Instructor:VS 鄧豪偉Presenter: CR 周益聖

CORRECT studyThe Lancet November 22, 2012

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

Int. J. Cancer: 129,245-255 (2011) Colo-205 CRC xenograft model

MDA-MB-231 breast xenograft model

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

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 -/-)

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)

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

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

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 Plan

ed Treatment(%

)

Dose Modificati

ons(%)

>=1 Dose Reductions(%

)

>=1 Dose Interru

ptions(%)

0102030405060708090

100

RegorafenibPlacebo

Dose of Treatment

0

5

10

15

20

25

30

35

40

45

RegorafenibPlacebo

41

15

Response Rate

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

OSsubgroup

PFSsubgroup

　 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

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

(%)

　 　 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

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

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

QLQ-C30 Base

line

QLQ-C30After

EQ-5D Visual

Analog B

aselin

e

EQ-5D Visual

Analog A

fter0

10203040506070

RegorafenibPlacebo

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

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?

OS PFS0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

ColonRectum

HR

• 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!