Instructor:VS 鄧豪偉 Presenter: CR 周益聖

1. Instructor:VS鄧豪偉 Presenter: CR 周益聖 CORRECT study The Lancet November 22, 2012

2. Introduction

3. 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

4. Management of mCRC Ther Adv Med Oncol. 2012 Nov; 4(6):347-8.

5. Regorafenib(BAY 73-4506) Int. J. Cancer: 129,245-255 (2011)

6. Int. J. Cancer: 129,245-255 (2011)

7. 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)

8. 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)

9. 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-HippelLindau gene -/-) Int. J. Cancer: 129,245-255 (2011)

10. Dose-escalation: mCRC, NHL, MM (n=15) Extension phases: CRC(n=23) Phase I Study in mCRC 21 days on, 7 days off British Journal of Cancer (2012) 106(11), 1722 – 1727

11. 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!

12. 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

13. CORRECT Design n=505 RANDO MIZ ATION Regorafenib 160mg PO QD mCRCs/p systemic therapy 2:1 Placebo n=760 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

14. 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)

15. Result

16. Characteristics

17. Characteristics

18. Algorithms

19. Dose of Treatment

20. Response Rate 41 15

21. 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 1.9 months HR 0·49, 95% CI 0·42–0·58 p<0·0001 1.7 months

22. OS subgroup

23. PFS subgroup

25. Adverse Effects (%)

27. Adverse Effects (%) One fatal case compatible with regorafenib-related, drug-induced liver Injury: 62 y/o male with liver metastasis, 43 days after Rx

28. Adverse Effects • pneumonia (n=2) • gastrointestinal bleeding (n=2) • intestinal obstruction (n=1) • pulmonary haemorrhage (n=1) • seizure (n=1) • sudden death (n=1)

29. Functioning & Quality of Life

30. Health Status

31. Discussion

32. 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

33. 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

34. The main effect is disease stabilisation, rather than tumour shrinkage • CR:0 • PR:1% • SD: 41%

35. Rectum vs. Colon? HR

36. 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%

37. 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 effectthan placebo on QoL

38. 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 differential responses to regorafenib treatment • Subgroup patients likely to obtain benefit from regorafenib • Analyses of relevant biomarkers in specimens currently underway

39. Conclusion • The firstrandomised phase 3 study in which small-molecule kinase inhibitor as monotherapyhas shown significant overall survival benefitin patients with refractory mCRCwhen compared with BSC • Regorafenibcould be a new standard of care in late-stage mCRC

40. Thanks for your attention!