COLON CANCER STAGE IV TREATMENT OPTIONS 2022.pptx

-PART I:
1ST AND 2ND LINE
TREATMENT OPTIONS FOR
MCRC.

-CRC: An overview:
2
– Colorectal cancer is the third most common cancer occurring worldwide, with
over 1.36 million new cases diagnosed and approximately 694,000 deaths each
year1–4
– The 5-year survival rate for CRC after diagnosis varies by geography, for example,
65% in the US, 57% in Germany and 39% in Poland4
– However, survival of patients with CRC has dramatically improved over the last decade potentially
related to improved earlier detection (screening and earlier diagnosis) and the use of new treatment modalities5
– Approximately 20% of the CRC patients will initially present with metastasis and
50–60% of the patients will develop metastasis over the course of the disease6
– With integration of chemotherapy plus biological agents and surgery, up to 30%
to 40% of patients with organ-limited metastatic disease can be cured7
– ANYWAY, much efforts are still needed to enhance clinical outcomes of
the remaining 60% to 70% of patients7
NEW CASES DEATHS 5-YEAR PREVALENCE
USA 134,000 55,000 413,000
European Union 345,000 152,000 953,000
WHO South East Asia region
(SEARO)
120,000 85,000 216,000
WHO Americas region (PAHO) 246,000 112,000 705,000

-COLON CANCER STAGE
IV
SYNCHRONOUS MERTACHRONOUS
RESECTAB
LE
RESECTABLE
(UN-RESECTABLE)

-CHEMOTHERAPY -5FU+LEUCOVORIN – BASED
-IRINOTECAN-BASED
-OXALIPLATIN-BASED
-EGFR-INH (lt. KRAS, NRAS, BRAF
WILD)
-CETUXIMAB
-PANITUMUMAB
-ANTI-VEGFR -BEVACIZUMAB
-RAMUCIRUMAB ,
-AFLIBERCEPTT,
-REGORAFANIB
-MSI-H, MMR-D -PIMBROLIZUMAB
- NIVO.+- IPILIMUMAMB
-ANTI BRAF -CETUXIMAB+ENCORAFENIB +-
BINIMETINIB
-FOLFIXIRI+-BEVACIZUMAB
-ANTI-HER2 -
PERTUZUMAB+TRASTUZUMAB/LAPAT
ANIB

“VASCULAR ENDOTHELIAL
GROWTH FACTOR INHIBITORS”
ANTI - VEGFR “

-BEVACIZUMAB (VEGF-A)
-RAMUCIRUMAB VEGFR2 Antagonist
-AFLIBERCEPT VEGF-A and VEGF-B, , placental
growth (PGF)
-REGORAFANIB ?

AVF0780g: phase II trial of Avastin + 5-
FU/LV for the 1L treatment of mCRC
• Phase II
• Primary endpoint: TTP, ORR
• Secondary endpoints: OS, duration of response
Kabbinavar, et al. JCO 2003
Previously
untreated
mCRC
(n=104)
Avastin 5 mg/kg q2w
+ 5FU/LV*
(n=35)
Avastin 10 mg/kg q2w
+ 5-FU/LV*
(n=33)
5-FU/LV*
(n=36)
R
*Roswell Park

AVF0780g: efficacy
5-FU/LV*
Avastin 5 mg/kg q2w
+ 5-FU/LV
Avastin 10 mg/kg q2w
+ 5-FU/LV
Median TTP, months (95%
CI) 5.2 9.0 (5.8–10.9) 7.2 (3.8–9.2)
HR 0.46 0.66
p-value 0.005 0.217
Median OS, months 13.8 21.5 16.1
HR 0.63 1.17
p-value 0.137 0.582
ORR, % 17 40 24
p-value 0.029 0.434
Kabbinavar, et al. JCO 2003
*22 patients received Avastin after progression
4 M
7.8 M
23%

AVF2107g: phase III trial of Avastin +
IFL for the 1L treatment of mCRC
• Phase III
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, duration of response, safety and QoL
Hurwitz, et al. NEJM 2004
*Pre-specified discontinuation of enrolment in arm 3 when Avastin in combination
with the bolus-IFL regimen was deemed no more toxic than with 5-FU/LV
Previously
untreated
mCRC
(n=923)
Avastin 5 mg/kg q2w + IFL
(n=402)
Avastin +
5-FU/LV (n=110)*
Placebo + IFL
(n=411)
R

AVF2107g: efficacy
OS
estimate
15.6 20.3
0 5 10 15 20 25 30
Time (months)
1.0
0.8
0.6
0.4
0.2
0
HR=0.66
p<0.001
Avastin + IFL (n=402)
Placebo + IFL (n=411)
PFS
estimate
6.2 10.6
0 5 10 15 20 25 30
Time (months)
1.0
0.8
0.6
0.4
0.2
0
HR=0.54
p<0.001
OS PFS
Hurwitz, et al. NEJM 2004
3.7 M 4.2 M

HR=0.69; p=0.26
13.6 19.9
0 5 10 15 20 25 30
17.6 27.7
HR=0.58; p=0.04
Hurwitz, et al. Oncologist 2009
KRAS wild-type
KRAS mutant
AVF2107g: OS by KRAS mutation
status*
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20 25 30
OS
estimate
OS
estimate
Time (months) Time (months)
*Retrospective analysis; tissue samples were available from
28% of patients for molecular analysis of the KRAS codon

NO16966: phase III trial of Avastin + FOLFOX4/
XELOX for the 1L treatment of mCRC1,2
• Phase III, 1L
• Primary endpoint: PFS
• Secondary endpoints: PFS ‘on treatment’, OS, ORR, duration of response, time to
treatment failure
Recruitment
June 2003 – May 2004
Recruitment
Feb 2004 – Feb 2005
1. Cassidy, et al. JCO 2008; 2. Saltz, et al. JCO 2008; 3. Hurwitz, et al. NEJM 2004
XELOX
(n=317)
FOLFOX4
(n=317)
Placebo +
XELOX (n=350)
Avastin 7.5mg/kg q3w
+ XELOX (n=350)
Placebo +
FOLFOX4 (n=351)
Avastin 5mg/kg q2w
+ FOLFOX4 (n=349)
Initial 2-arm,
open-label study
(n=634)
Protocol amended to 2x2 placebo-controlled design (n=1,400) after
Avastin phase III data became available3

NO16966: efficacy
Saltz, et al. JCO 2008
19.9 21.3
Avastin + XELOX/FOLFOX4 (n=699)
Placebo + XELOX/FOLFOX4 (n=701)
0 6 12 18 24 30 36
OS
estimate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
OS
HR=0.89
(97.5% CI: 0.76–1.03)
p=0.0769
8.0 9.4
HR=0.83
(97.5% CI: 0.72–0.95)
p=0.0023
0 5 10 15 20 25
PFS
estimate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
PFS
Avastin + XELOX/FOLFOX4 (n=699)
Placebo + XELOX/FOLFOX4 (n=701)
1.4 M
1.4 M

-AVEX: phase III of BEVACIZUMAB +
Xeloda for 1L treatment of mCRC
patients ≥70
Previously untreated
mCRC, age 70 years
(n=280)
Xeloda (n=140)
Avastin 7.5 mg/kg q3w
+ Xeloda (1000 mg/m2 b.i.d, days
1-14)
(n=140)
R
 Phase III
 Primary endpoints: PFS
 Secondary endpoints: ORR, time to response, duration of response, OS, safety
Cunningham, et al. ASCO GI 2013

AVEX: Efficacy
PFS
estimate
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42
Time (months)
5.1 9.1
HR 0.53
p<0.001
Xeloda + Avastin (n=140)
Xeloda (n=140)
PFS
1.0
0.8
0.6
0.4
0.2
0.0
0 6 12 18 24 30 36 42 46
OS
estimate
Time (months)
16.8 20.7
HR 0.79
p=0.182
Xeloda + Avastin (n=140)
Xeloda (n=140)
OS*
*Study was not powered to detect differences in OS between treatment arms
Cunningham, et al. ASCO GI 2013
4 M
4.1 M

25.8
22.9
23.7
German
registry
(n=1,075)2
BRiTE
(n=279)3
First-BEAT
(n=503)4
30
25
20
15
10
5
0
26.3
ARIES
(n=191)5
Avastin + FOLFIRI
FOLFIRI
Irinotecan-
based CT
FOLFIRI
10.4
10.8
11.6
9.5
OS
PFS
Median
OS/PFS
(months)
29.1
14.6
27.8
11.5
XELIRI FOLFIRI
-Summary: consistent OS and PFS in observational
studies of 1L Avastin plus irinotecan-based
regimens
Czech
registry
(n=74)1
Czech
registry
(n=111/112)1
1. Prausova, et al. WCGIC 2009; 2. Arnold, et al. WCGC 2010; 3. Kozloff, et al. Oncologist 2009
4. Van Cutsem, et al. Ann Oncol 2009; 5. Bendell, et al. Oncologist 2012 [Epub ahead of print]
26 M
12 M

