Current Trends in

Management of
Metastatic
Colorectal Cancer
Sangeetha Poovaneswaran
Clinical Oncologist and Radiotherapist
KPJ Damasara Specialist Hospital

Before..Bolus 5 FU

Now. Many choices.

1960s BSC
1970/80s 5-FU
1990s 5-FU/LV
IFL
FOLFOX
FOLFOX/FOLFIRI sequence
IFL + bevacizumab
FOLFIRI + Cetuximab
Elox-Fluoropyrimidine +
Bevacizumab (TREE-2)
0

12

18

Median overall survival (months)

24

In Metastatic CRC, Passenger Mutations in Multiple Pathways

Are Responsible for Oncogenesis, Angiogenesis, and Signaling
in the Tumor Microenvironment
Tumor Cell

EGFR

Endothelial Cell

KIT

VEGFR

PDGFR-

RAS
Pl3K
RAF

BRAF

AKT
MEK
mTOR

ERK

ONCOGENESIS
ANGIOGENESIS
TUMOR MICROENVIRONMENT
G.S.M.ON.04.2014.0882

or by the presence of
activating mutations in
downstream pathway kinases,
such as KRAS, NRAS, or BRAF

Knight ZA, et al. Nat Rev Cancer. 2010;10(2):130-137. Sharma SV, Settleman J. Genes Develop. 2007:21:3214-3231.

What is new in mCRC?

BIOLOGICAL AGENTS
Bevacizumab/ Avastin
Cetuximab/ Erbitux
Panitumumab/ Vectibix
Aflibercept/ Zaltrap
Regorafenib/ Stivarga

Biological agents in
combination chemotherapy

Bevacizumab

1st line + Irinotecan: Hurwitz IFL, BICC-C

2nd line + Eloxatin: ECOG E3200
1st line + Eloxatin: TREE , NO 16966

Cetuximab

2nd line + irinotecan: Bond

1st line + Irinotecan: CRYSTAL
1st line + Eloxatin: ACROBAT, OPUS

Bevacizumab

PFS benefit maintained with bevacizumab

irrespective of type of chemotherapy
received
8.0

Chemotherapy1,2

8.5
5.6

Phase II/III
clinical trials

Combined analysis3

10 months

11.1
11.4
10.4

AIO 06045

12.1

BICC-C6

11.2

AVIRI7

11.1

Daily
practice*

MD Anderson8

12.5
10.0
10.9

BRiTE9

11.3
11.6

BEAT10
0

*Large prospective,
observational trials

Bevacizumab + FOLFIRI
and/or XELIRI

10.4

PACCE4

Bevacizumab + 5-FU/LV
Bevacizumab + FOLFOX
and/or XELOX

8.8

NO169661

Chemotherapy only

6
8
10
Median PFS (months)

12

14

1. Saltz, et al. JCO 2008; 2. Tournigand, et al. JCO 2004; 3. Kabbinavar, et al. JCO 2005
4. Hecht, et al. JCO 2009; 5. Reinacher-Schick, et al. ASCO 2008 (poster)
6. Fuchs, et al. JCO 2007; 7. Sobrero, et al. Oncology. In press; 8. Kopetz, et al. ASCO 2007
9. Grothey, et al. JCO 2008; 10. Van Cutsem, et al. ESMO 2008 (poster)

Cetuximab

1st-line Erbitux plus FOLFIRI or FOLFOX : Consistent

efficacy in patients with KRAS wild-type tumors
CRYSTAL

1.0

CRYSTAL1
p=0.0025

OPUS2
p=0.011

30

0.6

HR=0.68

0.4
0.2

Cetuximab + FOLFIRI
FOLFIRI
0

61

59

50
40

32% risk reduction

for progression

0.8

60

PFS estimate

Response rate (%)

70

PFS estimate

Cetuximab + CT
CT alone

43
37

20

8
10
12
Time (months)

14

16

18

OPUS

1.0

43% risk reduction

for progression

0.8

HR=0.57

0.6
0.4

10
0.2

Cetuximab + FOLFOX
FOLFOX

0
FOLFIRI Cetuximab FOLFOX Cetuximab
(n=176) + FOLFIRI (n=73) + FOLFOX
(n=172)
(n=61)

courtesy of Sanofi Aventis

0
0

8
10
12
Time (months)

