1. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after standard therapies
Axel Grothey, MD
Co-investigators:
Alberto Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Heinz-Josef Lenz, Takayuki Yoshino, Frank Cihon, Andrea Wagner, Eric Van Cutsem
CORRECT: Patients with metastatic colorectal cancer treated with  regorafenib or placebo after failure of standard therapy

2. Standard management of mCRC
Globally, 1,234,000 new CRC cases and 608,000 deaths each year1
Vast majority of patients with mCRC are in a palliative situation2
Standard medical treatment options:2
5-Fluorouracil + folinic acid/leucovorin or capecitabine
Oxaliplatin
Irinotecan
Bevacizumab
Cetuximab or panitumumab for KRAS wild-type CRC
No standard salvage therapy, although many patients long retain good performance status
High unmet clinical need for active salvage therapy!
GLOBOCAN Cancer fact sheets: colorectal cancer
NCCN Guidelines. Colon cancer. v

3. Multiple signaling pathways activated in CRC
Figure adapted from Siena S et al 20092
Multiple pathways implicated in CRC, including:1–3
EGF / EGFR
VEGF / VEGFR
PDGF / PDGFR
FGF / FGFR
Downstream pathways:
RAS–RAF–MEK–ERK
PI3K–PTEN–AKT–mTOR
Kopetz et al showed that several compensatory pathways are activated during therapy with bevacizumab + FOLFIRI3
Provides rationale for using a multitargeted agent following progression
Macarulla T et al. Clin Colorectal Cancer 2006
Siena S et al. J Natl Cancer Inst 2009
Kopetz S et al. J Clin Oncol 2010

4. Mode of action of regorafenib (BAY 73-4506)
Regorafenib inhibits multiple cell-signaling kinases:
Angiogenic
VEGFR1–3, TIE2
Stromal
PDGFR-β, FGFR
Oncogenic
KIT, PDGFR, RET
T1/2 in man: approx hrs
Two major metabolites (M2, M5) are pharmacologically active
Wilhelm SM et al. Int J Cancer 2011

5. Clinical rationale for regorafenib in CRC: Phase I experience
38 patients with mCRC at dose levels of 60–220 mg/day (3 weeks on, 1 week off)
26 patients received regorafenib at 160 mg daily, the dose recommended for further studies
27 patients evaluable for response:
Disease control rate (DCR): 74%
Partial response n=1 (4%)
Stable disease ≥7 weeks n=19 (70%)
PFS: median 101 days (range 1–279 days)
At steady state, regorafenib and its active metabolites had similar systemic exposure
Pharmacodynamic assessment indicated decreased tumor perfusion in most patients
Strumberg D et al. ASCO 2009, abstr (poster update)

6. CORRECT study design Primary Endpoint: OS mCRC after standard therapy
RANDOM I ZAT I ON
Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off
Primary Endpoint: OS
90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025
mCRC after standard therapy
2 : 1
Placebo + BSC 3 weeks on, 1 week off
Multicenter, randomized, double-blind, placebo-controlled, phase III
2:1 randomization
Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region
Global trial: 16 countries, 114 active centers
1,052 patients screened, 760 patients randomized within 10 months
Secondary endpoints: PFS, ORR, DCR
Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers

7. Patient eligibility
Histological or cytological documentation of adenocarcinoma of the colon or rectum
Disease progression during, or within 3 months after last administration of approved standard therapies
Standard therapies had to include fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab (if KRAS wild-type)
Age ≥18 years, ECOG performance status 0–1, life expectancy ≥3 months

8. Patient demographics Regorafenib N=505 Placebo N=255
Age, median years (range)
61 (22–82)
61 (25–85)
Sex, %
Male
61.6
60.0
Female
38.4
40.0
Race, %
White
77.6
78.8
Black
1.2
3.1
Asian
15.0
13.7
Other/not reported
6.1
4.3
ECOG, %
52.5
57.3 1
47.5
42.7
Region, %
Asia (Japan, China)
North America, Western Europe, Israel, Australia
83.2
83.1
South America, Turkey, Eastern Europe
3.2