M
27.0
24.4
23.6
25.9
23.0
German
registry
(n=312)2
BRiTE
(n=1,093)3
BRiTE
(n=94)3
First-BEAT
(n=552)4
First-BEAT
(n=346)4
24.3
ARIES
(n=739)5
30
25
20
15
10
5
0
FOLFOX FOLFOX XELOX XELOX
Oxaliplatin-
based CT
FOLFOX
10.5
9.8
11.0
11.3
10.8
9.9
OS
PFS
Median
OS/PFS
(months)
Summary: consistent OS and PFS in observational
studies of 1L Avastin plus oxaliplatin-based
regimens
XELOX
FOLFOX4
Czech
registry
(n=301/n=304)1
Czech
registry
(n=373/375)1
NR
29.5
12.5
13.8
NR = not reached
Avastin +
25 M
11.5 M

-CHECKPOINT:
“DESPITE THE COMPARABLE PFS
AND OS DATA. BUT ,THE PANEL
,NCCN AND META-ANALYSIS
DEMONSTRATES THAT THE
BENEFIT OF BEVAZIZUMAB IN 1L
MCRC WAS LIMITED ONLY TO
IRINOTECAN-BASED REGIMENS”

E3200: phase III trial of Avastin +
FOLFOX4 for the 2L treatment of mCRC
• Phase III
• Primary endpoint: OS
• Secondary endpoints: PFS, ORR, safety
mCRC patients previously
treated with irinotecan
and fluoropyrimidine
(n=829)
Avastin 10 mg/kg q2w*
+ FOLFOX4 (n=286)
Avastin
(n=243)‡
FOLFOX4
(n=291)
Giantonio, et al. JCO 2007
*The dose of 10 mg/kg for Avastin was selected as preclinical and clinical data
suggested a dose response effect; AVF0780g demonstrated better outcomes with
5mg/kg but it was not powered for comparison therefore the investigators decided
that 10 mg/kg should be used; ‡Arm closed early based on interim analysis
suggesting inferior efficacy compared with combination arm
R

E3200: efficacy
12.9
10.8
Avastin +
FOLFOX4 (n=286)
FOLFOX4 (n=291)
HR=0.75
p=0.0011
7.3
4.7
Avastin +
FOLFOX 4 (n=280)
FOLFOX4 (n=279)
HR=0.61
p<0.0001
0 10 20 30 40 0 10 20 30
OS
estimate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
PFS
estimate
1.0
0.8
0.6
0.4
0.2
0
Time (months)
OS PFS
Giantonio, et al. JCO 2007
2 M
2.7 M

Avastin + standard 1L
chemo (either
oxaliplatin or
irinotecan-based)
(n=820)
Standard 2L chemo (oxaliplatin
or irinotecan-based) until PD
Avastin (2.5mg/kg/wk) +
standard 2L chemo (oxaliplatin
or irinotecan-based) until PD
PD
Key eligibility criteria • Histologically confirmed diagnosis of metastatic colorectal cancer
• ≥3 months of standard 1L Avastin plus chemo
• PD <3 months after last Avastin administration
ML18147: phase III trial of Avastin plus standard 2L chemotherapy
in mCRC patients progressing after standard 1LAvastin-based
treatment
• Phase III
• Primary endpoint: OS from randomisation
• Secondary endpoints: PFS, ORR, OS from start of 1L therapy
PD = disease progression
Bennouna, et al. Lancet Oncol 2013
CT switch:
Oxaliplatin  Irinotecan
Irinotecan  Oxaliplatin
R

ML18147: efficacy
*From randomisation
OS
estimate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30 38 42 48
Avastin + chemo (n=409)
Chemo (n=410)
9.8 11.2
OS*
PFS
estimate
Time (months)
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30 38 42
4.1 5.7
PFS*
Avastin + chemo (n=409)
Chemo (n=410)
HR=0.81
(95% CI: 0.69–0.94)
p=0.0062
HR=0.68
(95% CI: 0.59–0.78)
p<0.0001
Bennouna, et al. Lancet Oncol 2013
1.4 M 1.6 M

LEB.CRC.EDU.5.08.2016
Phase III studies with randomization maintenance versus
observation
*Assessed for eligibility; FP = 5-fluorouracil, folic acid, or capecitabine
1. Koeberle, ASCO 2012
2. Koopman, et al. ASCO 2014
3. Arnold, et al. ASCO 2014
Induction Maintenance
FOLFOX/CAPOX +
bev
(4–6 months)
Previously
untreated mCRC
(N=262)
SAKK 41/061
R
Bev
Observation
PD
PD
• Primary endpoint: non-inferiority in TTP from randomisation
CR
PR
SD
Re-induction
CAPOX + bev
(18 weeks)
Previously
untreated mCRC
(N=558)
CAIRO32
R
CAP+ bev
Observation
PD
• Primary endpoint: PFS2 (maintenance and re-induction treatment)
CR
PR
SD CAPOX + bev
FP + oxaliplatin
+ bev
(24 weeks)
Previously
untreated mCRC
(N=852)
AIO 02073
R
Observation
PD
• Primary endpoint: time to failure of strategy TFS
(maintenance and re-induction treatment)
CR
PR
SD
FP + Bev
Bev
FP ±
oxaliplatin ±
bev
Non-inferiority of bev
monotherapy could not
be demonstrated
BEVA OBSE
RVATI
ON
MEDIAN TTP 4.1 M 2.9 M
PFS 9.5 M 8.5 M
OS 25.1 M 24.M
FP+BEV
A
BEVA OBSER
VATION
PFS 6.2 4.8 3.6
OS 22.4 21.6 20.0

- BEVACIZUMAB :
1- NO RCT FOR USING FOLFIRI+BEVA. VS FOLFIRI ALONE
2-(AVF2017 G / IFL VS IFL+BEVA / 3.7 M I NCREASE OS )
3-(NO16966 / FOLFOIX VS FOLFOX+BEVA ) SHOWED NO OS BENEFIT WITH
ONLY MODEST (1.4M –PFS)
4 -SEVERAL META-ANALYSIS HAVE SHOWN THAT THE BENEFIT OF USING
BEVACIZUMAB WITH CHEMOTHERAPY IN 1ST LINE MCRC. WAS LIMITED
TO IRINO-TECAN BASED REGIMEN. ONLY.
5.-(E3200) CONFRMED BENEFITS OF BEVA. AS 2ND LINE MCRC IN BVA .NAIEVE
MCRC
6- (ML18147 (TML) , BRITE TRIALS) CONFIRMED THE BENEFITS OF
CONTINUING BEVACIZUMAB WITH SWITCHING CHEMOTHERAPY AFTER
PROGRESSION
7- (SAKK 41/06 + CAIRO-3 /AIO 0207
) showed iNCREASE PFS WITH ONLY
TREND TOWARD INCREASED OS, THUS ITS USE IS NOT THE

”Epidermal growth factor
receptor (EGFR) inhibitor ”:
1- CETUXIMAB:A chimeric
(mouse/human) monoclonal antibody
which binds to and inhibits EGFR.
2- PANITUMUMAB: fully humanized
monoclonal antibody specific to
the epidermal growth factor receptor

Primary endpoint
• Progression-free survival
Secondary endpoints
• Overall survival
• Response
• Safety
CRYSTAL: Cetuximab + FOLFIRI vs FOLFIRI alone
in 1st line mCRC1–3†
EGFR-
detectable
mCRC†
R
FOLFIRI
(Irinotecan + 5-
fluorouracil
[5-FU] + folinic acid
[FA], q2w) (n=599)
Stratification by
• ECOG PS and
region
Open-label, randomized,
controlled, multicenter
Phase III study
Treatment continued
until disease
progression,
unacceptable toxicity
1. Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019;
2. Van Cutsem E, et al. N Engl J Med 2009;360:1408–1417;
3. Van Cutsem E, et al. J Clin Oncol 2015;33:692–700;
4. Erbitux SmPC June/2014
Cetuximab
(400mg/m2 day 1
+ 250mg/m2 weekly)
+ FOLFIRI
(n=599)
*The protocol stated that cetuximab should be continued if CT
was delayed or discontinued for related toxicity; †Cetuximab is
indicated for use in RAS wt mCRC; cetuximab is not indicated for
the treatment of patients with mCRC whose tumors have RAS
mutations or for whom RAS tumor status is unknown;4
41
Erbitux 400 mg/m2 J1 then
250 mg/m2 every week
Every 2 weeks:
- Irinotecan 180mg/m2
- 5FU 400mg/m2 bolus then
2400 mg/m2 continuous
infusion (46h)
- Folinic acid
Every 2 weeks:
- Irinotecan 180mg/m2
- 5FU 400mg/m2 bolus
then 2400 mg/m2
continuous infusion
(46h)
- Folinic acid

42
• Primary criterion: mPFS is significantly improved with
the addition of Erbitux to FOLFIRI
• Secondary criteria:
-CRYSTAL
Erbitux + FOLFIRI vs FOLFIRI alone
1st line
RAS wt
Erbitux® + Folfiri
(n=178)
Folfiri
(n=189)
p
ORR (%) 66,3 38,6
Odds Ratio 3,11 (2,03 - 4,78)
p<0,0001
mOS (m) 28,4 20,2
HR 0,69 (0,54 – 0,88)
p=0,0024