14

16

18

1. Van Cutsem E, et al. N Engl J Med 2009;360:14081417;

2. Bokemeyer C, et al. J Clin Oncol 2009;27:663671

Panitumumab

Ph3 pmab and FOLFIRI

The 181 patients
2nd line treatment for mCRC
In KRAS WT
pmab +FOLFIRI vs FOLFIRI alone
median PFS 5.9 mths vs 3.9 mths
Median OS
14.5 mths vs 12.5 mths
No difference for KRAS MT
Peeters M et al. 2010 GI Cancers Symposium

PRIME: pmab and FOLFOX in 1st

line metastatic
N = 1183 patients with mCRC
Randomized to FOLFOX4 panitumumab
At 60% enrollment, only wild-type KRAS

Primary endpoint: PFS by KRAS status (HR: 0.71)

Median PFS 9.6 mos with panitumumab vs 8.0 mos with
FOLFOX alone (HR: 0.80; P = .02)
In patients with KRAS-mutant tumors
Median PFS: 7.3 mos with panitumumab vs 8.8 mos with FOLFOX
alone (P = .02)
Median OS: 15.1 mos with panitumumab vs 18.7 mos without
(P = .004)
Douillard J, et al. ECCO/ESMO 2009. Abstract 10LBA.

Now we know that adding a

biological agent to chemotherapy
gives a better response.
Further questions:
1. Are VEGFRi better than EGFRi?
2. Does combining biological agents improve
outcome?
3. Are there newer drugs?
4. Are there other mutations that affect responses
to biological agents?

Head to Head comparison

between Cetuximab and
Bevacizumab in KRAS WT
tumours

Head to Head Trials

1.CALGB 80405
2.FIRE III

18

CALGB 80405: H2H Bevacizumab vs

Cetuximab in First-line KRAS WT mCRC
Untreated
advanced or
metastatic CRC

(N=1142)

Bevacizumab
+ FOLFOX
or FOLFIRI q2w

PD

Cetuximab
+ FOLFOX
or FOLFIRI q2w

PD

Randomized
patients
with KRAS
WT tumors

Re-open: 6/09
Closed to accrual: 2/12
Patients enrolled:
N=2334 (total)
N=1177 (final endpoint)

Primary endpoint: OS

Approximately
70% FOLFOX
30% FOLFIRI

Superiority trial with 90% power to detect an OS HR of 1.25 (2-sided =0.05)

Secondary endpoints: ORR, PFS, TTF, DOR, and safety
Sponsor: CALGB + collaborators

PI: Charles D. Blanke (OHSU), Alan Venook (UCSF)

TTF=time to treatment failure.
Bergsland EK (Discussant). ASCO. 2013 (abstr 3504-3506). NCT identifier: NCT00265850.

19

CALGB-80405 failed to meet its primary endpoint of OS

Cetuximab is not superior to Avastin in 1L KRAS-WT mCRC

1.0

OS estimate

0.8

Arm

N (Events)

OS (m) Median

95% CI

Chemo + Cetux

578 (375)

29.9

27.0-32.9

Chemo + Bev

559 (371)

29.0

25.7-31.2

0.6

P=0.34
HR=0.925 (0.78-1.09)

0.4
0.2
0

29.0
0

12

24

29.9
36

48

Time (months)

Venook, et al. ASCO 2014. Abstract LBA3

60

72

84

CALGB-80405 failed to meet its secondary endpoint of

PFS
Cetuximab failed to show superiority to Avastin in PFS

1.0

PFS estimate

0.8
0.6

Arm

N (Events)

PFS (m) Median

95% CI

Chemo + Bev

559 (498)

10.8

9.7-11.4

Chemo + Cetux

578 (499)

10.4

9.6-11.3

P=0.55
HR=1.04 (0.91-1.17)

0.4
0.2
0

10.4

10.8

12

24

36

Time (months)

Venook, et al. ASCO 2014. Abstract LBA3

48

Safety was comparable between cetuximab and

Avastin with expected outcomes: more Rash in the
cetuximab arm and more Hypertension in the Avastin
arm
ARM A
CHEMO + BEV
n=559 (%)

ARM B
CHEMO + CETUX
n=578 (%)

Total Grade 3
Haematological
Non-haematological

278 (52)
142 (26.6)
234 (43.8)

295 (54)
150 (27.4)
259 (47.3)

Total Grade 4

66 (12.4)

75 (13.7)

Total Grade 5

7 (1.3)

3 (0.5)

Neuropathy Gr 3

71 (14)

