Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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!