44
TAILOR TRIAL: 1st line
1.8 M
4.3 M

45
-TAILOR:
Erbitux + FOLFOX4 vs FOLFOX4 alone
Qin S, et al. WCGC 2016 (Abstract no. O-
025)
1st line
Low proportion of patients
(46%)receiving any anti-cancer
therapy in 2nd or later lines may
have negatively impacted on OS
The subsequent use of anti-EGFR
therapies (15%) among patients
randomized to FOLFOX4 alone may
have slightly masked the overall
increase in OS observed with the
addition of cetuximab to FOLFOX4

Endpoint
TAILOR1 OPUS2
CRYSTAL3
Cetuximab +
FOLFOX4 (n=193)
FOLFOX4
alone
(n=200)
Cetuximab +
FOLFOX4
(n=38)
FOLFOX4
alone
(n=49)
Cetuximab +
FOLFIRI
(n=178)
FOLFIRI
alone
(n=189)
ORR
% 61 40 58 29 66 39
Absolute gain, % 22 29 28
OR (95% CI) 2.41 (1.61–3.61) 3.33 (1.36–8.17) 3.11 (2.03–4.78)
p-value <0.001 0.0084 <0.001
PFS
Median, months 9.2 7.4 12.0 5.8 11.4 8.4
∆PFS, months 1.8 6.2 3.0
HR (95% CI) 0.69 (0.54–0.89) 0.53 (0.27–1.04) 0.56 (0.41–0.76)
p-value 0.004 0.0615 <0.001
OS
Median, months 20.7 17.8 19.8 17.8 28.4 20.2
∆OS, months 2.9 2.0 8.2
HR (95% CI) 0.76 (0.61–0.96) 0.94 (0.56–1.56) 0.69 (0.54–0.88)
p-value 0.02 0.80 0.0024
46
-Efficacy in randomized trials of cetuximab + CT vs CT
alone (RAS wt) -

Primary endpoint
• OS
Secondary endpoints
• PFS
• Response
• Safety
• Quality of life
-EPIC: CETUXIMAB + irinotecan vs
irinotecan in 2nd line mCRC
Sobrero AF, et al. J Clin Oncol 2008;26:2311–2319
Patients with EGFR-expressing
mCRC after failure on
oxaliplatin-based CT
(N=1298)
CETUXIMAB
(400mg/m2 day 1, then
250mg/m2 q1w) +
irinotecan
Irinotecan
(350mg/m2 q3w)
n=648
n=650
R
Stratification by
• Study site
• ECOG PS (0‒1, 2)
controlled, multicenter Phase III
study

49
Several studies have evaluated 2nd line
cetuximab in mCRC
Continuum of
care
1
st
1. Sobrero AF, et al. J Clin Oncol 2008;26:2311–2319; 2. Langer C, et al. ESMO 2008 (Abstract No. 385P);
3. Ciardiello F. WCGIC 2015 (Abstract LBA09); 4. Ciardiello F, et al. Ann Oncol 2016;27:1055–61; 5. Bennouna J, et al. Poster at ESMO 2017 (Poster no.
477O).
EGFR-expressing mCRC
Irinotecan + cetuximab
(n=648; 400mg/m2 day 1,
then 250mg/m2 q1w)
Irinotecan (n=650)
(350mg/m2 q3w)
R
Oxaliplatin-based
CT
(N=1298)
KRAS (exon 2) wt mCRC
mFOLFOX6 + cetuximab
(n=74; q2w)
mFOLXFOX6
(n=79)
R
FOLFIRI +
Cetuximab
(N=340; q1w)
PD or
toxicit
y
KRAS (exon 2) wt mCRC
Cetuximab +
mFOLFOX6 or FOLFIRI
(n=67)
Bevacizumab +
mFOLFOX6 or FOLFIRI
(n=65)
R
Bevacizumab + CT
(N=133)
PD, toxicity or
patient refusal
P
D
PD (65%) or
toxicity (16%)
PD or
toxicit
y
PD
Cetuximab following 1st line CT: Phase III EPIC1,2
Cetuximab treatment beyond progression (CT switch): Phase II CAPRI-GOIM3,4
Cetuximab following 1st line bevacizumab + CT: Phase II PRODIGE 185
2nd line cetuximab + CT vs CT alone following 1st line CT significantly
improves PFS and ORR in EGFR-expressing mCRC*1,2
*Cetuximab is indicated for use in RAS wt mCRC; cetuximab is not indicated for the treatment of
patients with mCRC whose tumors have RAS mutations or for whom RAS tumor status is unknown3
1. Sobrero AF, et al. J Clin Oncol 2008;26:2311–2319;
2. Langer C, et al. ESMO 2008 (Abstract No. 385P); 3. Erbitux SmPC Dec 2016.
Cetuximab
+
irinotecan
(n=648)
Irinotec
an
(n=650)
HR
(95% CI)
p-
value
ORR, % 16.4 4.2 –
<0.00
01
Median
PFS,
months
4.0 2.6
0.69
(0.62–
0.78)
≤0.00
01
Median
OS,
months
10.7 10.0
0.98
(0.85–
1.11)
0.71
EPIC trial supports 2nd line cetuximab + irinotecan use after 1st line CT in patients with RAS wt
mCRC who missed the chance to receive cetuximab in the 1st line setting1,2
2nd line PFS in EGFR-expressing mCRC2
Months
0
25
50
75
100
18
6
0 12
PFS
(%)
2.6
4.0
Cetuximab + irinotecan
Irinotecan
X

-BOND: CETUXIMAB + irinotecan vs
Erbitux monotherapy in irinotecan-
refractory mCRC
Cunningham D, et al. N Engl J Med 2004;351:337–345
Primary endpoint
• Independently-confirmed response rate
Secondary endpoints
• TTP, DoR, OS
• Adverse effects
Patients with
EGFR-expressing, irinotecan-
refractory mCRC; no history of
EGFR therapy
(N=329)*
Erbitux + irinotecan
(Erbitux 400mg/m2
day 1, then 250mg/m2
q1w)
Erbitux
(400mg/m2 day 1,
then
250mg/m2 q1w)
n=218
n=111
R
controlled, multicenter Phase II
study
21% of patients in 2nd
line

-BOND: Erbitux + irinotecan improved
ORR and PFS vs Erbitux monotherapy
• Cunningham D, et al. N Engl J Med 2004;351:337–345
Confidential. Internal Use Only. Do Not Copy or Distribute
Endpoint
Erbitux +
irinotecan
(n=218)
Erbitux
(n=111)
ORR, % 22.9 10.8
p-value p=0.007
Median OS
(months)
8.6 7.9
HR (95% CI) 0.91 (0.68–1.21)
p-value p=0.48
PFS
Time to progression
(months)
HR=0.54
(95% CI:
0.42–0.71)
p<0.001
100
75
50
25
0
Patients
free
of
progression
(%)
0 2 4 6 8 10 12
Erbitux + irinotecan
Erbitux

-COIN-B: Intermittent vs continuous cetuximab
maintenance therapy in KRAS wt mCRC1†
1. Wasan H, et al. Lancet Oncol 2014;15:631–639;
2. Erbitux SmPC. June 2014.
Open-label, randomized, multicenter, exploratory Phase II trial
mFOLFOX
+ cetuximab
mFOLFOX
+ cetuximab
mFOLFOX
+ cetuximab‡
mFOLFOX
+ cetuximab‡
mFOLFOX
+ cetuximab‡
mFOLFOX
+ cetuximab‡
+ cetuximab + cetuximab‡
R 12 weeks
On PD: reintroduce
mFOLFOX + cetuximab‡ (N=44)
(On PD: reintroduce
mFOLFOX + continue
cetuximab
Intermittent cetuximab
(n=78 with KRAS wt tumors)
Continuous (maintenance)
cetuximab (n=91 with
KRAS wt tumors)
*The trial was not powered for comparison between treatment arms
†Cetuximab is indicated for use in RAS wt mCRC; cetuximab is not indicated for the
treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS
tumor status is unknown;2 ‡the combination of cetuximab + FOLFOX is approved for 1st
line therapy but not for subsequent lines of therapy2
12 weeks 12 weeks
P
D
P
D
P
D
P
D
53

COIN-B: PFS with continuous cetuximab + intermittent CT vs
intermittent cetuximab + CT1
KRAS codons 12, 13, 61 wt‡
Intermittent
(n=64)
Continuous
(n=66)
Median PFS from 12
weeks,*† months (95% CI)
3.1
(2.8–4.7)
5.8
(4.9–8.6)
Although the study was not powered for
comparison, median PFS (measured from
12 weeks) appeared longer for
continuous vs intermittent cetuximab
when added to intermittent CT§
54
6 12 18 24 30 36 42
0
Time (months)
Primary analysis cohort of patients still on trial without PD after 12
weeks
PFS from 12 weeks, KRAS/NRAS/BRAF wt*†
Continuous cetuximab
100
75
50
25
0
Progression-free
survival
(%)

