In group 2

Colorectal Cancer ESMO Preceptorship Program Berlin October 14-15th 2013
Metastatic Colorectal Cancer session 4
State of Art for Chemotherapy and Targeted Agents
for Group 2 and 3 Patients
JY Douillard MD, PhD
Professor of Medical Oncology
Integrated Center of Oncology R Gauducheau
Nantes France
Disclosure JY Douillard
• Compensated participations in:
– Advisory Boards and Symposia:
• Amgen
• Bayer
• Boehringer Ingelheim
• Merckserono
• Roche/Genentech
• Sanofi
– Research Funding
• Merckserono
Incremental Improvements in Overall Survival in the Last Decade
12.6
Saltz, NEJM 2000 5-FU bolus
14.1
Douillard, Lancet 2000 5-FU infusion
Saltz, NEJM 2000
14.8
IFL
Douillard, Lancet 2000
FOLFIRI
Goldberg, JCO 2004
FOLFOX
17.4
19.5
Tournigand, JCO 2004 FOLFOX followed by FOLFIRI
20.6
20.3
Hurwitz, NEJM 2004 IFL + bevacizumab
21.3
Saltz JCO 2008 FOLFOX + bevacizumab
22.8
Bokemeyer, Ann Onc 2011 FOLFOX + cetuximab
23.9
Douillard, JCO 2009 FOLFOX + panitumumab
VanCutsem, NEJM 2009 FOLFIRI + cetuximab
Douillard NEJM 2013
23.5
FOLFOX + panitumumab RAS Wild-type
0
5
10
15
OS (months)
20
26
25
Unresectable mCRC treatment in 2013
• Median expected OS: 20-30 months
• Most of the patients will receive several lines
of treatment
– From 100 in 1st line
• 60-70 will receive a 2nd line
• 30-40 will receive a 3rd Line
• 15-20% will receive 4+ lines
Schmoll H J et al. Ann Oncol 2012;23:2479-2516
Groups according to clinical presentation
ESMO Consensus Conference 2011 Schmoll H J et al. Ann Oncol 2012;23:2479
Groups
Group 0
Clinical Criteria
Upfront resectable metastasis,
Goal: cure, reduced relapse rate
Group 1
Potentially resectable metastasis
Goal: Objective Response, tumor shrinkage.
Group 2
Multiple metastasis, rapid progression, associated symptoms even
in patients without major co-morbidities
Goal: Disease control, symptom improvement.
Group 3
Multiple metastasis or organ involved, definitely never resectable,
Mild symptoms associated, co-morbidities
Goal: Disease control, increased survival with preserved quality of
life, regimen with mild toxicity profile prefered..
Clinical Groups for 1st-line treatment stratification
Clinical presentation
Treatment aim
Treatment intensity
Hierarchy of factors for definition of treatment aim/group.
Schmoll H J et al. Ann Oncol 2012;23:2479-2516
Factors influencing the choice of 1st-line treatment (1)
in group 2 and 3
Factors influencing the choice of 1st-line treatment (2)
in group 2 and 3
Groups according to clinical presentation
ESMO Consensus Conference 2011 Schmoll H J et al. Ann Oncol 2012;23
Groups
Group 0
Clinical Criteria
Upfront resectable metastasis,
Goal: cure, reduced relapse rate
Group 1
Potentially resectable metastasis
Goal: Objective Response, tumor shrinkage.
Group 2
Multiple metastasis, rapid progression, associated symptoms even
in patients without major co-morbidities
Goal: Disease control, symptom improvement.
Group 3
Multiple metastasis or organ involved, definitely never resectable,
Mild symptoms associated, co-morbidities
Goal: Disease control, increased survival with preserved quality of
life, regimen with mild toxicity profile preferred..