68 (12)

40 (7)

Diarrhea Gr 3

45 (8)

59 (11)

Hypertension Gr 3

35 (7)

3 (1)

GI events Gr 3

10 (2)

2 (0.5)

Toxicity

Rash

Gr 3

Venook, et al. ASCO 2014. Abstract LBA3

FIRE-3 (German AIO Study KRK-0306): A Phase III Trial of

FOLFIRI Plus Cetuximab vs FOLFIRI Plus Bevacizumab in
First-line Treatment of Patients With mCRC
FOLFIRI + cetuximab
Untreated
KRAS WT
mCRC
(n=592)

Cetuximab: 400 mg/m2 IV 120 min initial dose

250 mg/m2 IV 60 min q1w

R
1:1
FOLFIRI + bevacizumab
Bevacizumab: 5 mg/kg IV 30-90 min q2w

Key Inclusion Criteria: Patients 18 years with histologically confirmed diagnosis of mCRC;
ECOG PS 0-2; Prior adjuvant CT allowed if completed >6 month before inclusion
Primary endpoint: ORR (mRECIST1.0, investigators read)
Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to
FOLFIRI + bevacizumab (50%)
284 evaluable patients per arm needed to achieve 80% power for a one-sided Fishers exact test at
an alpha level of 2.5%

Secondary endpoints: PFS, OS, TFS, deepness of response (percent of tumor shrinkage
compared to baseline), secondary R0 resection rate, safety, and tolerability
Amendment in October 2008 to include only KRAS wildtype patients
150 active centers in Germany and Austria
FOLFIRI=leucovorin, fluorouracil, and irinotecan.
Heinemann, et al. Presented at ASCO. 2013 (abstr LBA3506). NCT Identifier: NCT00433927.

23

FIRE-3: PFS in KRAS WT and RAS WT

(KRAS and NRAS Exon 2, 3, and 4 WT)
KRAS Exon 2 WT
FOLFIRI + cetuximab
FOLFIRI + bevacizumab

0.75

Probability of Survival

Probability of Survival

1.00

HR=1.06 (95% CI, 0.88-1.26)

Log-rank P=0.547

0.50

0.25

10.0
mos

0
0

Patients
at risk: 297
295

10.3
mos
12

24

36

48

19
15

10
6

5
4

Median,
Months

(95% CI)

250/297 (84.2)

10.0

(8.8-10.8)

242/295 (82.0)

10.3

(9.8-11.3)

Events, n/N (%)

FOLFIRI + cetuximab
FOLFIRI + bevacizumab

0.75

HR=0.93 (95% CI, 0.74-1.17)

Log-rank P=0.54

0.50

0.25
10.4
mos

60

0.0

72

Time Since Start of Treatment, Months

100
99

RAS WT
(KRAS and NRAS Exon 2, 3, and 4 WT)

1.0

Patients
at risk: 171
171

10.2
mos
12

24

36

48

60

64
57

14
8

8
3

4
1

Time Since Start of Treatment, Months

Events
n/N (%)

Median,
Months

(95% CI)

144/171 (84.2)

10.4

(9.5-12.2)

143/171 (83.6)

10.2

(9.3-11.5)

Heinemann V, et al. Presented at: ASCO. 2013 (abstr LBA3506).

72

24

FIRE-3: OS in KRAS WT and RAS WT

(KRAS and NRAS Exon 2, 3, and 4 WT)
KRAS Exon 2 WT
FOLFIRI + cetuximab
FOLFIRI + bevacizumab

0.75

Probability of Survival

Probability of Survival

1.00

HR=0.77 (95% CI, 0.62-0.96)

Log-rank P=0.017

0.50

= 3.7
months

0.25
25.0
mos

0.0
0

12

RAS WT
(KRAS and NRAS Exon 2, 3, and 4 WT)

1.0

FOLFIRI + cetuximab
FOLFIRI + bevacizumab

0.75

HR=0.70 (95% CI, 0.53-0.92)

Log-rank P=0.011

0.50

= 7.5
months
0.25

28.7
mos
24

36

48

60

72

25.6
mos

0.0

218
214

111
111

60
47

29
18

9
2

12

24

36

48

60

128
127

71
68

39
26

20
9

6
1

Time Since Start of Treatment, Months

Time Since Start of Treatment, Months

Patients
at risk: 297
295

33.1
mos

Patients
at risk: 171
171

Events, n/N
(%)

Median,
Months

(95% CI)

Events, n/N (%)

Median,
Months

(95% CI)

158/297 (53.2)

28.7

(24.0-36.6)

185/295 (62.7)

25.0

(22.7-27.6)

91/171 (53.2)

33.1

24.5-39.4

110/171 (64.3)

25.6

22.7-28.6

Heinemann V, et al. Presented at: ASCO. 2013 (abstr LBA3506). Stintzing S, et al. ASCO GI. 2014 (abstr 445).