-COIN-B: OS with continuous cetuximab + intermittent CT vs
intermittent cetuximab + CT1
1. Wasan H, et al. Lancet Oncol 2014;15:631–639;
2. Erbitux SmPC. June 2014.
KRAS codons 12, 13, 61 wt‡
Intermittent
(n=64)
Continuous
(n=66)
Median OS,*† months
(95% CI)
16.8
(14.5–22.6)
22.2
(18.4–28.9)
Although the study was not
powered for comparison, median OS
appeared longer for continuous vs
intermittent cetuximab when added
to intermittent CT§
55
OS, KRAS/NRAS/BRAF wt*†
0 6 12
Time (months)
18 24 30 36 42
100
75
50
25
0
Overall
survival
(%)
Continuous cetuximab

57
-The CRICKET trial further demonstrates the potential of cetuximab
rechallenge in RAS wt/BRAF wt mCRC1* Continuum of
care
1
st
Phase II, single-arm study1
Bevacizu
mab +
FOLFOX/
FOLFOXI
RI/
XELOX
Cetuxi
mab +
FOLFIR
I/
FOLFO
XIRI
RAS/BRA
F wt*
mCRC
n=28
Cetuxi
mab +
irinoteca
n†
ENROLMENT
Primary endpoint met:1 ORR:
22% (PR n=6‡, SD n=9, DCR: 54%)
PFS by RAS status1
100
0
0 2 4
PFS
probability
(%)
Follow-up (months)
6 8 10
80
60
40
20
mPFS :4.0 months
mPFS : 1.9 months
12
OS by RAS status1
14
100
0
0 5 10 20
OS
probability
(%)
Follow-up (months)
15
80
60
40
20
mOS 7.5 months
mOS 5.2 months
]
The evaluation of RAS mutational status on ctDNA
IS THE GUIDANCE in selecting candidate

1. Clinical trials.gov NCT02934529, updated
Oct 2016, available at:
https://clinicaltrials.gov/ct2/show/NCT029
34529 (accessed April 2018).
Bevacizumab +
FP maintenance*
Cetuximab +
FOLFIRI (8–12 cycles)
Cetuximab + FOLFIRI
R1
1st line
PD†
RAS wt
mCRC
(N=550)
Bevacizumab
+ FOLFOX
2nd line
PD†
Cetuximab‡ +
irinotecan/FOLFIRI
Physician’s choice
Death
3rd line
R2
Primary endpoint:
OS from randomization to 3rd line
treatment
Ongoing Phase III FIRE-4 study investigating cetuximab rechallenge1
Secondary endpoints:
ORR1, 2 and 3, PFS1, 2 and 3, OS1, DpR, ETS during 1st and 3rd line, molecular
biomarkers for prediction of sensitivity and secondary resistance to anti-EGFR
treatment with cetuixmab, biomarker score, tumor marker evolution (CEA and CA
19-9), safety
Estimated study
completion:
December 2023

-1ST LINE:
PROVEN BENEFITS OF CETUXIMAB + CHEMOTHERAPY IN 1ST LINE
EITHER WITH FOLFIRI (CRYST TRIAL/ ( OS: 8M - PFS: 3M) 0R
FOLFOX(OPUS &TAILOR/(OS:4 M -PFS: 2M) ,TEXT SHOWED SOME
PREFERENCE OF USING IT WITH IRINOTECAN-BASED REGIMEN)
-2ND AND LATER LINES:
USING CETUXIMAB WITH CHEMOTHERAPY (EPIC & BOND)
SHOWED INCREASED ORR AND PFS. BUT , NO DATA ON INCREASE
D OS WAS FOUND
-MAINTENACE :
NO DEFINITIVE BENEFIT YET OF USING CETUXIMAB AS MAINTENANCE
AGENT EITHER ALON OR WITH CHEMOTHERAPY.
-BEYOND PROGRESSION:
(CRICKET TRIAL) SHOWED A CONTINUOUS RESPONSES TO
CETUXIMAB AFTER PROGRESSION IN EARLY LINES CETUXIMAB-
CONTAINING REGIMEN (FIRE-4 TRIAL IS STILL WAITED).
-CETUXIMAB

(MAPK signaling pathway)
(MEK-INHIBITORS)

-FIRE 4.5 RESULTS:
.
BEVA.+CHEMOTHERAPY CETUX.+CHEMOTHERAPY
ORR 66.7% 52.0%
PFS 8.3 M 5.8 M
OS IMMATURE RESULTS
-THIS GIVE US ANOTHER TREATMENT OPTION
FOR BRAF-MUTANT MCRC:
(TRIPLET CHEMOTHERAPY + BIOLOGICAL
AGENT)

• Randomized, open-label phase III study
*
KEYNOTE-177 Final Analysis: Study
Design
Patients with
treatment naive
MSI-H/dMMR stage
IV CRC; measurable
disease per RECIST
v1.1; ECOG PS 0/1
(N = 307)
Pembrolizumab
200 mg IV Q3W
(n = 153)
mFOLFOX-6 IV Q2W or
mFOLFOX-6 + Bevacizumab IV Q2W or
mFOLFOX-6 + Cetuximab IV Q2W or
FOLFIRI IV Q2W or
FOLFIRI + Bevacizumab IV Q2W or
FOLFIRI + Cetuximab IV Q2W
(n = 154)
Treatment
continued up to 35
cycles or until PD,
unacceptable
toxicity, or
withdrawal of
consent

Event
s, %
Median PFS2,
Mo (95% CI)
Pembr
o
44 54.0 (44.4-NR)
CT 62 24.9 (16.6-32.6)
HR: 0.61 (95% CI:
0.44-0.83)
Event
s, %
Median PFS,
Mo (95% CI)
Pembr
o
56 16.5 (5.4-38.1)
CT 76 8.2 (6.1-10.2)
HR: 0.59 (95% CI:
0.45-0.79)
KEYNOTE-177 Final Analysis: PFS and
PFS2
Slide credit: clinicaloptions.c
PFS2
PFS
André. ASCO 2021. Abstr 3500. Reproduced with permission.
Data cutoff: February 19, 2021
100
80
60
40
20
0
PFS
(%)
0 4 8 12162024283236404448525660
Mos
153
154
96
101
77
69
72
45
64
35
60
25
59
21
55
16
50
12
42
11
28
8
16
5
7
3
5
0
0
0
0
0
12-mo rate
55%
38%
36-mo rate
42%
11%
100
80
60
40
20
0
PFS2
(%)
0 4 8 12162024283236404448525660
Mos
153
154
131
136
120
117
116
100
107
88
103
78
99
73
97
69
93
62
87
53
67
43
43
29
26
11
15
6
3
2
0
0
12-mo rate
76%
67% 36-mo rate
60%
39%

KEYNOTE-177 Final Analysis: OS
Slide credit: clinicaloptions.c
André. ASCO 2021. Abstr 3500. Reproduced with permission.
Events,
n (%)
Median OS,
Mo (95% CI)
Pembro
62
(40.5)
NR (49.2-NR)
CT
78
(50.6)
36.7 (27.6-NR)
HR: 0.74 (95% CI: 0.53-
1.03)
100
80
60
40
20
0
OS
(%)
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60
Mos
153
153
134
137
123
121
119
110
112
99
107
95
104
88
101
85
97
79
92
71
70
53
48
36
28
18
16
11
4
3
0
0
12-mo rate
78%
74%
36-mo rate
61%
50%
No. at Risk

CheckMate 142 Study Design
Phase 2 multi-cohort trial in patients with recurrent or metastatic CRC1–6
CheckMate 142: NIVO+IPI, MSI-
H/dMMR, 2L+
2L+
Monothera
py Cohort
(n = 74)
2L+
Combinatio
n Cohort (n
= 119)
NIVO 3 mg/kg
Q2W
NIVO 3 mg/kg + IPI
1
mg/kg
Q3W
(4
doses, then
NIVO 3
mg/kg
Q2W)
Key inclusion
criteria
• Histologically
confirmed
metastatic/recurre
nt CRC
• MSI-
H/dMMR
per local
laboratory
1L
Combinatio
n Cohort (n
= 45)
NIVO 3 mg/kg Q2W + IPI
1
mg/kg Q6W
Primary endpoint:
ORR
Secondary endpoint:
ORR per blinded
independent central
review (BICR)
y
1 of
14
ASCO 2019.
Abstract 3521.

