Download an international, multicentre, randomised, placebo

CORRECT study
The Lancet November 22, 2012
Instructor:VS 鄧豪偉
Presenter: CR 周益聖
INTRODUCTION
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
Management of mCRC
Ther Adv Med Oncol. 2012 Nov; 4(6):347-8.
Regorafenib
(BAY 73-4506)
Int. J. Cancer: 129,245-255 (2011)
Int. J. Cancer: 129,245-255 (2011)
Regorafenib decrease
tumor microvessel area(MVA) and proliferation
• MDA-MB-231 breast xenograft model
MDA-MB-231 breast xenograft model
Colo-205 CRC xenograft model
Int. J. Cancer: 129,245-255 (2011)
Regorafenib inhibits tumor vasculature
and tumor growth
single dose
10 mg/kg QD x 4 days
Rat GS9L glioblastoma model
By DCE-MRI (Contrast with
Gadomer-17)
Int. J. Cancer: 129,245-255 (2011)
human CRC cell line Colo-205
(B-RAF V600E)
human BC cell line MDA-MB231 (K-RASG13D, B-RAF G464V)
human RCC cell line 786-O
(Von-Hippel Lindau gene -/-)
Int. J. Cancer: 129,245-255 (2011)
Dose-escalation: mCRC, NHL, MM (n=15)
Extension phases: CRC(n=23)
21 days on, 7 days off
Phase I Study in mCRC
British Journal of Cancer (2012) 106(11), 1722 – 1727
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!
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
CORRECT Design
n=505
mCRCs/p systemic
therapy
n=760
R
A
N
D
O
M
I
Z
A
T
I
O
N
Regorafenib 160mg PO QD
2:1
Placebo
n=255
• 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
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)
RESULT
Characteristics
Characteristics
Algorithms
Dose of Treatment
100
90
80
70
60
50
Regorafenib
Placebo
40
30
20
10
0
Dose of Planed
Dose
>=1 Dose
>=1 Dose
Treatment(%) Modifications(%) Reductions(%) Interruptions(%)
Response Rate
45
41
40
35
30
25
Regorafenib
20
Placebo
15
15
10
5
0
CR(%)
PR(%)
Disase
Control(%)
Median
Duration(m)
OS
HR 0·77,
95% CI 0·64–0·94
p=0·0052
5.0 months
6.4 months
Mean duration of treatment was 2∙8 months for regorafenib and
1.8 months for placebo
PFS
HR 0·49,
95% CI 0·42–0·58
p<0·0001
1.9 months
1.7 months
OS
subgroup
PFS
subgroup
Any event
Clinical adverse event
Fatigue
Hand-foot skin reaction
Diarrhoea
Anorexia
Voice changes
Hypertension
Oral mucositis
Rash or desquamation
Nausea
Weight loss
Fever
Constipation
Dry skin
Alopecia
Taste alteration
Vomiting
Sensory neuropathy
Nose bleed
Dyspnoea
Muscle pain
Headache
Pain,abdomen
Regorafenib
(N=500)
Any grade
465 (93%)
Grade 3
253 (51%)
237 (47%)
233 (47%)
169 (34%)
152 (30%)
147 (29%)
139 (28%)
136 (27%)
130 (26%)
72 (14%)
69 (14%)
52 (10%)
42 (8%)
39 (8%)
36 (7%)
35 (7%)
38 (8%)
34 (7%)
36 (7%)
28 (6%)
28 (6%)
26 (5%)
25 (5%)
46 (9%)
83 (17%)
35 (7%)
16 (3%)
1 (<1%)
36 (7%)
15 (3%)
29 (6%)
2 (<1%)
0
4 (1%)
0
0
0
0
3 (1%)
2 (<1%)
0
1 (<1%)
2 (<1%)
3 (1%)
1 (<1%)
Grade 4
17 (3%)
Placebo
(N=253)
Any grade
154 (61%)
Grade 3
31 (12%)
Grade 4
4 (2%)
2 (<1%)
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
71 (28%)
19 (8%)
21 (8%)
39 (15%)
14 (6%)
15 (6%)
9 (4%)
10 (4%)
28 (11%)
6 (2%)
7 (3%)
12 (5%)
7 (3%)
1 (<1%)
5 (2%)
13 (5%)
9 (4%)
5 (2%)
4 (2%)
7 (3%)
8 (3%)
10 (4%)
12 (5%)
1 (<1%)
2 (1%)
7 (3%)
0
2 (1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (<1%)
0
0
1 (<1%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Adverse Effects
100
90
80
70
60
(%)
50
40
30
20
10
0
Any grade
Grade 3
Grade 4
Regorafenib
(N=500)
Placebo
(N=253)
Grade 4
Any
grade
Any grade
Grade 3
Grade 3 Grade 4
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
Hypophosphataemia
25 (5%)
19 (4%)
0
1 (<1%) 1 (<1%)
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%)
0
1(0.4)
0
0
Lipase ↑
31(6.2%) 15(3.0%) 6(1.2%)
3(1.2)
0
0
Laboratory
abnormalities
4(0.8%)
0
0
Adverse Effects
14
12
10
8
(%) 6
Any grade
4
Grade 3
2
Grade 4
0
One fatal case compatible with regorafenib-related, drug-induced liver
Injury: 62 y/o male with liver metastasis, 43 days after Rx
Adverse Effects
•
•
•
•
•
•
pneumonia (n=2)
gastrointestinal bleeding (n=2)
intestinal obstruction (n=1)
pulmonary haemorrhage (n=1)
seizure (n=1)
sudden death (n=1)
Functioning & Quality of Life
70
60
50
40
Regorafenib
30
Placebo
20
10
0
QLQ-C30
Baseline
QLQ-C30After
EQ-5D Visual EQ-5D Visual
Analog Baseline Analog After
Health Status
0.8
0.7
0.6
0.5
Regorafenib
0.4
Placebo
0.3
0.2
0.1
0
EQ-5D Baseline
EQ-5D After
DISCUSSION
• 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
• 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
• The main effect is disease stabilisation, rather
than tumour shrinkage
– CR:0
– PR:1%
– SD: 41%
Rectum vs. Colon?
1
0.9
0.8
HR 0.7
0.6
0.5
Colon
0.4
Rectum
0.3
0.2
0.1
0
OS
PFS
• 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%
• 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
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
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
THANKS FOR YOUR ATTENTION!