1st-line options according to clinical groups
Group
2
RAS wild-type
Recommendationa
RAS mutant
Recommendationa
FOLFIRI + Cet
+++
FOLFOX/XEL
OX + Bev
+++
FOLFOX + Pan/Cet
+++
FOLFOX/XELOX +
Bev
FOLFIRI/XELIRI +
Bev
+++
++(+)
FOLFIRI/XELI
++(+)
RI + Bev
FOLFOX/XEL
++
OX
FOLFIRI/XELI
++
RI
FOLFOXIRI
+(+)
FOLFOXIRI
++
FOLFOX + Cet
+(+)
IRIS
+
FOLFOX/XELOX
+
FOLFIRI/XELIRI
+
IRIS
+
ESMO consensus Group 2 patients
• In addition to the selection criteria for group 2:
– Multiple metastasis, rapid progression, associated symptoms
even in patients without major co-morbidities
• Additional predictive biomarkers should be
incorporated in treatment decision
– Ras phenotype allows to select for anti-EGFR
therapy
PRIME RAS/RAF PFS analysis*
Refinement of patient population by WT RAS
Progression-free survival
Original WT KRAS exon 2 testing
HR = 0.80 (95% CI, 0.66–0.97)
P = 0.02
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Months
Events
n (%)
Median
(95% CI) months
Panitumumab +
FOLFOX4 (n = 325)
199 (61)
9.6 (9.2–11.1)
FOLFOX4 (n = 331)
215 (65)
8.0 (7.5–9.3)
Douillard JY et al New Engl J Medicine Sept 12 2013 .
100
90
80
70
60
50
40
30
20
10
0
Proportion event-free (%)
Proportion event-free (%)
100
90
80
70
60
50
40
30
20
10
0
WT RAS
HR = 0.72 (95% CI, 0.58–0.90)
P = 0.004
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Months
Events
n (%)
Median
(95% CI) months
Panitumumab +
FOLFOX4 (n = 259)
156 (60)
10.1 (9.3–12.0)
FOLFOX4 (n = 253)
170 (67)
7.9 (7.2–9.3)
*Predefined retrospective analysis;
7 patients harbouring Codon 59 mutations were not excluded from this analysis.
PRIME RAS/RAF OS analysis*
Refinement of patient population by WT RAS status
Overall survival
Original WT KRAS exon 2 testing
WT RAS
100
100
HR = 0.83 (95% CI, 0.67–1.02)
P = 0.072
80
70
60
50
40
30
90
Proportion alive (%)
Proportion alive (%)
90
70
60
50
40
30
20
20
10
10
0
HR = 0.78 (95% CI, 0.62–0.99)
P = 0.043
80
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Months
Events
n (%)
Median
(95% CI) months
Panitumumab +
FOLFOX4 (n = 325)
165 (51)
23.9 (20.3–28.3)
FOLFOX4 (n = 331)
190 (57)
19.7 (17.6–22.6)
1. Douillard JY, et al. J Clin Oncol 2010;28:4697–705;
2. Douillard JY et al New Engl J Medicine Sept 12 2013.
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Months
Events
n (%)
Median
(95% CI) months
Panitumumab +
FOLFOX4 (n = 259)
128 (49)
26.0 (21.7–30.4)
FOLFOX4 (n = 253)
148 (58)
20.2 (17.7–23.1)
*Predefined retrospective analysis;
7 patients harbouring Codon 59 mutations were not excluded from this analysis.
ESMO consensus mCRC Group 2
• Patients with RAS wt may be treated with targeted agents
combined to chemotherapy
• Recommendations from the consensus conference include antiEGFR as first choice before Bevacizumab
• New evidence was presented recently to reinforce this
recommendation
– FIRE 3 trial: FOLFIRI-Bevacizumab vs. FOLFIRI-Cetuximab
– PEAK trial: FOLFOX-Bevacizumab vs. FOLFOX-Panitumumab
PEAK vs. FIRE 3 (RAS wt)
PFS and OS
PEAK (1)
PEAK
FIRE 3 (2)
FIRE 3
Folfox Pani
Folfox Bev
HR
Folfiri Cetux
Folfiri Bev
HR
PFS
13
10.1
0.68
p=0.03
10.4
10.2
0.83
p=0.54
OS
41.3
28.9
0.63
p=0.058
33.1
25.6
0.70
p=0.011
1 Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631).
