1. Treating Advanced Colorectal Cancer: 15 minutes, 13 abstracts
Richard M Goldberg MD
Professor and Chief of Heme/Onc
Lineberger Comprehensive Cancer Center
University of North Carolina at Chapel Hill

2. Topics: Chemotherapy N = 2241
First-line chemotherapy comparisons
BICC (Fuchs et al): mIFL, CapeIRI, FOLFIRI
Ducreux et al: Xelox to FOLFOX
NO (Cassidy et al): Xelox to FOLFOX
GONO (Falcone et al): 5-FU/IRI to FOLFOXIRI
Second-line chemotherapy comparisons
Rothenberg et al: Xelox to FOLFOX

3. BICC-C: Fuchs et al: n = 547 FOLFIRI mIFL CapeIRI 1st-line mCRCD O M I Z T
1st-line
mCRC
N = 1000

4. Efficacy in 430 Patients mIFL CapeIRI FOLFIRI P-value
Response rate (%)
43.3
38.6
47.2
N.S.
PFS (mos)
6.0
5.7
8.2
0.01
OS (mos)
17.6
18.9
23.1

5. Period 1: Progression Free Survival
1.0
Regimen
Median PFS (Months)
P Value
FOLFIRI
8.2
0.01
mIFL
6.0
CapeIRI
5.7
0.9
0.8
0.7
0.6
Progression Free Survival
Proportion of
0.5
0.4
0.3
0.2
FOLFIRI
mIFL
0.1
CapeIRI 10 20 30
Time (months)

6. Proportion of Patients Survival Time (months)
Period 1: OS as of May 1st, 2007
Regimen
Median OS (Months)
1 Year
P Value
FOLFIRI
23.1
75% --
mIFL
17.6
65%
0.12
CapeIRI
18.9
66%
0.42 1
0.9
0.8
0.7
0.6
Proportion of Patients
Who Survived
0.5
0.4
0.3
FOLFIRI
0.2
mIFL
0.1
CapeIRI 10 20 30 40 50
Survival Time (months)

7. Period 1: Grade 3-4 AEs Nausea 8.8 7.3 18.4 Vomiting 15.6 Diarrhea
Adverse Event
Grade 3-4
FOLFIRI
n = 137
(%)
m-IFL
CapeIRI
n = 141
Nausea
8.8
7.3
18.4
Vomiting
15.6
Diarrhea
13.9 19
47.5
Dehydration
5.8
19.1
Neutropenia
43.1
40.9
31.9
Febrile neutropenia
3.6
12.4
7.1
Hand-foot syndrome
9.9
MI / stroke
0.7
60-day mortality
5.1
3.5

8. What is currently the best combination of irinotecan and 5-FU?
Question answered:
What is currently the best combination of irinotecan and 5-FU?
FOLFIRI
What about toxicity?
Beware the CapeIRI regimen used in this study
No more IFL, mIFL

9. Xelox vs FOLFOX: Ducreux et al Equivalence Study N= 306
Randomization
FOLFOX6

10. Efficacy Xelox N=156 FOLFOX6 N=150 P-value Response rate (%) 39% 46%na
PFS (mos)
8.8
9.3
OS (mos)
19.9
20.5

11. Progression-free & Overall survival

12. Toxicity (n=304) *
*p<0.05, Chi-square test * *

13. Questions Answered:
Does XELOX ≈ FOLFOX-6 in terms RR, Median PFS and OS?
Yes
What about comparative toxicity?
XELOX offers significantly less grade 3/4 neuropathy, neutropenia, and febrile neutropenia than FOLFOX-6.

14. Xelox vs FOLFOX: Cassidy et al
Recruitment June 03 – May 04
Recruitment Feb 04 – Feb 05
XELOX n=317
XELOX + placebo
n=350
XELOX + bevacizumab
n=350
FOLFOX-4
n=317
FOLFOX-4 + placebo n=351
FOLFOX-4 + bevacizumab
n=349
n=634
n=1400

15. Efficacy Xelox N=317 FOLFOX6 P-value Response rate (%) ? na PFS (mos)
8.0
pooled
8.5
OS (mos)
17.7
No bev
18.8

16. OS for XELOX vs. FOLFOX-4 in the 2-arm part of the study
n=317, 262 events
Proportion of patients
1.0
XELOX
n=317, 250 events
0.9
0.8
0.7
HR = 0.90 [97.5% CI: 0.74–1.10] (ITT)
HR = 0.92 [97.5% CI: 0.75–1.13] (EPP)
0.6
0.5
0.4
0.3
0.2
0.1
17.7
18.8
0.0 5 10 15 20 25 30 35 40 45
Months X
X/P
X/BV F
F/P
F/BV

