targeted therapy for advanced hepatocellular carcinoma...
TRANSCRIPT
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.
Systemic Targeted Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies
Patients in the Asia-Pacific Study also had more prior locoregional therapies
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.
Systemic Targeted Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies
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.
Systemic Targeted Therapy for Advanced Disease First-line sorafenib in HCC: Phase III SHARP and Asia-Pacific studies
One-third of patients required dose reductions due to toxicity
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.
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.
1. Kudo M et al. Lancet. 2018 Mar 24;391(10126):1163-1173
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
1. Kudo M et al. Lancet. 2018 Mar 24;391(10126):1163-1173
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.
1. Bruix J et al. Lancet. 2017; 389(10064):56-663.
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
1. Bruix J et al. Lancet. 2017; 389(10064):56-663.
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
1. Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63.
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
1. Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63.
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)
Immunotherapy for Advanced Disease Immune checkpoint inhibition with PD-1 antibodies
1. El-Khoueiry AB et al. Lancet 2017.
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
1. El-Khoueiry AB et al. Lancet 2017.
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)
Immunotherapy for Advanced Disease Immune checkpoint inhibition with PD-1 antibodies
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)
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