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SYSTEMIC THERAPY
WHAT IS REALISTIC IN THE LMIC SETTING ?
MITESH J. BORAD, M.D.
Director, Liver and Biliary Cancer Research Program
Mayo Clinic Arizona
COLDA 2019Cairo, Egypt
September 6-8, 2019
CONFLICTS OF INTEREST
RESEARCH FUNDING
Boston Biomedical
Mirna
Sunbiopharma
Senhwa
Medimmune
Bioline
Agios
Halozyme
Threshold
Celgene
Toray
Dicerna
Sillajen
Eisai
CONSULTANT
G1 Therapeutics
TD2
Fujifilm
Insys
Novartis
Arqule
Celgene
Inspyr
Halozyme
Exelixis
Taiho
Ionis
EMD Serono
Incyte
ARIAD
Imclone
Adaptimmune
Redhill Biopharma
HEPATOCELLULAR CANCER
1. Most common primary cancer of the liver
2. Common etiologies include hepatitis B/C,
NASH/metabolic syndrome, alcohol and others (e.g.
Wilson’s disease)
3. Global incidence ~782,000 cases
(~554,000 deaths : GLOBOCAN)
GLOBAL DISTRIBUTION OF HEPATITIS B
Schweitzer et al, The Lancet 2015
GLOBAL DISTRIBUTION OF HEPATITIS C
SOURCE: cdc.gov (2015)
Roswall et al, J Prev Public Health 2015
GLOBAL DISTRIBUTION OF ALCOHOL CONSUMPTION
LOW-MIDDLE INCOME COUNTRIES
SOURCE : worldbank.org
LENVATINIB
REGORAFENIB
SORAFENIB
ANTI-ANGIOGENIC TYROSINE KINASE
INHIBITORS USED IN HCC
CABOZANTINIB
VEGFR1, VEGFR2, VEGFR3, RET, PDGFRA, KITRAF1, BRAF
VEGFR2, MET, RET, TIE2, AXL, FLT3, KIT, RON
VEGFR1, VEGFR2, VEGFR3, RET, PDGFRA, KITFGFR1-4
VEGFR1, VEGFR2, VEGFR3, RET, PDGFRB, KITRAF1, BRAF
R
SORAFENIBN=299
PLACEBON=303
SHARP STUDY – SORAFENIB N HCC
ELIGIBILITYAdvanced HCCChild Pugh AECOG 0-2No prior treatmentAge >18 years
DESIGNDouble blind121 sites US/Europe/AsiaPrim End: OS
R
SORAFENIBN=150
PLACEBON=76
ASIA PACIFIC STUDY – SORAFENIB N HCC
ELIGIBILITYAdvanced HCCChild Pugh ANo prior treatmentAge >18 years
DESIGNDouble blindChina, Korea, TaiwanPrim End: OS
SORAFENIB IN HCC
A Phase 3 Trial of Lenvatinib vs Sorafenib
in First-line Treatment of Patients With
Unresectable Hepatocellular Carcinoma
(REFLECT Study)
Ann-Lii Cheng,1 Richard S. Finn,2 Shukui Qin,3 Kwang-Hyub Han,4 Kenji
Ikeda,5 Fabio Piscaglia,6
Ari Baron,7 Joong-Won Park,8 Guohong Han,9 Jacek Jassem,10 Jean
Frederic Blanc,11 Arndt Vogel,12 Dmitry Komov,13 TR Jeffry Evans,14 Carlos
Lopez,15 Corina Dutcus,16 Min Ren,16 Silvija Kraljevic,17 Toshiyuki Tamai,16
Masatoshi Kudo18
Used with permission of Dr. Ann-
Lii Cheng
Study SchemaGlobal, randomized, open-label, phase 3 noninferiority
studyPatients with unresectable HCC (N = 954)
• No prior systemic
therapy for
unresectable HCC
• ≥ 1 Measurable
target lesion per
mRECIST
• BCLC stage B or C
• Child-Pugh A
• ECOG PS ≤ 1
• Adequate organ
function
• Patients with ≥ 50%
liver occupation,
clear bile duct
invasion, or portal
vein invasion at the
main portal vein were
excluded
Stratification• Region:
(Asia-
Pacific or
Western)
• MVI and/or
EHS:
(yes or no)
• ECOG PS:
(0 or 1)
• Body
weight:
(< 60 kg or
≥ 60 kg)
Lenvatinib(n = 478)8 mg (BW <
60 kg) or
12 mg (BW ≥
60 kg)
once daily
Sorafenib(n = 476)
400 mg
twice daily
Primary endpoint:• OS
Secondary endpoints:
• PFS
• TTP
• ORR
• Quality of life
• PK lenvatinib
exposure
parameters
Tumor assessments were performed according to mRECIST by the investigator