Progression-
Free
Survival
NIVO+IPI NIVO
9-month rate % 70% 44.6) %
12-month rate % 68 % 44.6 %
NIVO+IPI
NIVO
15 18
Time (months)
No. at
risk
Progression-free
survival
(%)
a,1–3
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 1
2
2
1
2
4
2
7
3
0
-CheckMate 142: NIVO+IPI, MSI-H/dMMR, 2L+-

Overall
Survival
-CheckMate 142: NIVO+IPI, MSI-H/dMMR, 2L+-
NIVO+IPI NIVO
9-month rate 87 % 78 %
85% 73 %
100
90
80
70
60
50
40
30
20
10
0
Overall
survival
(%)
1–3
15
18
Time
(months)
NIVO+IPI
0 3 6 9 1
2
2
1
2
4
2
7
3
0
33
NIVO
12-month rate

-MSI-H AND MMR-D MCRC:
• In KEYNOTE-177, first-line pembrolizumab significantly
prolonged PFS/PFS2 vs chemotherapy in patients with MSI-
H/dMMR Mcrc1
• Pembrolizumab was associated with a reduction in mortality vs
chemotherapy No new safety signals emerged with longer follow-
up1
• CHECKMATE -142 IS MULTI-COHORT PHASE 2 TRIAL
SHOWED A BENEFIT OF USING NIVO +- IPI 1ST And 2nd
line msi-h and mmr-d mcrc .
• Investigators indicate that these data confirm

-ANTI HER-2:
1.MYPATHWAY + TAPUR TRIALS (57 PATIENTS)
PHASE II TRIALS SHOWED INCREASED ORR OF
USING DUAL ANTI HER-2
PERTUZUMAB+TRASTUZUMAB IN MCRC
(ORR :32% , 1 CR ,17 PR)
2-HERACLES TRIAL:
II TRIAL(27 PATIENTS)
SHOWED BENEFIT OF USING
TRASTUZUMAB+LAPATINIB IN HER-2 MUTATED
MCRC
(ORR: 30% , 1CR , 7PR)
3-DESTINY TRIAL:
PHASE II TRIAL OF T.DUREXTAN IN HER-2+VR
MCRCD

1.BEVACIZUMAB IN 1ST LINE MCRC SHOULD BE
USED WITH IRINOTECAN ONLY
2.BEVACIZUMAB CAN BE USED ON 2ND LINE
AFTER PROGRESSION
3.CETUXIMAB SHOULD BE USED IN 1ST LINE
4.BRAF: NEEDS AGGRESSIVE TTT(2 TRIPLET
OPTIONS )
5.PIMBROLIZUMAB IS PREFERRED OVER
NIVO+- IPI
6. DUAL ANTI HER-2 ARE REQUIRED FOR HER-

-PART II:
3RD LINE TREATMENT
OPTIONS FOR MCRC.

-NCCN practice guidelines for the
treatment of mCRC
8
0
-Treatment is predicated on therapies the patient received or is intolerant to in prior
lines. NCCN has recently incorporated tumor location (“sidedness”) into the
guidelines for first-line therapy options and recommends anti-EGFR therapy in
patients with RAS WT mCRC with left-sided tumors only.
-Regorafenib should be considered as soon as the patient has been treated with
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF
therapy, and an anti-EGFR therapy (if RAS WT).
First-line
mCRC
Post First
Progression
Post Second
Progression
Post Third
Progression
3L Mut
RAS
3L WT
RAS
5FU/LV-
based
regimens
± biologic*
2L Mut
RAS
2L WT
RAS
Oxaliplatin-
based
regimens
± biologic*
Irinotecan-based regimens
± bevacizumab or aflibercept or
ramucirumab; or ±
panitumumab or cetuximab
(RAS WT only) or +
vemurafenib (BRAF V600E
MUT only)
2L WT
RAS
2L MUT
RAS
Irinotecan-
based
regimens
± biologic*
Regorafenib or TAS-102; or
panitumumab or cetuximab ±
irinotecan**(RAS WT only); or +
MUT only); or pembrolizumab
or nivolumab (dMMR/MSI-H
only)
Regorafenib or
TAS-102;
or panitumumab
or cetuximab
± irinotecan**
(RAS WT ONLY);
pembrolizumab
or nivolumab
(dMMR/MSI-H
ONLY)
Regorafenib
or
TAS-102;
BSC
• Untreated mCRC
patients
• Stratified by RAS
mutation status
• *Biologic includes:
bevacizumab or
cetuximab or
panitumumab
• Anti-EGFR therapy
may only be used
in RAS WT mCRC
(and in first-line in
left-sided tumors
only)
2L Mut
RAS
2L WT
RAS
3L Mut
RAS
3L WT
RAS
Regorafenib or
TAS-102; or
pembrolizumab
or nivolumab
(dMMR/MSI-H
only)
FOLFOXIRI ±
bevacizumab
Oxaliplatin-based regimens
± bevacizumab; or ±
bevacizumab or
± panitumumab or cetuximab
(RAS WT only) or +
MUT only)
REGORAFENIB
DOSING
• NCCN (Version
2.2018) now
recommends the first
cycle dosing
optimization
approach from
ReDOS
• Cycle 1: 80 mg
W1→120 mg
W2→160 mg W3.
• Cycle 2 and
subsequent cycles:
160 mg 3W on/1W
off

LEB.CRC.EDU.5.08.2016
-ESMO guidelines: continuum of care in
patients with WT mCRC
CT = chemotherapy;
EGFR = epidermal growth factor receptor Van Cutsem, et al. Ann Oncol 2014
CT doublet + bevacizumab or
aflibercept
CT doublet + bevacizumab
Irinotecan or FOLFIRI + anti-
EGFR antibody
Regorafenib
CT doublet + anti-EGFR
antibody
CT doublet + bevacizumab
Regorafenib
CT doublet + bevacizumab or
aflibercept
CT doublet + anti-EGFR
antibody
Regorafenib
1L
2L
3L
4L
Scenario 1 Scenario 2 Scenario 3

-ESMO guidelines recommend regorafenib as a standard
option in pre-treated mCRC patients in the 3rd-/4th-line
setting
8
2
– Regorafenib is recommended in patients pre-treated with fluoropyrimidines,
oxaliplatin, irinotecan, bevacizumab and in RAS wild-type patients with
EGFR antibodies [Level of evidence I, grade of recommendation B]*
• TAS-102 is recommended with level of evidence [I, B]*
– Regorafenib is recommended for patients with relapsed mCRC with
regardless of RAS or BRAF mutation status
–
– Note: Recommendation 21 in the current ESMO guidelines only describes the use of cetuximab
plus irinotecan in irinotecan-refractory patients (and if RAS WT). To date, there is a lack of data to
support doublet chemotherapy + anti-EGFR therapy after 2nd-line failure
.
*Level of evidence, I: Evidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well
conducted randomized trials without heterogeneity. Grade of recommendation, B Strong or moderate evidence for efficacy but with a limited clinical benefit,
generally recommended.
a Patients assessed as fit or unfit according to medical condition not due to malignant disease. b EGFR antibodies: cetuximab and panitumumab. c If not yet
pretreated with an EGFR antibody.
SOURCE: Van Cutsem E, et al. Ann Oncol. 2016;27(8):1386-422.
ESMO
CATEGORY
FIT PATIENTSa
CYTOREDUCTION
(TUMOR SHRINKAGE)
DISEASE CONTROL
(CONTROL OF PROGRESSION)
THIRD-LINE RAS WT RAS MUT BRAF MUT RAS WT RAS MUT BRAF MUT
Preferred
choice (s)
CT doublet +
EGFR antibodyb,c
or
irinotecan +
cetuximabc
Regorafe
nib
or TAS-
102
Regorafe
nib
or TAS-
102
CT doublet +
EGFR
antibodyb or
irinotecan +
cetuximab
Regorafe
nib
or TAS-
102
Regorafe
nib
or TAS-
102
Second choice
EGFR antibody
monotherapyc
EGFR antibody
monotherapyc
Third choice
Regorafenib or
TAS-102
Regorafenib or
TAS-102

.DEVELOPED BY BAYER TO
TARGET ANGIOGENIC, STROMAL
RECEPTOR TYROSINE KINASE
(RTK)
.WAS APPROVE ON:
- SEP.21.2012 FOR REFRACTORY
MCRC
-FEB,25,2013 FOR REFRACTORY
GIST
-NOV.29.2018 FOR REFRACTORY
HCC

-Antitumor mechanisms of regorafenib
Numerous studies demonstrate the broad antitumor activity of the multikinase inhibitor regorafenib,
providing putative mechanisms for its robust antitumor efficacy in CRC24–26
8
4
• Inhibits several tyrosine kinase
receptors (e.g. VEGFR1,
VEGFR2, VEGFR3, PDGFRβ,
FGFR1, and TIE-2) involved in
angiogenesis, lymphatic vessel
formation, and vessel
stabilization within the tumor
microenvironment24,25
• Blocks autophosphorylation of
VEGFR2 in human umbilical vein
endothelial cells and VEGFR3 in
human lymphatic endothelial
cells in vitro22,25
• Inhibits VEGFR2 and VEGFR3
involved in endothelial cell
growth and migration22,25
• Blocks PDGFR, which is
involved in cancer-associated,
fibroblast-induced metastasis
of CRC24,28
• Inhibits metastasis in various
colon
cancer models26,28
• Suppresses the proliferation of
CRC cells in vitro22
• Potently inhibits growth of
patient-derived CRC tumor
xenografts22,31
• Inhibits CSF-1R, a receptor
involved
in macrophage recruitment
and differentiation into tumor-
associated macrophages6,7,25
• Reduces macrophage
infiltration in preclinical CRC
models26,32
β-
catenin
PI3K
mT
OR
PTE
N
TP5
3
SMA
D4
BRA
F
KRA
S
NRA
S
ERK
TIE-2
Ang
CSF-1R
CSF-
1
HGF
MET
LRP/
Frizzled
Wnt
FGF
FGFR
VEGFR
VEGF
EGFR
EGF
Regorafenib
inhibition12,2
4–26
Metastasis & tumor
microenvironment
Angiogenesis
Cell proliferation
Immunosuppression
Ligand1–13
Intracellular
signaling
pathways1,2,11,14
–16
Receptors1–
14
GDN
F
RET
fusio
n
PDGFR
PDG
F
TGFBR
2
TGFβ
AKT
APC
MEK