17. Questions Answered: Do XELOX and FOLFOX-4 yield ≈ OS? Yes
What about XELOX and FOLFOX-4 toxicities?
As expected.

18. 5-FU/IRI vs FOLFOXIRI: Falcone et al N = 244
Douillard
Randomization
FOLFOXIRI

19. 5FU flat continuous infusion
FOLFOXIRI Schedule
Day Day 2 Day 3
CPT-11
165 mg/m2
Oxaliplatin
85 mg/m2
L-LV
200 mg/m2
5FU flat continuous infusion
3200mg/m2
1 hour
2 hours
48 hours
Repeated every 14 days

20. Efficacy 5-FU/IRI N=122 FOLFOXIRI P-value Response rate (%) 41% 66% ?
PFS (mos)
6.9
(BICC = 8.3)
9.9
0.0009
OS (mos)
16.7
23.6
0.042

21. Post-ChemoRx Resections (patients with liver mts only)
FU/IRI
(42 pts)
FOLFOXIRI
(39 pts) R0
12%*
(5 pts)
36%*
(14 pts)
* p=0.017

22. Progression Free & Overall Survival
Medians
Douillard: 6.9 mos
FOLFOXIRI: 9.9 mos P=
Medians
Douillard: 16.7 mos
FOLFOXIRI: 23.6 mos
P= 0.042

23. Grade 3-4 Toxicity
(N=122)
(N=122)
p =0.0006

24. Survival improves with availability of three active drugs*
FOLFOXIRI
P=0.0001
Grothey A, Sargent D. J Clin Oncol. 2005;23: 24

25. Questions Answered/Raised
Is FOLFOXIRI more active than 5-FU/IRI?
Yes, including better resection rates
Is FOLFOXIRI too toxic?
Generally not
How do 3 drug regimens compare?

26. Xelox vs FOLFOX 2nd Line: Rothenberg et al N = 627
Randomization
FOLFOX

27. Efficacy Xelox N=313 FOLFOX4 N=314 P-value Response rate (%) 15.3 12.4na
PFS (mos)
4.7
4.8
OS (mos)
11.9
12.6

28. Progression-free survival
Estimated probability
XELOX FOLFOX-4
1.0
0.8
0.6
0.4
0.2
4.7
4.8
Months

29. Overall Survival Estimated probability XELOX FOLFOX-4 1.0 0.8 0.6 0.4
0.2
11.9
12.6
Months

30. Questions Answered/Raised
Does XELOX ≈ FOLFOX-6 in terms RR, Median PFS and OS in second line?
Yes
Were there any unexpected toxicities? No
Do we need another XELOX/FOLFOX study in MCRC?
No, 1561 patients reported on in this session
MR: I would clarify the first point to state that “Progression-free survival with XELOX is non-inferior to FOLFOX-4 as second-line treatment for MCRC”.

31. Topics: Biologics N = 5379 Chemotherapy + Bevacizumab EGFR Antibodies:
BICC (Fuchs et al): mIFL or FOLFIRI +/- Bev
NO (Saltz et al) Xelox or FOLFOX +/- Bev
Schmiegel et al: CapeOx or CapeIri + Bev
EGFR Antibodies:
Rash/Response
Humbet et al: Panitumumab rash/response
EVEREST (Tejpar et al) Iri + Cetuximab escalation trial
OPUS (Bokemeyer et al) FOLFOX +/- cetuximab

32. BICC-C Part 2: N= 114
FOLFIRI
+ Bev
Randomization
mIFL
+ Bev

33. Efficacy mIFL + Bev N=60 FOLFIRI + Bev N=57 P-value Response rate (%)?
PFS (mos)
8.3
11.2
0.28
OS (mos)
19.2
Not reached
0.01

34. PFS Regimen PFS (Mos) P Value FOLFIRI + BEV 11.2 -- mIFL + BEV 8.3
0.28 1
0.9
0.8
0.7
0.6
Proportion of Subjects Who Did Not Progress
0.5
0.4
0.3
FOLFIRI + Bevacizumab
mIFL + Bevacizumab
0.2
0.1 10 20 30
Time to Progression (months)

35. Proportion of Subjects Who Survived Survival Time (months)
Regimen
Median OS (Months)
1 Year
P Value
FOLFIRI+ BEV
Not Reached
87% --
mIFL + BEV
19.2
61%
0.01 1
0.9
0.8
0.7
0.6
Proportion of Subjects Who Survived
0.5
0.4
0.3
FOLFIRI + Bevacizumab
mIFL + Bevacizumab
0.2
0.1 10 20 30 40
Survival Time (months)

36. Period 2: Grade 3-4 AEs Nausea 10.7 5.1 Vomiting Diarrhea 11.9
Adverse Event
Grade 3-4
FOLFIRI + bevacizumab
n = 56 (%)
m-IFL + bevacizumab
n = 59 (%)
Nausea
10.7
5.1
Vomiting
Diarrhea
11.9
Dehydration
5.4
1.7
Neutropenia
53.6
28.8
Febrile neutropenia
Hand-foot syndrome
3.6
0.0
Hypertension
12.5
MI / stroke
1.8
60-day mortality
6.8

37. Questions Answered/Raised
Does FOLFIRI + bev = mIFL + bev
FOLFIRI + bev > mIFL + bev
Is a 6.8% 60-day mortality acceptable in PS 0,1 pts?
No, but this is a small study with wide confidence intervals
What will the OS be for FOLFIRI/Bev?
What is the best chemo partner for Bev?