9. Baseline disease characteristics
Regorafenib N=505
Placebo N=255
Primary site of disease, %
Colon
64.0
67.5
Rectum
29.9
27.1
Colon and rectum
5.9
5.5
KRAS mutation, %* No
40.6
36.9
Yes
54.1
61.6
Unknown
5.3
1.6
Histology, %
Adenocarcinoma
98.0
97.3
Other
2.0
2.8
Prior systemic anti-cancer therapies (palliative), % 2
16.0
15.3 3
24.0
23.5
≥ 4
59.8
60.8
Prior bevacizumab, %
100
*KRAS status based on historical patient record

10. Overall survival (primary endpoint)
Median mos mos
95% CI – –5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value:
Regorafenib Placebo
1.00
0.75
Survival distribution function
0.50
0.25
Placebo N=255
Regorafenib N=505 50
100
150
200
250
300
350
400
450
Days from randomization
Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p< at approximately 74% of events required for final analysis)

11. Progression-free survival (secondary endpoint)
1.00
Regorafenib Placebo
Median mos mos
95% CI – –1.7
Hazard ratio: 0.49 (95% CI: 0.42–0.58)
1-sided p-value: <
0.75
Survival distribution function
0.50
Placebo N=255
0.25
Regorafenib N=505 50
100
150
200
250
300
350
Days from randomization

12. Overall response and disease control rates (secondary endpoints)
Best response, %
Regorafenib N=505
Placebo N=255
Complete response
Partial response
1.0
0.4
Stable disease
43.8
14.9
Progressive disease
49.5
80.0
Disease control rate, %*
44.8
15.3
*DCR = PR + SD; p<

13. Efficacy subgroup analyses
Based on preliminary results, no apparent effect of historical KRAS status on efficacy was observed
Biomarker analyses of plasma and tissue samples collected in this study are ongoing
Quality of life analysis ongoing

14. Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade
Regorafenib
N=500
Placebo
N=253
All grades
Grade 3
Grade 4
Grade 5
Hand–foot skin reaction
46.6
16.6
7.5
0.4
Fatigue
47.4
9.2
28.1
4.7
Hypertension
27.8
7.2
5.9
0.8
Diarrhea
33.8
7.0
0.2
8.3
Rash/desquamation
26.0
5.8
4.0
Anorexia
30.4
3.2
15.4
2.8
Mucositis, oral
27.2
3.0
3.6
Thrombocytopenia
12.6
2.6
2.0
Fever
10.4
Nausea
14.4
11.1
Bleeding
11.4
Voice changes
29.4
5.5
Weight loss
13.8
2.4

15. Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade
Regorafenib
N=500
Placebo
N=253
All grades
Grade 3
Grade 4
Grade 5
Hand–foot skin reaction
46.6
16.6
7.5
0.4
Fatigue
47.4
9.2
28.1
4.7
Hypertension
27.8
7.2
5.9
0.8
Diarrhea
33.8
7.0
0.2
8.3
Rash/desquamation
26.0
5.8
4.0
Anorexia
30.4
3.2
15.4
2.8
Mucositis, oral
27.2
3.0
3.6
Thrombocytopenia
12.6
2.6
2.0
Fever
10.4
Nausea
14.4
11.1
Bleeding
11.4
Voice changes
29.4
5.5
Weight loss
13.8
2.4
Adverse events leading to permanent Tx discontinuation
8.2%
1.2%

