Instructor:VS 鄧豪偉 Presenter: CR 周益聖
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Instructor:VS 鄧豪偉Presenter: CR 周益聖
CORRECT studyThe Lancet November 22, 2012
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INTRODUCTION
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mCRC Worldwide
• 1 million new cases of colorectal cancer (CRC) a each year worldwide
• 500,000 deaths attributed to this disease annually
• 50% develop metastasis, most unresectable• median overall survival (OS) for mCRC : 24-28
months
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Management of mCRC
Ther Adv Med Oncol. 2012 Nov; 4(6):347-8.
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Regorafenib (BAY 73-4506)
Int. J. Cancer: 129,245-255 (2011)
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Int. J. Cancer: 129,245-255 (2011)
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Regorafenib decrease tumor microvessel area(MVA) and proliferation
• MDA-MB-231 breast xenograft model
Int. J. Cancer: 129,245-255 (2011) Colo-205 CRC xenograft model
MDA-MB-231 breast xenograft model
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Regorafenib inhibits tumor vasculature and tumor growth
Int. J. Cancer: 129,245-255 (2011)
Rat GS9L glioblastoma modelBy DCE-MRI (Contrast with Gadomer-17)
single dose 10 mg/kg QD x 4 days
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Int. J. Cancer: 129,245-255 (2011)
human CRC cell line Colo-205 (B-RAF V600E)
human BC cell line MDA-MB-231 (K-RASG13D, B-RAF G464V)
human RCC cell line 786-O (Von-Hippel Lindau gene -/-)
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Phase I Study in mCRC
British Journal of Cancer (2012) 106(11), 1722 – 1727
21 days on, 7 days off
Dose-escalation: mCRC, NHL, MM (n=15)Extension phases: CRC(n=23)
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Methods• Double blind, 2: 1 Randomised, placebo-controlled, phase 3
study based on the intention to treat population– Stratified by
• VEGF-targeting drugs ( Yes vs. No)• time from diagnosis of metastatic disease ( >=18 months vs. <18 months)• geographical region
• 114 centers in 16 countries in North America, Europe, Asia, and Australia
• Adenocarcinoma of the colon or rectum • Disease progression during or within 3 months after the last
standard therapy – stop standard therapy because of unacceptable toxic effects
• No cross over!
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Inclusion Criteria
• Aged 18 years or older• ECOG of 0 or 1• life expectancy of at least 3 months• Adequate bone-marrow, liver, and renal
function• Have received locally and currently approved
standard therapies
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CORRECT Design
mCRCs/p systemic therapy
RANDOMIZATION
2:1
n=505
n=255
Regorafenib 160mg PO QD
Placebo
n=760
• Assumption: 25% relative risk reduction with regorafenib• a power of 90% to detect 33.3% increase in median overall
survival ( assuming HR of 0.75)• One sided α of 0.025
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Efficacy and Safety• Primary end points: overall survival• Secondary end points: progression free survival, objective tumor
response rate, disease control rate, safety• Tumor response assessed radiologically with Response
Evaluation Criteria in Solid Tumors (RECIST, version 1.1) • Tertiary end points: health-related quality-of-life and health
utility values– European Organisation for Research and Treatment of Cancer
(EORTC) general health status and quality-of-life questionnaire QLQ-C30
– the EuroQol five dimension (EQ-5D) index questionnaire and visual analogue scale
• Adverse events graded with the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0)
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RESULT
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Characteristics
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Characteristics
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Algorithms
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Dose of Plan
ed Treatment(%
)
Dose Modificati
ons(%)
>=1 Dose Reductions(%
)
>=1 Dose Interru
ptions(%)
0102030405060708090
100
RegorafenibPlacebo
Dose of Treatment
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0
5
10
15
20
25
30
35
40
45
RegorafenibPlacebo
41
15
Response Rate
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HR 0·77, 95% CI 0·64–0·94 p=0·0052
HR 0·49, 95% CI 0·42–0·58p<0·0001
PFS
OS
Mean duration of treatment was 2 8 months for regorafenib and ∙1.8 months for placebo
6.4 months5.0 months
1.9 months
1.7 months
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OSsubgroup
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PFSsubgroup
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Regorafenib (N=500) Placebo
(N=253) Any grade Grade 3 Grade 4 Any grade Grade 3 Grade 4