38. Xelox vs FOLFOX+/- Bev: Saltz et al
Recruitment Feb 04 – Feb 05
XELOX n=317
XELOX + placebo
n=350
XELOX + bevacizumab
n=350
FOLFOX-4
n=317
FOLFOX-4 + placebo n=351
FOLFOX-4 + bevacizumab
n=349
n=634
n=1400

39. Efficacy XELOX/FOLFOX N=701 XELOX/FOLFOX + bev N=699 P-value
Response rate (%)
49%
from GI
47%
symposium
0.99
PFS (mos)
8.0
9.4
0.0023
OS (mos)
19.9
20.3
0.076

40. PFS 1.0 0.8 0.6 0.4 0.2 HR=0.83 [97.5% CI 0.72–0.95] PFS estimate
XELOX / FOLFOX-4 + bevacizumab n=699 (513 events)
XELOX / FOLFOX-4 + placebo n=701 (547 events)
1.0
0.8
0.6
0.4
0.2
HR=0.83 [97.5% CI 0.72–0.95]
p=0.0023
PFS estimate
8.0
9.4
Months

41. Figure 3. Separation after ~6 months in bevacizumab-containing arms between ‘general’ and ‘on treatment’ PFS
XELOX / FOLFOX-4 + bevacizumab
XELOX / FOLFOX-4 + placebo
1.0
0.8
0.6
0.4
0.2
ON TREATMENT: HR=0.63 (97.5% CI 0.52–0.75, p<0.0001)
PFS estimate
When you compare the pooled PFS general and on treatment analysis you can observe that both Avastin curves separate nicely in the begining but the PFS general Avastin curve starts to run parallel around 6 month. This reflects the observed phenomenon that a large group of patients in the 966 trial discontinued treatment at 6 month and was not treated until progression, as recommended in the protocol.
GENERAL: HR= (97.5% CI 0.72–0.95, p=0.0023)
Months

42. Figure 4. Overall survival
XELOX / FOLFOX-4 + bevacizumab n=699 (420 events)
XELOX / FOLFOX-4 + placebo n=701 (455 events)
1.0
0.8
HR=0.89 (97.5% CI 0.76–1.03) p=0.0769
Survival estimate
0.6
0.4
0.2
19.9
21.3 6 12 18 24 30 36
Months

43. Questions Answered/Raised
Does Bevacizumab add to oxaliplatin based regimens?
Not as dramatically as in irinotecan studies
Should chemotherapy + bev be continued when oxaliplatin must be stopped?
Yes, probably
Why no difference in response rates?
Does this mean we are not optimizing 1st line Rx?

44. CapeOx + Bev vs CapeIRI + Bev: Schmiegel et al; N= 233
Randomization
CapeIRI
+ Bev

45. Treatment protocol Arm A: d 1 d 15 q 3wks
Oxaliplatin
130mg/m2, 120min i.v.
Bevacizumab
7,5 mg/kg i.v.
Capecitabine
1000mg/m2 p.o., 2x daily
Arm B: (*)
Irinotecan
200mg/m2, 30min i.v.
800mg/m2 p.o., 2x daily
q 3wks
note dose reduction of CapIri compared to previous trials for safety reasons

46. Efficacy CapeOX + bev N=118 CapeIRI N=115 P-value Response rate (%)
45%
48% na
PFS at 6 months (%)
74%
84%
OS (mos)

47. CTC grade 3 and 4 Toxicities (n=229)
Related toxicities
Arm A (117)
[%], 3°/4°
Arm B (112)
Diarrhoea
16 (16/0) 13
Sensory neuropathy
13 (12/1)
Hand-Foot-Syndrome
6 (6/0)
4 (4/0)
Vomiting
3 (3/0)
4 (4/0)å
Fever 1
Neutropenia
2 (2/0)

48. Questions Answered/Raised
Is 800 mg/m2 bid a better dose for CapeIRI?
Likely
Final results?

49. OPUS: Bokemeyer et al, N = 337 Phase II “Superiority trial”
FOLFOX
Randomization
FOLFOX +
Cetuximab

50. Efficacy FOLFOX N=168 + cetuximab N=169 P-value Response rate (%)
35.7%
45.6% na
PFS
OS (mos)

51. Questions Answered/Raised
Does the addition of cetuximab to FOLFOX increase the response rate?
Yes, by 10%
How do we integrate this with Acrobat?
This is a larger study and likely more reliable