16. Summary of CORRECT results
The study met its primary endpoint at the preplanned interim analysis
Regorafenib vs placebo:
Overall survival: 6.4 vs 5.0 months, HR=0.77, p=0.0052
Crossed prespecified boundary (1-sided p< )
Progression-free survival: 1.9 vs 1.7 months, HR=0.49, p<
Disease control rate (PR + SD): 44.8% vs 15.3%, p<
No new or unexpected safety findings:
Main treatment-related adverse events observed in the regorafenib arm were fatigue, hand–foot skin reaction, diarrhea, anorexia, voice changes, hypertension, oral mucositis, and rash/desquamation

17. Conclusions Regorafenib:
Increases overall survival vs placebo in patients with mCRC progressing after standard therapies
First small-molecule multi-kinase inhibitor with proof of efficacy in CRC
Potential new standard of care in this patient population
CORRECT demonstrates that:
We can accrue to placebo-controlled trials in a patient population with an unmet need
Refractory CRC is a realistic setting for drug development

18. Thanks to the investigating centers and study participants
Lead investigators: AUSTRALIA: Philip Beale, Kathryn Field, Peter Gibbs, Nick Pavlakis, Timothy Price; BELGIUM: Eric van Cutsem, Jochen Decaestecker, Alain Hendlisz, Yves Humblet, Marc Peeters, Jean-Luc Van Laethem; CANADA: Mary Mackenzie, Wilson Miller, Mark Rother, Rafal Wierzbicki, Asif Shaik, Scott Berry; CHINA: Jianming Xu; CZECH REPUBLIC: Vladimira Stahalova, Ilona Kocakova, Bohuslav Melichar, Eugen Kubala; FRANCE: Marc Ychou, Olivier Bouche, Thierry Andre, Antoine Adenis, Mohamed Hebbar, Olivier Dupuis, Jean-Francois Seitz, Laurent Mineur, Christian Borel; GERMANY: H.-J. Schmoll, Martin Becker, Claudio Denzlinger, Volker Heinemann, Meinolf Karthaus, Claus-Henning Koehne, Nicolas Ziegenhagen, Hendrik Kroening, Wolfgang Schepp, Tanja Trarbach, Michael Clemens, Gunnar Folprecht, Ulrich Hacker, Ralf-Dieter Hofheinz, Arndt Vogel; HUNGARY: Janos Szanto, Laszlo Thurzo; ISRAEL: Adi Shani, Eina Shaham-Shmueli, Alex Beny, Ayala Hubert, Sofia Man, Baruch Brenner; ITALY: Alberto Sobrero, Giacomo Carteni, Gabriele Luppi, Alfredo Falcone, Salvatore Siena, Alberto Zaniboni, Carlo Barone, Fortunato Ciardiello, Corrado Boni; JAPAN: Hideo Baba, Eishi Baba, Tadamichi Denda, Hirofumi Fujii, Junji Furuse, Etsuko Warita, Yoshito Komatsu, Nobuyuki Mizunuma, Tomohiro Nishina, Yasutsuna Sasaki, Hiroya Takiuchi, Kazuma Kobayashi, Hiroyuki Uetake, Takashi Ura, Yasuhide Yamada, Kensei Yamaguchi, Kentarou Yamazaki, Takayuki Yoshino, Hideyuki Mishima; NETHERLANDS: A. J. Gelderblom, D. H. Verheul; SPAIN: Josep Tabernero, Rocio Garcia-Carbonero, Carles Pericay Pijaume, Cristina Gravalos, Manuel Benavides, Javier Sastre, Jaime Feliu, Mercedes Martinez Villaca; SWITZERLAND: Arnaud Roth; TURKEY: Mustafa Benekli, Faruk Aykan; USA: Axel Grothey, Billy Clowney, Martin Hyzinski, Ali Khojasteh, Marc Saltzman, Heinz-Josef Lenz, Udit Verma, John Kugler, Jyotsna Fuloria, Kenneth Nahum, George Kim, Rex Mowat, Philip Stella, Martin Wiesenfeld, Brian Dicarlo, George Geils, Youram Nassir
The CORRECT trial was sponsored by Bayer HealthCare AG, Leverkusen, Germany