2 Heinemann V ECCO/ESMO 2013 LBA 17
Anti-EGFR vs. Bevacizumab in RAS wt mCRC: FIRE and PEAK
PFS
FIRE 3
PEAK
WT RAS (exons 2,3,4 of KRAS/NRAS)
WT RAS (exon 2 ,3,4 of KRAS/NRAS)
100
HR*=0.93 (95% CI: 0.74–1.17)
p=0.54
Proportion event-free (%)
90
80
70
HR*=0.66 (95% CI: 0.46–0.95)
p=0.03
60
50
40
30
20
10
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Months
Events
n (%)
Median (95% CI)
months
Cetuximab+ Folfiri
(n=142)
144 (171)
10.4 (9.5–12.2)
Bevacizumab +
Folfiri(n=143)
143 (171)
10.2 (9.3–11.5)
Heinemann V ECCO/ESMO 2013 LBA 17
Events
n (%)
Median (95% CI)
months
Panitumumab +
mFOLFOX6 (n=88)
57 (65)
13.0 (10.9–15.1)
Bevacizumab +
mFOLFOX6 (n=82)
66 (80)
10.1 (9.0–12.7)
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631).
Anti-EGFR vs. Bevacizumab in RAS wt mCRC: FIRE and PEAK
OS
FIRE 3
PEAK
WT RAS (exons 2,3,4 of KRAS/NRAS)
WT RAS (exons 2,3,4 of KRAS/NRAS)
100
90
80
70
HR*=0.70 (95% CI: 0.53–0.92)
p=0.011
Proportion alive (%)
60
50
40
30
20
10
HR*=0.63 (95% CI: 0.39–1.02)
p=0.058
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
Months
Months
Events
n (%)
Median (95% CI)
Months
Cetuximab+ Folfiri
(n=142)
91 (171)
33.1 (24.5–39.4)
Bevacizumab +
Folfiri (n=143)
110 (171)
25.6 (22.7–28.6)
Heinemann V ECCO/ESMO 2013 LBA 17
Events
n (%)
Median (95% CI)
months
Panitumumab +
mFOLFOX6 (n=88)
30 (34)
41.3 (28.8–41.3)
Bevacizumab +
mFOLFOX6 (n=82)
40 (49)
28.9 (23.9–31.3)
Schwartzberg L, et al. J Clin Oncol 31, 2013 (suppl; abstr 3631).
1st-line options according to clinical groups
Group
2
RAS wild-type
Recommendationa
RAS mutant
Recommendationa
FOLFIRI + Cet
+++
FOLFOX/XEL
OX + Bev
+++
FOLFOX + Pan/Cet
+++
FOLFOX/XELOX +
Bev
FOLFIRI/XELIRI +
Bev
+++
++(+)c
FOLFIRI/XELI
++(+)c
RI + Bev
FOLFOX/XEL
++
OX
FOLFIRI/XELI
++
RI
FOLFOXIRI
+(+)b
FOLFOXIRI
++b
FOLFOX + Cet
+(+)
IRIS
+
FOLFOX/XELOX
+
FOLFIRI/XELIRI
+
IRIS
+
ORR and PFS in mCRC with available regimen
ORR %
Median PFS months
FOLFOX –Pani
PRIME RAS WT
62
10.1
FOLFIRI –Cetux
FIRE 3 RAS WT
61
10
FOLFOXIRI
GONO
66
9.8
FOLFOX Bev
38-62
8-9.5
FOLFOX
34-45
8
53
9
40-45
6.5-8
FOLFIRI-Bev
MEXICO
FOLFIRI
Progression-free survival (PFS) in the overall pooled population and
in individual studies (first- and second-line trials of bevacizumab).
Hurwitz H I et al. The Oncologist 2013;18:1004-1012
ESMO Group 2 mCRC
Conclusion
• Need for an active regimen for an agressive tumor to stop
tumor growth
• Doublets or Triplets chemo-regimen are preferred
• To be selected according to tolerance profile/pre-existing conditions
• Targeted agents may be used in combination with chemotherapy
for improved efficacy
• Decision should be based on RAS phenotype and contra-indications
• In some cases, patient file should be reviewed in a MDT
to discuss possible resection.
Preceptorship program: colorectal cancer
Group 3 patients
Clinical Groups for 1st-line treatment stratification
Clinical presentation
Treatment aim
Treatment intensity
Proposal for sequence of salvage-chemotherapy.
Schmoll H J et al. Ann Oncol 2012;23:2479-2516
© The Author 2012. Published by Oxford University Press on behalf of the European
Society for Medical Oncology. All rights reserved. For permissions, please email:
journals.permissions@oup.com.