-VEGF-targeted agents used in GI tumor
types
8
5
CRC HCC GASTRIC/GEJ GIST CCA
Bevacizumab
Pazopanib
Ramucirumab
Regorafenib
Sorafenib
Sunitinib
Ziv-aflibercept
*Drug not approved in this indication.
CCA, cholangiocarcinoma; CRC, colorectal cancer; GEJ, gastroesophageal junction; GI, gastrointestinal; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma;
VEGF, vascular endothelial growth factor.
1. Avastin Summary of Product Characteristics, Roche Pharma AG, Germany, 2018. 2. Avastin Prescribing Information, Genentech Inc., USA, 2018. 3. Mir O, et al. Lancet
Oncol. 2016;17:632–641. 4. Cyramza Summary of Product Characteristics, Eli Lilly, The Netherlands, 2018. 5. Cyramza Prescribing Information, Eli Lilly and Company, USA,
2018. 6. Zhu AX, et al. J Clin Oncol. 2018;36(15_Suppl):4003. 7. Stivarga Summary of Product Characteristics, Bayer AG, Germany, 2018. 8. Stivarga Prescribing Information,
Bayer Healthcare Pharmaceuticals, USA, 2017. 9. Pavlakis N, et al. J Clin Oncol 2016;34:2728–2735.
10. Sun W, et al. J Clin Oncol. 2017;35(15_Suppl):4081. 11. Nexavar Summary of Product Characteristics, Bayer AG, Germany, 2018. 12. Nexavar Prescribing Information,
Bayer Healthcare Pharmaceuticals Inc., USA, 2017. 13. Kefeli U, et al. Oncol Lett. 2013;6:605–611. 14. Sutent Summary of Product Characteristics, Pfizer Ltd., UK, 2018. 15.
Sutent Prescribing Information, Pfizer Inc., USA, 2017; 16. Zaltrap Summary of Product Characteristics, sanofi-aventis Group, France, 2017. 17. Zaltrap Prescribing
Information, sanofi-aventis US LLC., USA, 2016.

(1,2
)

(4,5
)

(7,8
)

(16,
17)

(10
*)
(3*)

(7,8
)

(13
*)

(14,
15)

(4,5
)
(9*)
(6*)

(7,8
)

(11,1
2)

-Colorectal cancer is not one disease
Impact on main competitors in 3rd-line and later-treatment lines.
8
6
EFFECTIVENESS
IRRESPECTIVE
OF: REGORAFENIB TAS-102 ANTI-EGFR
CHEMOTHERAPY
RECHALLENGE
RAS status Only in WT patients7
BRAF status Only in WT patients8
Tumor sidedness
as surrogate
marker of efficacy
More impactful in
left-sided tumors9,10
MSI status 
(1,2
)
(2)
(3)
(4)




?
?
(5)
(6)


? ?
?
(11
*)
(11
*)


*Chemotherapy activity in CRC is independent of RAS and BRAF mutation status; rechallenge is not recommended in guidelines. EGFR, epidermal growth factor receptor;
MSI, microsatellite instability; WT, wild-type.
1. Grothey A, van Cutsem E, et al. Lancet. 2013;381:303–312. 2. Li J, et al. Lancet Oncol. 2015;16:619–629. 3. Ducreux M, et al. J Clin Oncol. 2017;35(suppl_15):3567. 4.
Kochert K, et al. Ann Oncol. 2017:28(Suppl_5):534P. 5. Mayer RJ, et al. N Engl J Med. 2015;372:1909–1919. 6. Hochster H, et al. Ann Oncol. 2015;26(Suppl_4):iv111 (O-010).
7. Karapetis CS, et al. N Engl J Med. 2008;359:1757–1765;
8. Pietrantonio F, et al. Eur J Cancer. 2015;51:587–594. 9. Venook AP, et al. J Clin Oncol. 2016;34(Suppl);3504. 10. NCCN clinical practice guidelines in oncology. Colon
cancer. V 2.2018 (March 14, 2018).
11. Van Cutsem E, et al. Ann Oncol. 2016;27:1386–1422.

CORRECT and CONCUR
Results from the two randomized phase III trials of regorafenib for
metastatic colorectal cancer (mCRC)

CORRECT was a global study conducted in Australia, Belgium, Canada, China, Czech
Republic, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Spain, Switzerland,
Turkey, and USA1
CONCUR is an Asian trial conducted in China, Hong Kong, Korea, Taiwan, and Vietnam2
Regorafenib 160 mg orally once
daily (3 weeks on, 1 week off)
+ best supportive care
Placebo (3 weeks on, 1 week off)
PATIENTS (N=760)
With mCRC after
standard therapy:
fluoropyrimidine,
oxaliplatin, irinotecan,
bevacizumab, and
cetuximab or
panitumumab (if KRAS
wild-type)
Primary Endpoint:
Overall survival
Secondary Endpoints:
PFS, ORR, DCR, and safety
Tertiary Endpoints:
Duration of response/stable
disease, QOL, PK,
biomarkers
R 2:1
Primary Endpoint:
Overall survival
Secondary Endpoints:
PFS, ORR, DCR, and
safety
Tertiary Endpoints:
Duration of response/stable
disease, QOL, PK,
biomarkers
Regorafenib 160 mg orally once
daily (3 weeks on, 1 week off)
Placebo (3 weeks on, 1 week off)
R
PATIENTS (N=204)
• With mCRC after
standard therapy:
fluoropyrimidine,
oxaliplatin, irinotecan
• Patients may have
received
bevacizumab, and
cetuximab or
panitumumab (if
KRAS wild-type)
2:1
CORRECT and CONCUR: Two randomized phase III trials of
regorafenib in mCRC patients
8
8
1. Grothey A, et al. Lancet. 2013;381:303–312. 2. Li J, et al. Lancet Oncol. 2015;16:619–629.

-CORRECT & CONCUR: Baseline characteristics
8
9
*In CONCUR, prior anti-VEGF therapy use was noted as 2 categories – “anti-VEGF but not anti-EGFR”, and “both anti-VEGF and anti-EGFR”.
ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; IQR, interquartile range; VEGF,
vascular endothelial growth factor.
CORRECT1 CONCUR2
REGORAFENIB
(N=505)
PLACEBO
(N=255)
REGORAFENIB
(N=136)
PLACEBO
(N=68)
Median age, years (IQR) 61 (54–67) 61 (54–68) 58 (50–66) 56 (49–62)
Male, % 62 60 63 49
Race, %
Asian 15 14 100 100
Median body mass index,
kg/m2 25 26 23 23
ECOG PS 0/1, % 52/48 57/43 26/74 22/78
KRAS wild-
type/mutant/unknown, %
41/54/5 37/62/2 37/34/29 43/26/31
>3 prior treatment lines for
metastatic disease, %
49 47 38 40
Previous targeted biological
treatment, %
None
Anti-VEGF (bevacizumab)
Anti-EGFR, but not anti-
VEGF
Anti-VEGF and anti-EGFR
0
100
-
-
0
100
-
-
41
24*
18
18*
38
19*
25
18*
Patients in CONCUR received less exposure to biologic therapy and were less heavily pre-
treated.
42
%

CORRECT & CONCUR: Secondary endpoints
9
0
*Non-CR/Non-PD included in disease control rate and followed the same criteria as SD.
†CORRECT: CR or PR or SD (subjects with SD as response performed earlier than 6 weeks after
randomization, were not taken into account); CONCUR: CR or PR or SD (≥6 weeks after
randomization). Both according to RECIST v1.1.
CORRECT1 CONCUR2
REGORAFENIB
(N=505)
PLACEBO
(N=255)
REGORAFENIB
(N=136)
PLACEBO
(N=68)
PFS, Median, months 1.9 1.7 3.2 1.7
HR (95% CI) P-value 0.49 (0.42–0.58) <0.0001 0.31 (0.22–0.44) <0.0001
CR, n (%) 0 0 0 0
PR, n (%) 5 (1) 1 (<1) 6 (4) 0
SD, n (%) 216 (43) 37 (15) 62 (46) 5 (7)
Non-CR/Non-PD*, n
(%)
4 (1) 1 (<1) 2 (1) 0
DCR†, n (%) 207 (41) 38 (15) 70 (51) 5 (7)
One-sided P-value P<0.0001 P<0.0001