Any event 465 (93%) 253 (51%) 17 (3%) 154 (61%) 31 (12%) 4 (2%)Clinical adverse event Fatigue 237 (47%) 46 (9%) 2 (<1%) 71 (28%) 12 (5%) 1 (<1%)Hand-foot skin reaction 233 (47%) 83 (17%) 0 19 (8%) 1 (<1%) 0Diarrhoea 169 (34%) 35 (7%) 1 (<1%) 21 (8%) 2 (1%) 0Anorexia 152 (30%) 16 (3%) 0 39 (15%) 7 (3%) 0Voice changes 147 (29%) 1 (<1%) 0 14 (6%) 0 0Hypertension 139 (28%) 36 (7%) 0 15 (6%) 2 (1%) 0Oral mucositis 136 (27%) 15 (3%) 0 9 (4%) 0 0Rash or desquamation 130 (26%) 29 (6%) 0 10 (4%) 0 0Nausea 72 (14%) 2 (<1%) 0 28 (11%) 0 0Weight loss 69 (14%) 0 0 6 (2%) 0 0Fever 52 (10%) 4 (1%) 0 7 (3%) 0 0Constipation 42 (8%) 0 0 12 (5%) 0 0Dry skin 39 (8%) 0 0 7 (3%) 0 0Alopecia 36 (7%) 0 0 1 (<1%) 0 0Taste alteration 35 (7%) 0 0 5 (2%) 0 0Vomiting 38 (8%) 3 (1%) 0 13 (5%) 0 0Sensory neuropathy 34 (7%) 2 (<1%) 0 9 (4%) 0 0Nose bleed 36 (7%) 0 0 5 (2%) 0 0Dyspnoea 28 (6%) 1 (<1%) 0 4 (2%) 0 0Muscle pain 28 (6%) 2 (<1%) 0 7 (3%) 1 (<1%) 0Headache 26 (5%) 3 (1%) 0 8 (3%) 0 0Pain,abdomen 25 (5%) 1 (<1%) 0 10 (4%) 0 0
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Adverse Effects
Any Eve
nt
Fatigu
e
Hand-Fo
ot reacti
on
Diarrhea
Anorexia
Hyperte
nsion
Voice Chan
ge
Mucositi
s
Rash or d
esqumati
on
Nausea
Weight lo
ssFe
ver
0102030405060708090
100
Any gradeGrade 3Grade 4
(%)
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Regorafenib
(N=500)
Placebo
(N=253)
Any
gradeGrade
3Grade
4Any
gradeGrade 3
Grade 4
Laboratory
abnormalities
Thrombocytopenia
63 (13%)
13 (3%)
1 (<1%) 5 (2%)
1 (<1%
)0
Hyperbilirubinaemia 45 (9%) 10
(2%) 0 4 (2%) 2 (1%) 0
Proteinuria 35 (7%) 7 (1%) 0 4 (2%)1
(<1%)
0
Anaemia 33 (7%) 12 (2%)
2 (<1%) 6 (2%) 0 0
Hypophosphataemia 25 (5%) 19
(4%) 0 1 (<1%)
1 (<1%
)0
ALT ↑ 27(5.4%)
9(1.8%)
1(0.2%) 5(2.0) 0 0
AST ↑ 35(7.0%)
12(2.4%) 0 10(4.0
)3(1.2
) 0
ALP ↑ 32(6.4%)
11(2.2%) 0 8(3.2) 4(1.6
) 0
Hypokalemia 45(9.0%)
13(2.6%) 0 5(2.0) 1(0.4
) 0
Hypocalcemia 32(6.4%)
4(0.8%) 0 1(0.4) 0 0
Lipase ↑ 31(6.2%)
15(3.0%)
6(1.2%) 3(1.2) 0 0
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Adverse Effects
0
2
4
6
8
10
12
14
Any gradeGrade 3Grade 4
(%)
One fatal case compatible with regorafenib-related, drug-induced liver Injury: 62 y/o male with liver metastasis, 43 days after Rx
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Adverse Effects
• pneumonia (n=2)• gastrointestinal bleeding (n=2)• intestinal obstruction (n=1)• pulmonary haemorrhage (n=1)• seizure (n=1)• sudden death (n=1)
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Functioning & Quality of Life
QLQ-C30 Base
line
QLQ-C30After
EQ-5D Visual
Analog B
aselin
e
EQ-5D Visual
Analog A
fter0
10203040506070
RegorafenibPlacebo
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Health Status
EQ-5D Baseline EQ-5D After0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
RegorafenibPlacebo
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DISCUSSION
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• Fewer in the regorafenib group (273 of 505, 54%) had KRAS mutation compared with the placebo group (157 of 255, 62%)
• All patients had received previous anti-VEGF treatment
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• Regorafenib increases overall survival, compared with best supportive care only, in patients with metastatic colorectal cancer who have received all currently approved standard therapies, also PFS and DCR
• Difference in median overall survival was modest at 1 4 months ∙
• HR of 0 77 ∙ translates into a 23% reduction in risk of death
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• The main effect is disease stabilisation, rather than tumour shrinkage – CR:0– PR:1%– SD: 41%
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Rectum vs. Colon?
OS PFS0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
ColonRectum
HR
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• fewer patients with rectal cancer in the regorafenib group received post-study anticancer therapies compared with the overall population– Placebo vs. Overall: 36% vs. 30%– Regorafenib vs. Overall: 23% vs. 26%
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• Most frequent AE of grade 3 or higher were hand-foot skin reaction, fatigue, diarrhoea, hypertension, and rash or desquamation
• Most events occurred early in the course of treatment (within 1–2 cycles) and were readily manageable with dose reduction or interruption
• no worse effect than placebo on QoL
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Limitations
• No independent review– Singinificant difference in OS, PFS and RR
• Mechanism of action of regorafenib in human colorectal cancer remains to be elucidated
• Kaplan-Meier curves for PFS suggest that different subgroups of patients might have diff erential responses to regorafenib treatment– Subgroup patients likely to obtain benefit from
regorafenib• Analyses of relevant biomarkers in specimens
currently underway
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Conclusion
• The first randomised phase 3 study in which small-molecule kinase inhibitor as monotherapy has shown significant overall survival benefit in patients with refractory mCRC when compared with BSC
• Regorafenib could be a new standard of care in late-stage mCRC
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THANKS FOR YOUR ATTENTION!