52. Association of skin toxicity severity with clinical outcomes and health-related quality of life with panitumumab
Y Humblet, M Peeters, S Artale, A Hendlisz, B Neyns, A Sobrero, M Wolf, M Woolley, R Amado, E Van Cutsem

53. Skin Toxicity & Outcomes with P-Mab: Humblet et al, N = 391
BSC
Randomization
Panitumumab
+ BSC

54. OS by Worst Skin Tox & mDLQI Score
Patients with worst grade of 2-4 had better overall survival vs those with a worst grade of 1

55. Questions Answered/Raised
Does rash correlate with outcomes?
From this exploratory analysis improved PFS, overall survival, and HRQOL were associated with worse skin toxicity.
Can we find a predictive marker for EGFR antibody response that does not require treatment?
Amphiregulin, heregulin?

56. cetuximab dose escalation Not eligible for randomization
EVEREST: Tejpar at al
Arm A
standard cetuximab
regime
(250 mg/m2/w)
Cetuximab
(400 mg/m2initial dose
then 250 mg/m2/w)
+ irinotecan
(180 mg/m2 q2w)
Day 22
Screening
Randomization
Arm B
cetuximab dose escalation
(dose increases of
50 mg/m2 q2w
up to maximum
500 mg/m2/w)
Not eligible for randomization
Arm C
standard cetuximab regime
(250 mg/m2/w)

57. Efficacy Standard dose N=45 Escalated dose N=44 P-value
Response rate (%)
16%
30%
Not done
PFS (mos)
3.9
4.8
OS (mos)
10.0
8.6

58. Toxicity Standard dose N=45 Escalated dose N=44 Diarrhea 11% 23%
Low Mg 2% 9%
Grade≥ 2
rash
36%
57%

59. Questions Answered/Raised
Can Cetuximab be escalated to doses of up to 500 mg/m2/week?
Yes
Is it useful?
Higher RR, longer PFS, OS no better
Is it practical?
Can we find a predictive biomarker?

60. Topics: Miscellaneous
Brite registry (Grothey et al) Bev after 1st progression
Confirm 2 (Kohne et al) FOLFOX +/- PTK787
RTOG 0315 (Zachariah et al) Octreotide for chemo/rads diarrhea

61. The BRITE Registry: Grothey et al, N=1953
OBJECTIVES
To evaluate the association between exposure to BV beyond 1st PD (BBP) and survival beyond 1st PD in an exploratory analysis in BRiTE
Evaluable
Evaluable
Patients
Patients
(N=1953)
(N=1953)
Median follow-up time 19.6 mo 1 1 st st
Progression*
Progression*
(n=1445)
(n=1445)
BV and
No treatment
CT/Biologics
No Post-PD
treatment
No BBP
CT/Biologics
BBP
(n=181)
(n=486)
(n=778)
(n=531)
(n=642)
(n=253)
BBP=bevacizumab beyond 1st PD

62. A previous report: median OS = 27.1 months
Figure 2. Definition of Survival Beyond 1st PD OS OS
TTP
TTP
BV start
BV start
1st 1 st
Progression
Progression
Death
Death
Survival beyond 1st PD
Survival beyond 1 st PD
A previous report: median OS = 27.1 months
1st line PFS median = 10.1 months

63. Figure 4. Kaplan-Meier Estimates by Subgroups Based on Treatment Post-1st PD A) Survival Beyond 1st PD B) Overall Survival A B

64. Questions Answered/Raised
What does the data suggest?
That OS with bev continuation exceeds that observed in comparable groups
How useful is registry data?
It is hypotheses generating (iBET study)
Is this enough evidence to sway practice?
Should it be?

65. CONFIRM 2 (2nd Line PTK 787): Koehne et al N = 852
FOLFOX4
Randomization
FOLFOX4 +
PTK787

66. Overall OS & PFS

67. PFS & OS in High LDH Patients

68. Questions Answered/Raised
Is PTK useful when added to FOLFOX in this setting? No
What does an elevated LDH mean?
Should investigators lead or participate in Phase III trials that skip Phase II?

69. Octreotide for Radiation Related Diarrhea: Zachariah et al, N = 218
Chemo + RT
Randomization
Chemo + RT +
Octreotide

70. Questions Answered/Raised
Does octreotide help in this setting? No

71. Summary N= 7620 Patients FOLFIRI best irinotecan regimen
Xelox ≈ FOLFOX 1st and 2nd line
3 Strategies pushed the OS >23 months
GONO: FOLFOXIRI > 5-FU/IRI (not FOLFIRI)
BICC: FOLFIRI + Bev
Brite: bevacizumab continuation
How to optimize bev/oxaliplatin regimens?
How to optimize doses of biologics?