CORRECT & CONCUR: OS (primary endpoint)
9
1
20
0
40
60
80
100
Overall
Survival,
%
Months Since Randomization
0 4 8 14
12
10
6
2
CORRECT MEDIAN OS
(months)1
━ Regorafenib (n=505)6.4
━ Placebo (n=255): 5.0
HR (95% CI): 0.77 (0.64–0.94)
P =0.0052
CI, confidence interval; HR, hazard ratio..
20
0
40
60
80
100
Overall
Survival,
%
CONCUR MEDIAN OS
(months)2
━ Regorafenib (n=136):8.8
━ Placebo (n=68): 6.3
HR (95% CI): 0.55 (0.40–0.77)
P =0.00016
Months Since Randomization
18
16
14
12
10
8
6
4
2
•Note: Patients were more heavily pretreated in CORRECT – 49% and
47% of patients in the regorafenib and placebo arms, respectively, had
received >3 prior lines of therapy for metastatic disease versus 38%
and 40%, respectively, in the CONCUR study. 100% of patients in both
arms of CORRECT received anti-VEGF therapy (bevacizumab)
compared to only 41% and 37% in the regorafenib and placebo arms,
respectively, in CONCUR.
1.4 M 2.5 M

SOURCE: Grothey A, et al. Lancet. 2013;381:303–312.
Regorafenib showed OS benefit
across most subgroups in CORRECT
9
2
SUBGROUP N HR 95% CI
All patients 760 0.77 0.64-0.94
Sex
Male 464 0.77 0.60-1.00
Female 296 0.75 0.55-1.02
Age
<65 years 475 0.72 0.56-0.91
≥65 years 285 0.86 0.61-1.19
Region
North America, Western Europe, Israel, Australia 632 0.77 0.62-0.95
Asia 104 0.79 0.43-1.46
Eastern Europe 24 0.69 0.20-2.47
Baseline ECOG PS
0 411 0.70 0.53-0.93
1 349 0.77 0.59-1.02
Primary site of disease
Colon 495 0.70 0.56-0.89
Rectum 220 0.95 0.63-1.44
Colon and rectum 44 1.09 0.44-2.70
Time from first diagnosis of metastatic
disease to randomization
<18 months 140 0.82 0.53-1.25
≥18 months 620 0.76 0.61-0.95
Prior anticancer treatment
Fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab 375 0.83 0.63-1.09
Fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, anti-
EGFR 385 0.71 0.54-0.94
Prior treatment lines for metastatic disease
≤3 395 0.79 0.60-1.04
>3 365 0.75 0.56-0.99
KRAS mutation at study entry
No 299 0.65 0.48-0.90
Yes 430 0.87 0.67-1.12
Favors Regorafenib
Favors Placebo
0.0 3.0
1.5
0.5 1.0 2.0 2.5
Hazard ratio (95% confidence interval)

Regorafenib has been widely studied in 2 randomized phase
III studies and 5 large open-label studies in relapsed mCRC*
9
3
PRIMARY ENDPOINT: Safety
EFFICACY ENDPOINT: PFS
EFFICACY ENDPOINT: PFS
EFFICACY ENDPOINTS: OS, time
to
treatment failure
PRIMARY ENDPOINT: OS
SECONDARY ENDPOINTS: PFS, ORR,
DCR, and safety
TERTIARY ENDPOINTS: duration of
response/stable disease, QOL,
pharmacokinetics, biomarkers
PATIENTS (N=760)
With mCRC after standard therapy:
fluoropyrimidine, oxaliplatin, irinotecan,
bevacizumab, and cetuximab or
panitumumab (if KRAS WT)
Regorafenib 160 mg
orally once daily
(3 weeks on, 1 week off)
+ BSC
n=505
Placebo (3 weeks on, 1
week off) + BSC
n=255
R
2:
1
PATIENTS (N=204)
With mCRC after standard therapy:
fluoropyrimidine, oxaliplatin, irinotecan
Patients may have received
bevacizumab, and cetuximab or
panitumumab (if KRAS WT)
Regorafenib 160 mg
orally once daily
+ BSC
n=136
Placebo (3 weeks on, 1
week off) + BSC
n=68
R
2:1
SECONDARY ENDPOINTS: PFS,
RR,
DCR (defined as CR + PR + SD ≥28
days),
and safety
CORRECT RCT1
CONCUR RCT2
PATIENTS (N=2872)
With mCRC progressing ≤3 months of
approved standard therapies. ECOG PS
0–1
Regorafenib 160 mg
orally once daily
N=2864
CONSIGN3
PATIENTS (N=654)
With mCRC refractory to standard
therapies
Regorafenib 160 mg
orally once daily
N=654
REBECCA4
PATIENTS (N=1227)
With histologically or cytologically
confirmed unresectable metastatic or
recurrent CRC
Regorafenib 160 mg
orally once daily
N=1227
Japanese PMS5
EFFICACY ENDPOINTS: PFS, OS
PATIENTS (N=1037)
With mCRC previously treated with other
approved therapies
Regorafenib 160 mg
orally once daily
N=1037
CORRELATE6
EFFICACY ENDPOINTS: PFS,
TTP, DCR, safety
PATIENTS (N=464)
With mCRC previously treated with other
approved therapies§
Regorafenib 160 mg
orally once daily
N=464
RECORA7

Consistent with CORRECT and CONCUR, similar outcomes were reported
in CONSIGN, REBECCA, Japanese PMS, CORRELATE and RECORA
9
4
RANDOMIZED CONTROLLED PHASE III TRIALS* OPEN-LABEL REAL WORLD STUDIES*
CORRECT1 CONCUR2
CONSIG
N3
REBEC
CA4
JAPANESE
PMS5
CORRELA
TE6
RECOR
A7
EFFICACY
REGORAFE
NIB
(N=500)
PLACEB
O
(N=253)
REGORAFE
NIB
(N=136)
PLACEBO
(N=68) (N=2864) (N=654) (N=1227) (N=1037) (N=463¶)
OS, Median,
months
6.4 5.0 8.8 6.3 - 5.6 6.9 7.6 5.86
HR (95% CI) P-
value
0.77 (0.64–0.94) 0.0052 0.550 (0.395–0.765)
0.0002
- - - - -
PFS, Median,
months
1.9 1.7 3.2 1.7 2.7 2.7 2.2 (TTF†) 2.8 3.13
HR (95% CI) P-
value
0.49 (0.42–0.58)
<0.0001
0.311 (0.222–0.435)
<0.0001
- -
-2.7 M - -
ORR, % 1 0.4 4 0 - - - 3.1 3.6
PR, % 1 0.4 4 0 - - - 3.1 3.6
SD, % 40 15 46 7 - - - - 23.1
DCR, % 41 15 51 7 - - - 21.0 26.7
P-value <0.001 <0.001 - - - - -
The HR for OS was 0.77 and 0.55 in the CORRECT and CONCUR trials, representing a 23% to 45%
decrease, respectively, in the risk of death in favor of regorafenib1,2
In REBECCA, RECORA, and CORRELATE, the 12-month OS rates were 22%, 23.2%, and 33.8%,
respectively, comparable to that of CORRECT (24%)1,4,6,7
Of note, in REBBECA, median OS from the time of progression on regorafenib to death in
patients who received post-progression treatment was 7.9 vs 3.4 months in patients who did
not receive any post-progression therapy4
6.5 M

-Treatment-emergent AEs* from
CORRECT & CONCUR
9
6
*During treatment or up to 30 days post treatment. †Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0
(CONCUR).
‡Safety analyses are based on 753 patients who initiated treatment.
PATIENTS (%)
CORRECT1† CONCUR2†
REGORAFENIB
(N=500)‡
PLACEBO
(N=253)‡
REGORAFENI
B
(N=136)
PLACEBO
(N=68)
Any grade,
regardless of
relationship to study
drug
100 97 100 88
Grade ≥3 78 49 71 44
Serious 44 40 32 26
Grade 4 13 15 9 10
Any grade, drug-
related
93 61 97 46
Grade ≥3 54 14 54 15

Drug-related AEs* from CORRECT &
CONCUR
9
7
*Adverse events were graded using the NCI-CTC for Adverse Events version 3.0 (CORRECT) and version 4.0 (CONCUR).
The most commonly regorafenib-related AEs include :HFSR, fatigue, hypertension,
diarrhea, and increased AST & ALT.
DRUG-RELATED
ADVERSE EVENT, %
CORRECT1 CONCUR2
REGORAFENIB (n=500) PLACEBO (n=253) REGORAFENIB (n=136) PLACEBO (n=68)
ALL
GRADES
GRADE
3/4
ALL
GRADES
GRADE
3/4
ALL
GRADES
GRADE
3/4
ALL
GRADES
GRADE
3/4
HFSR 47 (9%) 17(3%) 8 <1 73(53%) 16(12%) 4 0
Fatigue 47(9%) 9(2%) 28 5 17(12%) 3(2%) 7 1
Hypertension 28(6%) 7(1.5%) 6 1 23 (17%) 11(8%) 4 3
Diarrhea 34(7%) 7(1.5%) 8 1 18(13%) 1 2 1
Rash/desquamation 26 6 4 0
Anorexia 30 3 15 3 8 1 4 9
Mucositis, oral 27 3 4 0
Hyperbilirubinemia 36 6 7 1
ALT increased 24 7 7 0
AST increased 24 6 9 0
Thrombocytopenia 13 3 2 <1 10 3 1 0
Fever 10 1 3 0 NR NR NR NR
Nausea 14 <1 11 0 NR NR NR NR
Voice changes 29 <1 6 0 21 1 0 0
Weight loss 14 0 2 0 NR NR NR NR