1st-line options according to clinical groups
Group
3
RAS wild-type
Recommendationa
RAS mutant
FUFOL/Cape (mono)
+++
FUFOL/Cape + Bev
+++
XELOX/FOLFOX
++
FOLFIRI/XELIRI
++
FOLFIRI/XELIRI ++
IRIS
+
IRIS
+
Cet/Pan (mono)
(+)
watchful
waiting
+ selected pts.d
Recommendationa
FUFOL/Cape
+++
(mono)
FUFOL/Cape +
+++
Bev
XELOX/FOLFO
++
X
Watchful waiting
+ selected pts.d triplets (±Bev)
Triplets (+/−Bev or
Cet/Pan)
+ option for
spec.
+ option for
spec.
situations
ESMO Group 3 mCRC
• Multiple strategies are possible
• Several lines will be used
• The important points are:
– To try to use all available agents
– To improve survival and preserve quality of life
• Several clinical trials have addressed the question:
– Watchful Waiting
– Sequential approach: FOCUS, CAIRO, FOCUS 2, LIFE….
Watchful Waiting or Immediate Chemotherapy
(Mayo Clinic regimen)
OverallSurvival
PFS:
13 vs. 11 m
HR 1.15 (0.79-1.72)
p=0.49
10.2 vs. 10.8
HR 1.08 (0.71-1.64)
p=0.73
Ackland et al Br J Cancer 2005; 93: 1236
QoL QLQ C-30
AVEX (Ph.III) Design
Elderly
(> 70 ans)
mCCR untreated
(n=280)
Capecitabine
P
Bevacizumab
+ Capecitabine
P
R
Primary Endpoint : PFS
Secondary Endpoints : ORR, Time To Response, Response duration, OS,
Tolerance
Sponsor: Roche
Saunders MP et al. ASCO 2013 (abst. 3521)
Etude AVEX (Ph.III)
Primary Endpoint : PFS
100
Capecitabine + Bevacizumab (n = 140)
Capecitabine (n = 140)
Probability PFS
80
HR : 0,53 (IC 95 : 0,41-0,69)
P < 0,001
60
40
20
5,1 m
0
0
4
9,1 m
8
12
16
20
24
Time (m)
28
32
36
40
46
Saunders MP et al. ASCO 2013 (abst. 3521)
Etude AVEX (Ph.III) OS
100
Capecitabine + Bevacizumab (n = 140)
Capecitabine (n = 140)
Probability OS
80
HR : 0,79 (IC 95 : 0,57-1,09)
P = 0,182
60
40
20
16,8 m
0
0
4
8
12
16
20,7 m
20
24
28
32
36
40
44
Temps (mois)
Saunders MP et al. ASCO 2013 (abst. 3521)
Etude AVEX (Ph.III): ORR Tolerance
Cap. + Beva.
Cap.
p
ORR (%)
19,3
10,0
0,042
DCR (OR + stable)
74,3
57,9
0,005
Tolerance
%
Cap. + Beva.
Cap.
0
0,7
HBP
2,2
1,5
VTE
8,2
4,4
ATE
3,7
1,5
0
0
14,9
6,6
Diarrhea
6,7
6,6
Asthenia
5,2
4,4
Hemorrage
Fistulas
HFS
Saunders MP et al. ASCO 2013 (abst. 3521)
AVEX (Ph.III): age sub-groups
70 – 74 ans
Median PFS
M (IC95%)
HR
(IC95%)
Log Rank
Median OS,
m (IC95%)
HR
(IC95%)
Log Rank
ORR
≥ 80 ans
Cape + Bev
(n=55)
Cape
(n=46)
Cape + Bev
(n=57)
Cape
(n=56)
Cape + Bev
(n=28)
Cape
(n=28)
7,6
(6,0 – 11,8)
5,0
(4,0 – 6,5)
9,8
(7,1 – 11,4)
5,1
(4,1 – 7,4)
10,5
(5,0 – 14,5)
5,1
(2,2 – 7,1)
0,52
(0,32 – 0,83)
<0,001
20,7
(13,7 – 26,1)
22,2
(9,7 – 42,7)
0,91
(0,50 – 1,66)
0,55
25,5
p
EI grade ≥3, %
75 – 79 ans
10,9
0,60
(0,40 – 0,89)
0,016
19,8
(13,8 – 27,3)
0,79
(0,48 – 1,30)
0,37
15,8
0,076
N=54
63,0
17,4
(11,9 – 23,0)
12,1
0,36
(0,19 – 0,71)
0,003
19,7
(7,5 – 26,9)
0,62
(0,31 – 1,24)
0,24
14,3
0,607
N=46
41,3
N=53
54,7
12,6
(6,6 – 17,0)