72

25

What about Combining

biological agents?

CAIRO2
CapeOx + Bev
(COB, n = 368)
EGFR-detectable
mCRC

Primary endpoint: PFS

R
CapeOx + Bev + Cetuximab
(COB-C, n = 368)

Secondary endpoints
Response rate
Overall survival
Toxicity
Translational research
Tol J, et al. N Engl J Med. 2009;360:563-572.

Oxaliplatin stopped after 6 cycles

(18 wks = 4.5 mos)

CAIRO2: KRAS Genotyping (N = 520)

Outcome

COB

COB-C

P Value

WT KRAS (n = 314), mos

10.6

10.5

.30

Mutant KRAS (n = 206),

mos

12.5

8.1

.003

P value

.80

.04

WT KRAS (n = 314), mos

22.4

21.8

.64

Mutant KRAS (n = 206),

mos

24.9

17.2

.03

P value

.82

.06

Median PFS

Median OS

Tol J, et al. N Engl J Med. 2009;360:563-572.

PACCE Trial: Chemotherapy +

Bevacizumab Panitumumab
Oxaliplatin-CT + Bevacizumab
(n = 410)

Patients with
metastatic
colorectal
cancer and
ECOG 1

Oxaliplatin-CT + Bevacizumab +
Panitumumab
(n = 413)
Irinotecan-CT + Bevacizumab
(n = 115)

(N = 1053)
Irinotecan-CT + Bevacizumab +
Panitumumab
(n = 115)

Hecht JR, et al. J Clin Oncol. 2009;27:672-680.

PACCE results
Outcome, mos

CT +
Bevacizumab +
Panitumumab

CT +
Bevacizumab

Oxaliplatin
cohort

(n = 413)

(n = 410)

Median PFS

10.0

11.4

1.27 (1.06-1.52)

Median OS

19.4

24.5

1.43 (1.11-1.83)

(n = 115)

(n = 115)

Median PFS

10.1

11.7

1.19 (0.79-1.79)

Median OS

20.7

20.5

1.42 (0.77-2.62)

Irinotecan cohort

Hecht JR, et al. J Clin Oncol. 2009;27:672-680.

HR (95% CI)

PACCE Trial: conclusions

patients receiving both biologics did not benefit
regardless of whether they had wild-type or mutated
KRAS

Doubling up on biological
agents are NOT
beneficial.

Role of Other mutations:

The European Consortium evaluated the role of
various genetic markers in a large cohort of
chemorefractory metastatic colorectal cancer
patients treated with cetuximab plus irinotecan.
In 773 primary tumor samples, they aimed to
identify KRAS, BRAF, NRAS and PIK3CA mutations
and relate these to clinical endpoints.

Other mutations (continued)

They found that approximately 40% of tumors
harbored a KRAS mutation, 14% had a PIK3CA
mutation, 5% had a BRAF mutation, and about 3%
had an NRAS mutation.
In KRAS wild-type patients, carriers of BRAF and NRAS
mutations had a significantly lower response rate
than did BRAF and NRAS wild-types. PIK3CA exon 20
mutations also conferred worse outcomes.
The authors concluded that if KRAS is not mutated,
assessing BRAF, NRAS, and PIK3CA exon 20
mutational status gives additional predictive
information for lack of benefit to cetuximab (Erbitux).

