or HCV- HCC (resolved or active HCV infection)

Primary endpoint: time to progression, OS Secondary endpoints: ORR, PFS, PD-L1 expression

ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; OS, overall survival; ORR, overall response rate; PFS, progression free survival.

1. Sangro B et al. ASCO 2016. Abstract TPS4147. 2. ClinicalTrials.gov. NCT02576509.

Sorafenib PO BID

Nivolumab 30 min IV Q2W

Systemic Therapy for Advanced Disease Targeted and immunotherapy

1. Llovet JM et al. Nat Rev Clin Oncol 2018.

Future perspectives

Select Ongoing First-line Phase III Trials in Advanced HCC

TTP, OS (NCT02576509) advanced HCC

1112; NCT01730937) OS vascular tumor thrombosis analysis

(NCT01906216) Advanced HCC of AFP response

First-Line Study N Population Primary Notes Endpoint

Atezolizumab + 480 Locally advanced or metastatic OS, RR PD-L1 antibody, bevacizumab vs sorafenib and/or unresectable HCC VEGF antibody (NCT03434379)

Nivolumab vs sorafenib 726 Unresectable or progressive

Sorafenib ± SBRT (RTOG 368 HCC with ≥ 1 liver lesion or Biomarker

Sorafenib ± TACE 246 Analysis of

(BCLC Stage C) OS prognostic value

Promising Phase I Activity Combination immune checkpoint inhibition plus targeted therapy

Select Ongoing Second-line Phase III Trials in Advanced HCC

OS MET inhibitor (NCT01755767) 1 prior therapy

OS MET inhibitor (NCT02029157) sorafenib

(KEYNOTE-240; NCT02702401) PFS, OS PD-1 antibody sorafenib

Second-Line Study N Population Primary Notes Endpoint(s)

Tivantinib vs BSC 368 Unresectable HCC after

Tivantinib vs placebo 160 c-MET high HCC after

Pembrolizumab vs BSC 408 HCC with progression on

Managing toxicities:

treatment-related regorafenib

General Dose Modification Guidelines • Any grade 3 or 4 AE (other than hepatotoxicity)

•

•

Interrupt therapy; upon recovery, reduce dose to 120mg OD If any grade 3 or 4 AE occurs while on 120mg OD, may further 80mg OD upon recovery

reduce to

• For any grade 4 AE, only resume therapy if the benefit outweighs the risk Permanently discontinue therapy if unable to tolerate 80mg OD •

Hand-Foot Skin Reaction Typical onset within 2-4 weeks of therapy Severity can be reduced by

(HFSR) •

• •

•

•

Prophylactic strategies Early detection / dose modification

Immediate symptomatic treatment

Hand-Foot Skin Reaction (HFSR)

Hand-Foot Skin Reaction (HFSR) • Keratolytic creams

• Use sparingly and only • Urea-based creams • Salicylic acid 6%

to hyperkeratotic areas

• Alpha-hydroxy acid (AHA) based creams • Approximately 5-8% provides gentle chemical exfoliation • Apply liberally two times each day

Topical analgesics (eg. lidocaine 2%) for pain control

Topical steroids (eg. clobetasol 0.05%) for grade 2 or

Avoid systemic steroids

•

•

•

3 HFSR

Treatment-related Hypertension • Monitoring parameter

• Blood pressure weekly for the first 6 weeks and with every subsequent cycle, or more frequently if indicated

Treatment-related Hypertension

Hepatotoxicity

Hepatotoxicity • Monitoring parameter

• LFT at baseline, every 2 weeks during the first 2 months, then monthly or more frequently if clinically necessary (weekly until improvement, if LFT elevated)

Hepatotoxicity

Other Serious Treatment-related •

AEs Gastrointestinal perforation • Discontinue permanently

Severe or life-threatening haemorrhage • Discontinue permanently

Reversible posterior leukoencephalopathy • Discontinue

Wound dehiscence • Discontinue

•

• syndrome (RPLS)

•

Conclusions

Conclusions • Sorafenib and lenvatinib

advanced HCC

are approved agents for the first-line treatment of

• Regorafenib, cabozantinib and ramucirumab improve survival in patients with disease progression following sorafenib

• Immune checkpoint inhibition is approved in patients with disease progression following sorafenib

• Many Phase III studies are ongoing, including those combining immune checkpoint inhibition plus targeted therapy

Thanks for your attention [email protected]

mailto:[email protected]








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