3,6
0,352
N=64
40,6
N=27
59,3
N=26
57,7
Saunders MP et al. ASCO 2013 (abst. 3521)
Trials of combined versus sequential therapy
FOCUS
CAIRO
LIFE
FOCUS2
FFCD
2135
803
725
460
410
median age (years)
64
64
62
75
69
performance status 2
9%
5%
6%
29%
16%
1st-line
FU
Cap
FU
FU / Cap
FU
2nd-line
Ir / IrFU / OxFU
Ir
Ir
OxFU / OxCap
OxFU
3rd-line
[OxCap / IrCap]
OxCap
-
[Ir]
IrFU
1st-line
IrFU / OxFU
IrCap
OxFU
OxFU / OxCap
OxFU
2nd-line
[OxCap / IrCap]
OxCap
Ir
[Ir]
IrFU
survival
survival
survival
survival
2nd PFS
Number
sequential
arm(s)
combination
arm(s)
(n=4218)
primary endpoint
Matthew T. Seymour Current Colorectal Cancer Reports, 2008, Vol 4, Number 3, P 130-138
CAIRO primay end-point: survival
OS 17.3 vs. 16.3 m HR: 0.92 (0.79-1.08) p=0.32
Koopman et al Lancet 2007; 370: 135
FOCUS: Survival by sub-groups
Seymour et al Lancet 2007; 370: 143
FOCUS: OS by sub-groups
Overall and progression free survival
LIFE trial
Arm A: LV5FU > Irinotecan vs Arm B FOLFOX4 > Irinotecan
(5FU CIV)
(Oxaliplatin + 5FU CIV)
Cunningham D et al, Annals of Oncology 20: 244–250, 2009
Survival comparisons between sequential and first
line combination chemotherapy trials
sequential combination
HR
CI
p
FOCUS
(BvC)
15.1
15.9
0.94
0.83–1.03
NS
CAIRO
16.3
17.4
0.92
0.79–1.08
0.33
LIFE
15.2
15.9
0.93
0.78–1.10
0.16
FOCUS 2
10.6
11.5
0.99
0.81-1.18
0.91
FFCD
17.0
16.0
1.05
0.84–1.32
0.67
Seymour MT, Maughan TS, Ledermann JA, et al.: Different strategies of sequential and combination chemotherapy for patients with poor-prognosis
advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007, 370:143–152. Koopman M, Antonini NF, Douma J, et al.: Sequential
versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled
trial. Lancet 2007, 370:135–142. Seymour MT, Maughan TS, Wasan HS, et al.: Capecitabine (Cap) and oxaliplatin (Ox) in elderly and/or frail patients with
metastatic colorectal cancer: The FOCUS2 trial [abstract 9030]. J Clin Oncol 2007, 25(2007 ASCO Annual Meeting Proceedings Part I).
Bouché O, Castaing M, Etienne PL, et al.: Randomized strategical trial of chemotherapy in metastatic colorectal cancer (FFCD 2000-05): preliminary results
[abstract 4069]. J Clin Oncol 2007, 25(2007 ASCO Annual Meeting Proceedings Part I). Pluzanska A, Mainwaring P, Cassidy J, et al.: Final results of a
randomized phase III study evaluating the addition of oxaliplatin first line to 5-FU followed by irinotecan at progression in advanced colorectal cancer (LIFE
study) [abstract 3517]. J Clin Oncol 2005, 23(2005 ASCO Annual Meeting Proceedings Part I).
Regression plot and relationship between percentage of patients (pts) receiving fluorouracil
(FU)/leucovorin (LV), irinotecan, and oxaliplatin (3 drugs) in the course of their disease and
the reported median overall survival (OS).