Random
izati
on 1
:1
Used with permission of Dr. Ann-
Lii Cheng
Primary Endpoint: Kaplan-Meier
Estimate of OS
Used with permission of Dr. Ann-
Lii Cheng
Secondary Endpoint: Kaplan-Meier Estimate of
PFS by mRECIST
Used with permission of Dr. Ann-
Lii Cheng
Maximum Change in Tumor Size by
mRECISTn, (%) Lenvatinib (n =
478)
Sorafenib (n =
476)
Odds Ratio
(95% CI)
ORR
95% CI
115 (24.1)
20.2−27.9
44 (9.2)
6.6−11.8
3.13
(2.15−4.56)
P < 0.00001CR 6 (1.3) 2 (0.4)
PR 109 (22.8) 42 (8.8)
SD 246 (51.5) 244 (51.3)
Durable SD 167 (34.9) 139 (29.2)
PD 71 (14.9) 147 (30.9)
Unknown/NE 46 (9.6) 41 (8.6)
DCR
95% CI
361 (75.5)
71.7−79.4
288 (60.5)
56.1−64.9
Percentage change in tumor size is truncated at 100% (rectangles). ORR is defined as CR+PR, according to mRECIST; durable SD is
defined as SD lasting ≥ 23 weeks.
CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
CR
(n=6
)
CR
(n=2
)
Used with permission of Dr. Ann-
Lii Cheng
RECIST 1.1 response: 18.8% vs 6.5%
Most Frequent TEAEs (≥ 15%)Adverse event, n (%) Lenvatinib (n = 476) Sorafenib (n = 475)
Any grade Grade 3/4 Any grade Grade 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)
Palmar-plantar
erythrodysesthesia 128 (27) 14 (3) 249 (52) 54 (11)
Proteinuria 117 (25) 27 (6) 54 (11) 8 (2)
Dysphonia 113 (24) 1 (0) 57 (12) 0 (0)
Nausea 93 (20) 4 (1) 68 (14) 4 (1)
Decreased platelet count 87 (18) 26 (6) 58 (12) 16 (3)
Abdominal pain 81 (17) 8 (2) 87 (18) 13 (3)
Hypothyroidism 78 (16) 0 (0) 8 (2) 0 (0)
Vomiting 77 (16) 6 (1) 36 (8) 5 (1)
Constipation 76 (16) 3 (1) 52 (11) 0 (0)
Elevated aspartate
aminotransferase 65 (14) 24 (5) 80 (17) 38 (8)
Rash 46 (10) 0 (0) 76 (16) 2 (0)
Alopecia 14 (3) 0 (N/A) 119 (25) 0 (N/A)Used with permission of Dr. Ann-
Lii Cheng
ANTI-ANGIOGENICS IN HCC
TIME
GROWTH
RECIST
PD
NO
THERAPY
ANTI-ANGIOGENIC D/C
ANTI-ANGIOGENIC
CONTINUOUS
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Efficacy and safety of regorafenib versus
placebo in patients with hepatocellular
carcinoma (HCC) progressing on sorafenib:
Results of the international, randomized
phase 3 RESORCE trial
J Bruix, P Merle, A Granito, Y-H Huang, G Bodoky, O Yokosuka,
O Rosmorduc, V Breder, R Gerolami, G Masi, PJ Ross, S Qin,
T Song, J-P Bronowicki, I Ollivier-Hourmand, M Kudo,
M-A LeBerre, A Baumhauer, G Meinhardt, G Han
on behalf of the RESORCE Investigators
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Regorafenib160 mg po once daily
3 weeks on / 1 week off
(4-week cycle)
(n=379)
Placebo(n=194)
• HCC patients with documented
radiological progression during
sorafenib treatment
• Stratified by:
− Geographic region (Asia vs ROW)
− Macrovascular invasion
− Extrahepatic disease
− ECOG PS (0 vs 1)
− AFP (<400 ng/mL vs ≥400 ng/mL)
RESORCE trial designClinicaltrials.gov NCT01774344
N= 573
ROW, rest of the world; ECOG PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein
R2:1
• 152 centers in 21 countries in North and South America, Europe, Australia, Asia
• All patients received best supportive care
• Treat until progression, unacceptable toxicity, or withdrawal