FIRE-3: OS in KRAS WT and RAS WT

(KRAS and NRAS Exon 2, 3, and 4 WT)
KRAS Exon 2 WT
FOLFIRI + cetuximab
FOLFIRI + bevacizumab

0.75

Probability of Survival

Probability of Survival

1.00

HR=0.77 (95% CI, 0.62-0.96)

Log-rank P=0.017

0.50

= 3.7
months

0.25
25.0
mos

0.0
0

12

RAS WT
(KRAS and NRAS Exon 2, 3, and 4 WT)

1.0

FOLFIRI + cetuximab
FOLFIRI + bevacizumab

0.75

HR=0.70 (95% CI, 0.53-0.92)

Log-rank P=0.011

0.50

= 7.5
months
0.25

28.7
mos
24

36

48

60

72

25.6
mos

0.0

218
214

111
111

60
47

29
18

9
2

12

24

36

48

60

128
127

71
68

39
26

20
9

6
1

Time Since Start of Treatment, Months

Time Since Start of Treatment, Months

Patients
at risk: 297
295

33.1
mos

Patients
at risk: 171
171

Events, n/N
(%)

Median,
Months

(95% CI)

Events, n/N (%)

Median,
Months

(95% CI)

158/297 (53.2)

28.7

(24.0-36.6)

185/295 (62.7)

25.0

(22.7-27.6)

91/171 (53.2)

33.1

24.5-39.4

110/171 (64.3)

25.6

22.7-28.6

Heinemann V, et al. Presented at: ASCO. 2013 (abstr LBA3506). Stintzing S, et al. ASCO GI. 2014 (abstr 445).

72

34

New Drugs
Regorafenib
Aflibercept

CORRECT: Multicenter, Randomized, Double-Blind,

Placebo-Controlled Phase III Trial of Regorafenib in
mCRC

mCRC after standard

therapy
Stratification
Prior anti-VEGF therapy
Time from diagnosis of
metastatic disease
Geographical region
N= 760

R
A
N
D
O
M
I
Z
A
T
I
O
N

Regorafenib + BSC
(n = 505)
160 mg once daily
3 weeks on, 1 week off

2:1

Treatment continuation
until progression,
unacceptable toxicity, or
patient refusal

Placebo + BSC
(n = 255)
3 weeks on, 1 week off
Radiological assessment every 8 weeks

Global trial: 16 countries, 114 centers

Recruitment: May 2010 to March 2011
Primary endpoint: OS
Secondary endpoints: PFS, Objective tumor response, DCR, and safety
Grothey A, et al. Lancet. 2013;381:303-312.

51% Reduction in the Risk of Progression or Death

with Regorafenib vs Placebo

PFS Distribution Function

1.00
Median PFS, months (IQR)
0.75

Regorafenib
n = 505

Placebo
n = 255

1.9 (1.6-3.9)

1.7 (1.4-1.9)

HR (95% CI)

0.49 (0.42-0.58)

P value

<.0001

0.50

0.25
Regorafenib 160 mg
Placebo

0
Patients at risk, N
Regorafenib
Placebo
G.SM.ON.04.2014.0880

10

12

Time from Randomization, months

238
51

98
9

42
2

12
2

3
0
PFS, progression-free survival.
Grothey A, et al. Lancet. 2013;381:303-312.

Aflibercept- VELOUR Trial in

patients pretreated with
chemo and Bevacizumab
Adding aflibercept to FOLFIRI significantly
improved overall survival relative to
placebo plus FOLFIRI with median survival
of 13.50 versus 12.06 months, respectively.
Aflibercept also significantly improved
progression-free survival with median PFS of
6.90 versus 4.67 months, respectively.

CONCLUSION

Towards Personalized
Therapy of metastatic CRC
Bevacizumab vs Cetuximab in KRAS WT

Equal PFS but OS may be better with Cetuximab

EGFR antibodies
KRAS, NRAS and BRAF mutations correlate with
lack of response

Combining EGFR and VEGF antibodies

Data do not demonstrate benefit
New drugs
Suitable in 2nd and 3rd line setting

First Line

FOLFOX bevacizumab
FOLFOX cetuximab or
panitumumab (KRAS WT)
CapeOx bevacizumab
FOLFIRI + bevacizumab

FOLFIRI cetuximab or
Panitumumab (KRAS WT)
5-FU/FA bevacizumab

Second Line

Third Line

FOLFIRI bevacizumab
or Aflibercept

Irinotecan
cetuximab

Irinotecan Aflibercept

FOLFOX

FOLFIRI cetuximab or
panitumumab
Irinotecan cetuximab
or panitumumab

CapeOx

Single agent cetuximab /

panitumumab (KRAS
WT)

Single agent
cetuximab /
panitumumab
(KRAS WT)
Regorafenib

FOLFOX Bevacizumab

Clinical trial

CapeOx
Bevacizumab

BSC

FOLFOXIRI
bevacizumab
National Comprehensive Cancer Network 2014

THANK YOU