--CORRECT & CONCUR: Study drug
administration
9
8
CORRECT1 CONCUR2
REGORAFENI
B
(N=500)*
PLACEBO
(N=253)*
REGORAFENI
B
(N=136)
PLACEBO
(N=68)
Median duration of treatment,
months†
1.7 1.6 2.4 1.6
Median daily dose, mg 160.0 160.0 153.5 160.0
Any treatment modification, n (%) 378 (76) 97 (38) 102 (75) 15 (22)
Treatment interruptions/delays, n
(%)
352 (70) 95 (38) 90 (66) 15 (22)
Discontinued 18% 14%

CORRECT: Incidence of worst and any grade AEs occurs
early in treatment and decreases over time
9
9
SOURCES: Grothey A, et al. J Clin Oncol. 2013;31(suppl):abstr 3637. Grothey A, et al. J Clin Oncol. 2013; 31(suppl 4): abstr 467.
n 500417229193119 91 55 43
n 500417229193119 91 55 43
n 500417229193119 91 55 43
n 500417229193119 91 55 43
n 500417229193119 91 55 43
5
0
Frequency
of
AE
(%)
15
20
10
1 3 5 8
7
6
4
2
Treatment cycle
DIARRHEA
1 3 5 8
7
6
4
2
Treatment cycle
HFSR
5
0
Frequency
of
AE
(%)
15
20
10
1 3 5 8
7
6
4
2
Treatment cycle
FATIGUE
5
0
Frequency
of
AE
(%)
15
20
10
1 3 5 8
7
6
4
2
Treatment cycle
RASH/DESQUAMATION
5
0
Frequency
of
AE
(%)
15
20
10
1 3 5 8
7
6
4
2
Treatment cycle
HYPERTENSION
5
0
Frequency
of
AE
(%)
15
20
10
━ Grade 1
━ Grade 2
━ Grade 3
━ Grade 4

-Regorafenib first cycle dosing optimization approaches
1
0
– In the CORRECT trial, in the regorafenib arm (160 mg)1
• 93% of TAEs
• 20% required ≥1 dose reduction
• 70% required ≥1 dose interruption
– Most of the AEs occurred during the first two cycles (before the 1st tumor evaluation)
– phase II clinical trials evaluated different dosing approach during the 1st Cycle followed by standard
approach from Cycle 2
ALT, alanine aminotransferase; AST, aspartate aminotransferase; C, cycle; AE, adverse event; W, week.
1. Bayer data on file. 2. Bekaii-Saab TS, et al. J Clin Oncol. 36, 2018 (suppl 4S; abstr 611). 3. Kudo T, et al. J Clin Oncol. 36, 2018 (suppl 4S; abstr 821).
Will report at ASCO 2019.1
Primary endpoint: total safety.
Reported results at ASCO GI 2018.2
Primary endpoint was met (see slide).
Reported results at ASCO GI 2018.3
Primary endpoint was met: DCR of 38.3%
(90% CI: 28.0-48.7) > pre-specified
threshold (27%).
Median PFS: 2.45 mo; median OS: 6.93
mo.
2 (3.3%) patients dose escalated to 160
mg.
RE-ARRANGE ReDOS REGOCC
Patients
with
mCRC
(N=299)
Active Comparator:
Arm A
160 mg/day
3W on/1 W off
Experimental: Arm B
120 mg/day
3W on/1W off C1
160 mg/day
3W on/1W off C2 on
Experimental: Arm C
160 mg/day
1W on/1W off C1
160 mg/day
3W on/1W off C2 on
R
1:1:1
Patient
s with
previou
sly
treated
mCRC
(N=123)
R
1:1:1:1
Patients
with
unresectabl
e mCRC
who have
progressed
after
standard
chemo
(N=60)
C1
120 mg/day 3W
on/1W off
C2 (and later)
120 mg/day 3W
on/1W off, option to
increase to 160
mg/day 3W on/1W off
(only if well tolerated
[i.e., no AE grade ≥2,
and no grad
e ≥1 for ALT, AST,
bilirubin])
ARM B: STANDARD-DOSE
Arm B1: Preemptive
Clobetasol*
Arm B2: Reactive
Clobetasol*
C1
160 mg/day 3W
on/1W off
ARM A: LOWER-DOSE
Arm A1: Preemptive
Clobetasol*
Arm A2: Reactive
Clobetasol*
INDUCTION PHASE: C1
80 mg/day W1
120 mg/day W2
160 mg/day W3
1W off W4
AFTER C1 (C2 on)
160 mg/day 3W
on/1W off
CAN TOLERABILITY
BE INCREASED?

-ReDOS: Cycle 1 dose escalation approach permitted significantly more patients to
start cycle 3 compared to standard dosing
1
0
– ReDOS was a randomized phase II US-based study of regorafenib dose escalation (Arm A: 80 mg/day
[week 1], 120 mg/day [week 2], and up to 160 mg/day [week 3]) versus standard dose (Arm B: 160
mg/day) in mCRC patients for 21 days of a 28-day cycle1
– A total of 123 refractory mCRC patients were randomized with 116 ( A, n=54; B, n=62) evaluable for
safety and efficacy1
– Primary endpoint: Proportion of patients in each arm starting Cycle 3 of treatment. This composite
endpoint integrates both efficacy (at least SD at the first tumor evaluation) and tolerability1
• ReDOS also investigated the use of pre-emptive or reactive clobetasol for HFSR (not reported here)1
– The primary endpoint was met1,2
43
24
Escalating
Dose
Standard
Dose
Percentage
of
patients
who
started
cycle
3
P =0.0281*2 SECONDARY
ENDPOINTS1,2
ESCALATING
DOSE
N=54
STANDARD
DOSE
N=62
HR (95% CI) P-
VALUE
OS, Median, months 9.0 5.9 0.65 (0.39-1.08)
0.0943
PFS, Median, months 2.5 2.0 0.89 (0.59-1.33)
0.5534
SAFETY (SELECTED AEs, GRADE 3/4)1
HFSR, % 15 16
Hypertension, % 7 15
Fatigue, % 13 18
1. Bekaii-Saab TS, et al. J Clin Oncol. 36, 2018 (suppl 4S; abstr 611). 2. Bekaii-Saab T, et al. WCGIC 2918. abstr O-014.
35%
PD
47%
PD

-In Summary: 1ST CYCLE DOSING
APPROACH
1
0
– In ReDOS, the first cycle dosing optimization strategy of weekly dose-escalation of
regorafenib from 80 mg to 160 mg/day during the 1st cycle (3W on/ 1w off) followed by
160 mg in the subsequent cycles (3W on/1W off) was found to be superior to a
starting dose of 160 mg/day (3W on/1W off) in patients with Mcrc
– The REDOS data allow more flexibility to physicians to treat their mCRC patients without
deleterious impact on efficacy, with rapid escalation from 80 mg during the first week of
Cycle 1 followed by 120 mg during week 2, and final dosing of 160 mg if warranted
– Based on the ReDOS study results, the current NCCN guidelines (Version 2.2018)
now recommend this dosing strategy as an option for mCRC patients1
– The Japanese REGOCC study, with a starting dose of 120 mg, showed similar efficacy
to CORRECT
– Results for the ongoing RE-ARRANGE (NCT02835924, N=295) study will be presented
at ASCO
NOTE: The results of ReDOS are specific to mCRC. Bayer cannot recommend any other dosage of
regorafenib than 160 mg daily (on a 3W on/1W off schedule) in GIST and HCC.
1. NCCN Guidelines. Colon cancer. Version 2.2108 (March 14, 2018). 2. RE-ARRANGE. Available at:
https://www.clinicaltrials.gov/ct2/show/NCT02835924?term=NCT02835924&rank=1. Accessed March 2, 2018.

-In Summary: SAFETY
In CORRECT and CONCUR,
67% and 71% of regorafenib
patients underwent dose
modification due to Aes,BUT:
1.Maximal AEs occur early (≤
first 2 cycles) AND improved
with time
2.Regorafenib-associated AEs
are non-cumulative unlike
other agents (e.g.,
chemotherapy)
3.but only 18% and 14%
discontinued (S/E)
4. DOSE ESCALATING
APPROACH :HIGH EFFICACY
AND LOWER TOXICITY
-EFFICACY
Regorafenib demonstrated significant OS
benefit in patients in the large global
CORRECT and smaller Asian CONCUR
studies, compared to placebo
Regorafenib showed consistent benefit
across multiple subgroups (RAS
WT/mutated, age, etc)
Consistent with the results from CORRECT
and CONCUR, in the real world setting,
regorafenib has demonstrated similar
outcomes in 5 large open-label studies
(CONSIGN, REBECCA, Japanese PMS,
CORRELATE and RECORA)
These results confirm regorafenib as an
important treatment option for mCRC
patients who have progressed after
standard treatments, demonstrated by its
approved use, and inclusion in both ESMO
and NCCN treatment guidelines for mCRC

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