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Overall survival (OS)Primary endpoint
Pro
ba
bil
ity o
f S
urv
iva
l (%
)
Regorafenib
Placebo
Regorafenib
n=379
Placebo
n=194
Events 232 (61%) 140 (72%)
Censored 147 (39%) 54 (28%)
Median OS
(95% CI)
10.6 months
(9.1, 12.1)
7.8 months
(6.3, 8.8)
HR 0.62 (95% CI: 0.50, 0.78)
P<0.001 (2-sided)
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Subgroup analysis of OS
AFP, alpha-fetoprotein
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Progression-free survival (PFS)
Pro
ba
bilit
y o
f P
rog
res
sio
n-f
ree
Su
rviv
al
(%)
Regorafenib
Placebo
Regorafenib
n=379
Placebo
n=194
Events 291 (77%) 181 (93%)
Censored 88 (23%) 13 (7%)
Median PFS
(95% CI)
3.1 months
(2.8, 4.2)
1.5 months
(1.4, 1.6)
HR 0.46 (95% CI: 0.37, 0.56)
P<0.001 (2-sided)
Based on mRECIST
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Best overall tumor response mRECIST RECIST 1.1
Regorafenib
n=379
Placebo
n=194
Regorafenib
n=379
Placebo
n=194
Response rate10.6% 4.1% 6.6% 2.6%
P=0.01 (2-sided) P=0.04 (2-sided)
Disease control rate65.2% 36.1% 65.7% 34.5%
P<0.001 (2-sided) P<0.001 (2-sided)
Complete response 0.5% 0 0 0
Partial response 10.0% 4.1% 6.6% 2.6%
Stable disease 54.4% 32.0% 58.8% 32.0%
Non CR/Non PD 0.3% 0 0.3% 0
PD 22.7% 55.7% 22.4% 57.2%
Not evaluable 5.0% 4.1% 5.0% 4.6%
Not assessed 7.1% 4.1% 6.9% 3.6%
Clinical progression* 22.7% 20.6% 22.7% 20.6%
*Worsening of ECOG PS≥3 or symptomatic deterioration including increase in liver function tests
PD, progressive disease
Bruix J, et al. Presented at World Congress on Gastrointestinal Cancer 2016
Treatment-emergent grade 3 or 4 adverse events
occurring in at least 5% of patients in either group
Treatment-emergent Drug-related treatment-emergent
Regorafenib
n=374
Placebo
n=193
Regorafenib
n=374
Placebo
n=193
Any
gradeGr 3 Gr 4
Any
gradeGr 3 Gr 4
Any
gradeGr 3 Gr 4
Any
gradeGr 3 Gr 4
HFSR 53% 13% NA 8% 1% NA 52% 13% NA 7% 1% NA
Fatigue 41% 9% NA 32% 5% NA 30% 6% NA 19% 2% NA
Hypertension 31% 15% <1% 6% 5% 0 23% 13% <1% 5% 3% 0
Bilirubin increased 29% 10% 1% 18% 8% 3% 19% 6% <1% 4% 2% 0
AST increased 25% 10% 1% 20% 10% 2% 13% 4% 1% 8% 5% 1%
Ascites 16% 4% 0 16% 6% 0 2% 1% 0 1% 1% 0
Anemia 16% 4% 1% 11% 5% 1% 6% 1% <1% 1% 1% 0
Hypophosphatemia 10% 8% 1% 2% 2% 0 6% 4% 1% 1% 1% 0
Lipase increased 7% 5% 2% 3% 2% 0 5% 4% <1% 2% 1% 0
AST, aspartate aminotransferase; HFSR, hand-foot skin reaction; NA, not applicable
NCI-CTCAE v4.03
COST EFFECTIVENESS - REGORAFENIB
SHLOMAI ET AL, PLOS ONE 2018
COST EFFECTIVENESS - REGORAFENIB
SHLOMAI ET AL, PLOS ONE 2018
COST EFFECTIVENESS - CABOZANTINIB
SOTO-PEREZ-DE-CELIS ET AL, JNCCN 2019
OTHER OPTIONS : FOLFOX ?
QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013
FOLFOX IN HEPATCELLULAR CANCER
QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013
FOLFOX IN HEPATCELLULAR CANCER
QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013
FOLFOX IN HEPATCELLULAR CANCER
QIN ET AL, JOURNAL OF CLINICAL ONCOLOGY 2013
COST EFFECTIVENESS – FOLFOX VS SORAFENIB
ZHANG ET AL, DIGESTIVE AND LIVER DISEASE 2016
ANTI-VIRAL RX ANTI-VIRAL RX
ANTI-VIRAL HEP B THERAPY IN ADVANCED
HCC PATIENTS ?