Grothey A , and Sargent D JCO 2005;23:9441-9442
ESMO Group 3 mCRC
Targeted agents + Chemotherapy
• Bevacizumab is active in combination with chemotherapy
–
–
–
–
–
Survival benefit is not constantly seen but PFS is
Risk factors should be considered
If used, should be preferred in early lines
No activity as single agent
To be discussed if maintenance is used
ESMO Group 3 mCRC
• Anti-EGFR Monoclonal Antibodies are generally used at a
later line of treatment in this patients population
– Patients should be selected according to K and N RAS wt
– No sequential trials in this group of patients are available
– Upfront use of anti EGFR MoAb has been reported in small trial
with high efficacy
– Most frequently used in 3rd or 4th line
ESMO Group 3 mCRC
– Regorafenib (Stivarga)
• Oral MultiKinase Inhibitor (maily anti-angiogeneic)
• Has been recently approved after failure or intolerance to all
available agents
• The CORRECT trial showed a benefit in PFS and OS when
compared to BSC
CORRECT: Patients with metastatic colorectal cancer
treated with regorafenib or placebo after failure of
standard therapy
mCRC treated with
all available standard
therapies and
progressing during
or ≤3 months after
last standard therapy
(n=760)
RA
ND
OM
I
Z
E
D
Regorafenib + BSC (n=505)
160 mg orally once daily 3
weeks on, 1 week off
2:1
Placebo + BSC (n=255)
once daily
3 weeks on, 1 week off
Treatment continuation
until disease
progression,
unacceptable toxicity, or
patient/investigator
decision to stop
Primary endpoint: overall survival (OS)
Baseline disease characteristics
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 (adenosquamous
or unspecified carcinoma)
2.0
2.8
Number of prior lines 1-2
of therapy for
3
metastatic disease, % ≥4
26.7
24.7
24.8
28.2
48.5
47.1
Prior bevacizumab, %
100
100
Primary site of
disease, %
KRAS mutation, %*
Histology, %
*KRAS status based on historical patient record
Overall survival (updated analysis)
Extended analysis shows that significant benefit is maintained
after 566 events (97% of planned total)
Survival distribution function
1.00
Median OS, months (95% CI)
Regorafenib,
N=505
Placebo,
N=255
6.4 (5.8-7.0)
5.0 (4.4-5.9)
HR (95% CI)
0.75
0.79 (0.66-0.94)
p value
OS rate at 6 months
52.2%
43.1%
at 12 months
24.1%
17.0%
0.50
0.25
0.0038
Regorafenib 160 mg
Placebo
0
0
2
4
6
8
10
12
Time from randomization, months
14
16
18
Objective response and disease control rates
Best response, %
Complete response
Partial response
Stable disease
Progressive disease
Disease control rate*
Regorafenib
N=505
Placebo
N=255
0
1.0
42.8
49.5
41.0
0
0.4
14.5
80.0
14.9
*DCR = PR + SD ≥6 weeks after randomization; p<0.000001
Subgroup analysis of overall survival
(interim analysis)
Regorafenib benefit vs placebo is achieved across subgroups
N
HR (95% CI)
760
0.774 (0.636-0.942)
<18 months
140
0.816 (0.532-1.251)
≥18 months
620
0.760 (0.609-0.948)
375
0.825 (0.625-1.089)
All patients
Time from first diagnosis
of metastatic disease
to randomization
Prior anticancer treatment F, Ox, Iri, Bev
Prior treatment lines for
metastatic disease
KRAS mutation (based on
historical patient record)
F, Ox, Iri, Bev,
385
anti-EGFR
≤3
395
0.710 (0.538-0.938)
0.788 (0.599-1.038)
>3
365
0.747 (0.564-0.988)
No
299
0.653 (0.476-0.895)
Yes
430
0.867 (0.670-1.123)
0.0 0.5 1.0 1.5 2.0 2.5 3.0
F: fluoropyrimidine; Ox: oxaliplatin;
Iri: irinotecan; Bev, bevacizumab
Favors regorafenib Favors placebo
Drug-related treatment-emergent adverse events
occurring in ≥10% of patients
Adverse event, %
Regorafenib
N=500
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
*Grade 5 drug-related adverse events: 1.0% in regorafenib arm vs 0% in placebo arm
State of Art for Chemotherapy and Targeted Agents
for Group 2 and 3 Patients
• ESMO consensus guidelines as a reference in clinical practice
• Each individual patient should be referred to 1 of the 4 groups
– Treatment goal will be stated upfront
– Treatment options will be identified for discussion
• In group 2: Stop rapid progression in symptomatic patients
Eventually rediscuss in MDT if fit to move to group 1
•
In group 3: Improve overall survival with maintained quality of
life