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
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!
1. GLOBOCAN Cancer fact sheets: colorectal cancer. 2008.
2. NCCN Guidelines. Colon cancer. v.2.2012.
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
1. Macarulla T et al. Clin Colorectal Cancer 2006
2. Siena S et al. J Natl Cancer Inst 2009
3. Kopetz S et al. J Clin Oncol 2010
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. 26-28 hrs
– Two major metabolites (M2,
M5) are pharmacologically
active
Wilhelm SM et al. Int J Cancer 2011
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. 3560 (poster update)
CORRECT study design
mCRC after
standard therapy
R
A
N
D
O
M
I
Z
A
T
I
O
N
Regorafenib + BSC
160 mg orally once daily
3 weeks on, 1 week off
Primary
Endpoint: OS
2:1
Placebo + BSC
3 weeks on, 1 week off
90% power to
detect 33.3%
increase
(HR=0.75), with
1-sided overall
a=0.025
• 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
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
Patient demographics
Regorafenib
N=505
Placebo
N=255
61 (22–82)
61 (25–85)
Male
61.6
60.0
Female
38.4
40.0
White
77.6
78.8
Black
1.2
3.1
Asian
15.0
13.7
Other/not reported
6.1
4.3
0
52.5
57.3
1
47.5
42.7
Asia (Japan, China)
13.7
13.7
North America, Western Europe, Israel, Australia
83.2
83.1
South America, Turkey, Eastern Europe
3.2
3.1
Age, median years (range)
Sex, %
Race, %
ECOG, %
Region, %
Baseline disease characteristics
Primary site of disease, %
KRAS mutation, %*
Histology, %
Prior systemic anti-cancer
therapies (palliative), %
Regorafenib
N=505
Placebo
N=255
Colon
64.0
67.5
Rectum
29.9
27.1
Colon and rectum
5.9
5.5
No
40.6
36.9
Yes
54.1
61.6
Unknown
5.3
1.6
Adenocarcinoma
98.0
97.3
Other
2.0
2.8
2
16.0
15.3
3
24.0
23.5
≥4
59.8
60.8
100
100
Prior bevacizumab, %
*KRAS status based on historical patient record
Overall survival (primary endpoint)
1.00
Survival distribution function
Median
95% CI
Regorafenib
Placebo
6.4 mos
5.0 mos
5.9–7.3
4.4–5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
0.75
0.50
0.25
Placebo N=255
Regorafenib N=505
0
0
50
100
150
200
250
300
350
400
450
Days from randomization
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
Progression-free survival
(secondary endpoint)
Survival distribution function
1.00
Median
95% CI
0.75
Regorafenib
Placebo
1.9 mos
1.7 mos
1.9–2.1
1.7–1.7
Hazard ratio: 0.49 (95% CI: 0.42–0.58)
1-sided p-value: <0.000001
0.50
Placebo N=255
Regorafenib N=505
0.25
0
0
50
100
150
200
Days from randomization
250
300
350
Overall response and disease control rates
(secondary endpoints)
Best response, %
Regorafenib
N=505
Placebo
N=255
Complete response
0
0
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<0.000001
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
Drug-related, treatment-emergent adverse events
occurring in ≥10% of patients at any grade
Regorafenib
N=500
Adverse event, %
All
Grade
grades
3
Grade
4
Placebo
N=253
Grade
All
Grade
5
grades
3
Grade
4
Grade
5
Hand–foot skin reaction
46.6
16.6
0
0
7.5
0.4
0
0
Fatigue
47.4
9.2
0.4
0
28.1
4.7
0.4
0
Hypertension
27.8
7.2
0
0
5.9
0.8
0
0
Diarrhea
33.8
7.0
0.2
0
8.3
0.8
0
0
Rash/desquamation
26.0
5.8
0
0
4.0
0
0
0
Anorexia
30.4
3.2
0
0
15.4
2.8
0
0
Mucositis, oral
27.2
3.0
0
0
3.6
0
0
0
Thrombocytopenia
12.6
2.6
0.2
0
2.0
0.4
0
0
Fever
10.4
0.8
0
0
2.8
0
0
0
Nausea
14.4
0.4
0
0
11.1
0
0
0
Bleeding
11.4
0.4
0
0.4
2.8
0
0
0
Voice changes
29.4
0.2
0
0
5.5
0
0
0
Weight loss
13.8
0
0
0
2.4
0
0
0
Drug-related, treatment-emergent adverse events
occurring in ≥10% of patients at any grade
Regorafenib
N=500
Adverse event, %
All
Grade
grades
3
Grade
4
Placebo
N=253
Grade
All
Grade
5
grades
3
Grade
4
Grade
5
Hand–foot skin reaction
46.6
16.6
0
0
7.5
0.4
0
0
Fatigue
47.4
9.2
0.4
0
28.1
4.7
0.4
0
Hypertension
27.8
7.2
0
0
5.9
0.8
0
0
Diarrhea
33.8
7.0
0.2
0
8.3
0.8
0
0
Rash/desquamation
26.0
5.8
0
0
4.0
0
0
0
Anorexia
30.4
3.2
0
0
15.4
2.8
0
0
Mucositis, oral
27.2
3.0
0
0
3.6
0
0
0
Thrombocytopenia
12.6
2.6
0.2
0
2.0
0.4
0
0
Fever
10.4
0.8
0
0
2.8
0
0
0
Nausea
14.4
0.4
0
0
11.1
0
0
0
Bleeding
Adverse events
Voice changes
leading
to permanent
11.4
0.4
0
0.4
2.8
0
0
0
29.4
0
5.5
0 1.2%0
0
Tx
discontinuation
Weight
loss
0.28.2%0
13.8
0
2.4
0
0
0
0
0
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<0.009279)
– Progression-free survival: 1.9 vs 1.7 months, HR=0.49, p<0.000001
– Disease control rate (PR + SD): 44.8% vs 15.3%, p<0.000001
• 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
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
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