ZHANG ET AL, JOURNAL OF GASTRO AND HEPATOLOGY 2016
PFS: 6.0 vs. 4.5 mth OS: 12.2 vs. 8.0 mth
ANTI-VIRAL HEP B THERAPY IN ADVANCED
HCC PATIENTS ?
ZHANG ET AL, JOURNAL OF GASTRO AND HEPATOLOGY 2016
Sangro et al, J Hepatology 2013
Sangro et al, J Hepatology 2013
▪Total evaluable patients (n=17)
▪Complete response (n=0; 0%)
▪Partial response (n=3; 17.6%) [Duration of response 3.6, 6.9 and 15.2 mths]
▪Stable disease (n=10; 58.8%)
▪Alpha-fetoprotein evaluable patient (n=11)
▪Alpha-fetoprotein response (>50% decrease): n=4 (36%)
▪Median time to tumor progression (TTP): 6.48 mth (95% CI: 3.95-9.14 mth)
▪Median overall survival (OS): 8.2 mth (95% CI: 4.64-21.34 mth)
EFFICACY
Sangro et al, J Hepatology 2013
NIVOLUMAB IN HEPATOCELLULAR CANCER
El-Khoueiry et al, Lancet 2017
NIVOLUMAB IN HEPATOCELLULAR CANCER
El-Khoueiry et al, Lancet 2017
NIVOLUMAB IN HEPATOCELLULAR CANCER
NIVOLUMAB IN HEPATOCELLULAR CANCER
El-Khoueiry et al, Lancet 2017
NIVOLUMAB IN HEPATOCELLULAR CANCER
PEMBROLIZUMAB IN HCC
Zhu et al, Lancet Onc 2018
N =104
RESPONSE RATE = 17%
200 MG IV Q3W
PEMBROLIZUMAB IN HCC
Zhu et al, Lancet Onc 2018
PFS =4.9 MTHS
OS = 12.9 MTHS
ATEZOLIZUMAB + BEVACIZUMAB IN HCC
Stein et al, ASCO 2018
Stein et al, ASCO 2018
ATEZOLIZUMAB + BEVACIZUMAB IN HCC
UPDATED RESPONSE RATE 32%, PFS = 14.9 MONTHS
ATEZOLIZUMAB + BEVACIZUMAB IN HCC
Stein et al, ASCO 2018
NIVOLUMAB240 MG Q2WK
SORAFENIB400 mg BID
RANDOMIZATION 1:1
N=1723
CHECKMATE 459 – NIVOLUMAB IN HCC
(1st LINE)
PRIMARY END POINT : OVERALL SURVIVAL
OVERALL SURVIVAL: HR = 0.85 [95% CI: 0.72-1.02]; P = 0.0752
PEMBROLIZUMAB200 MG Q3WK
BEST SUPPORTIVE CARE
RANDOMIZATION 2:1
N=278
N=135
KEYNOTE 240 – PEMBROLIZUMAB IN HCC
(2nd LINE)
PRIMARY END POINT : OVERALL SURVIVAL
▪ OS PROLONGED BUT FAILED TO MEET PRE-SPECIFIED SIGNIFICANCE 13.9 VS 10.6 MOS (HR: 0.781; 95% CI: 0.611-0.998; P = .0238)
▪ FAILED TO REACH PRE-SPECIFIED LEVEL OF STATISTICAL SIGNIFICANCE (P = .0174)
CONCLUSIONS
▪ ANTI-ANGIOGENICS ARE EFFICACIOUS IN THE FIRST (SORAFENIB/LENVATINIB/FOLFOX) AND SECOND+ LINE SETTINGS (REGORAFENIB/CABOZANTINIB/RAMUCIRUMAB) IN ADVANCED HCC
▪ ONLY FOLFOX ACHIEVED COST-EFFECTIVENESS IN A LMIC SETTING
▪ ANTI-VIRAL THERAPY FOR HEPATITIS B MAY HELP IN ADVANCED HCC PATIENTS AND IS COST-EFFECTIVE IN LMIC SETTING
▪ IMMUNE THERAPIES ARE PROMISING IN ADVANCED HCC AND COST-EFFECTIVENESS IN LMIC SETTING NEEDS TO BE DETERMINED
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