1. Clinical Review of Current Treatment Strategies for Colorectal Cancer
Oncology Journal Club
Clinical Review of Current Treatment Strategies for Colorectal Cancer
John L. Marshall, MD
Chief, Division Hematology and Oncology
Director, Developmental Therapeutics and GI Oncology
Lombardi Cancer Center
Georgetown University
Washington, DC

2. Management of mCRC: An Evolving Treatment Algorithm
Diagnosis of mCRC
Resectable
Unresectable
Adjuvant therapy
Surgery
Neo-adjuvant/
Pre-operative therapy
First-line
Second-line
Third-line
Borderline/
Potentially
Fourth-line
Treatment continuum

3. Advances in the Treatment of Colorectal Cancer
1980
1985
1990
1995
2000
2005
Therapeutic concepts
Palliative chemotherapy
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Capecitabine
Oxaliplatin
Cetuximab
Bevacizumab
Irinotecan
5-FU
Panitumumab
Targeted Therapies {

4. News from ASCO 2008 EGFR/KRAS: Colon Cancer is split in two
Trials close to re-tool
MSI-H: Colon Cancer is split again?
5-FU harmful in adjuvant setting
VEGF/EGFR: Dual inhibition may be bad
PACCE
CAIRO-2

5. Management of mCRC: An Evolving Treatment Algorithm
Diagnosis of mCRC
Resectable
Unresectable
Adjuvant therapy
Surgery
Neo-adjuvant/
Pre-operative therapy
First-line
Second-line
Third-line
Borderline/
Potentially
Fourth-line
Treatment continuum

6. NCCN Guidelines: Advanced mCRC
Good Tolerance to Intensive Therapy
Poor Tolerance to Intensive Therapy
First-line
Second-line
Third- or Fourth-line
FOLFOX + BEV or
CapeOx + BEV
FOLFIRI + BEV
5-FU/LV + BEV
Cape ± BEV or
5-FU + LV ± BEV
FOLFIRI or
Irinotecan
FOLFIRI + cetuximab or
Cetuximab + irinotecan
FOLFOX or CapeOx
Cetuximab or panitumumab or cetuximab + irinotecan
Improvement in functional status
No improvement in functional status
Cetuximab or panitumumab
or cetuximab + irinotecan
Clinical trial or best supportive care
Irinotecan or FOLFIRI
Best supportive care
Therapy after first progression as above
NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. v

7. Arm A – Camptosar + infusional
BICC-C Trial
N = 900
Arm A – Camptosar + infusional
+ Celecoxib or Placebo
400 mg bid
RANDOMI
ZAT
ION
Camptosar: 180 mg/m2 D 1 q 2wk
LV: 400 mg/m2 over 2hr D 1 q 2 wk
5-FU: 400 mg/m2 (bolus) D1 q 2 wk
5-FU: 2,400 mg/m2 (46 hr infusion)
D 1 q 2 wk
+ Bevacizumab
Metastatic Disease
Arm B – D1, D8 bolus
+ Celecoxib or Placebo
400 mg bid
Camptosar: 125 mg/m2
5-FU: 500 mg/m2
LV: 20 mg/m2
D 1, 8, q 3 wks
Arm C - Campcape
Camptosar: 250 mg/m2 d1 q 3 wks
Capecitabine: 1,000 mg/m2 bid d1-14 q 3 wks

8. Period 1: Progression Free Survival Data thru March 1, 2006 (ITT)
Months
Proportion of PFS
FOLFIRI
mIFL
CapeIRI
Regimen
Median PFS (Months)
HR (95% CI)
P Value
FOLFIRI
7.6 --
mIFL
5.8
1.55 (1.2, 2.0)
0.0009
CapeIRI
5.5
1.47
(1.1, 1.9)
0.0049

9. Period 2: Overall Survival Data Thru March 1, 2006 (ITT)
Regimen
Median OS (Months)
1 Year
HR (95% CI)
P Value
FOLFIRI+ BEV
Not Reached
87% --
mIFL + BEV
18.7
61%
2.5
(1.3,5.0)
0.01
Proportion of Patients
Who Survived
Survival Time (months)
mIFL + bevacizumab
FOLFIRI + bevacizumab

10. FOLFOX4 + bevacizumab N=350
Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC Study Design and Drugs
Protocol amended to 2x2 placebo-controlled design after bevacizumab Phase III data1 became available (N=1,401) 1Hurwitz H., et al. Proc ASCO 2003;22 (Abstract 3646)
XELOX + placebo N=350
FOLFOX4 + placebo N=351
XELOX + bevacizumab N=350
FOLFOX4 + bevacizumab N=350
XELOX N=317
FOLFOX4 N=317
Recruitment June 2003–May 2004
Recruitment Feb 2004–Feb 2005
Initial 2-arm open-label study (N=634)
OX = oxaliplatin; LV = leucovorin; BV = bevacizumab; PL = placebo; 5-FU = 5-fluorouracil
XELOX + bevacizumab/placebo: 21-day cycle D1 D2
D15
Rest
Oral capecitabine 1,000 mg/m2 BID
BV or PL
7.5mg/kg IV 30–90 min
OX 130mg/m2 IV 2 h
D21
FOLFOX4 + bevacizumab/placebo: 14-day cycle
OX 85mg/m2
IV 2 h
5mg/kg IV 30–90 min
5-FU 600mg/m2 IV 22 h D3
LV 200mg/m2
5-FU 400mg/m2 IV bolus
Cassidy et al. ESMO Oral Presentation

11. Primary Objective Achieved Based on ITT
Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC PFS XELOX Non-inferiority
FOLFOX/FOLFOX + placebo/FOLFOX + bevacizumab N = 1,017; 826 events XELOX/XELOX + placebo/XELOX + bevacizumab N = 1,017; 813 events
Primary Objective Achieved Based on ITT
Roche Medical Affairs. All rights reserved.
Cassidy et al. ESMO Oral Presentation

12. Phase III Trial of XELOX vs
Phase III Trial of XELOX vs. FOLFOX4 + Bevacizumab or Placebo in First-line mCRC PFS Superiority of Bevacizumab + CT
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
P =
Primary Objective Achieved
XELOX Subgroup FOLFOX Subgroup
HR = 0.77 [97.5% CI 0.63–0.94] (ITT)
P =
XELOX + placebo N = 350; 270 events XELOX + bevacizumab N = 350; 258 events
HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
P =
FOLFOX + placebo N = 351; 277 events FOLFOX + bevacizumab N = 349; 255 events
FOLFOX + placebo/XELOX + placebo N = 701; 547 events FOLFOX + bevacizumab/XELOX+ bevacizumab N = 699; 513 events
Roche Medical Affairs. All rights reserved.
Cassidy et al. ESMO Oral Presentation

13. Maindrault-Goebel F, et al.
ASCO 2007, Abstract 4013
Final Results of OPTIMOX-2 - A Large Randomized Phase II Study of Maintenance Therapy or Chemotherapy-free Intervals (CFI) After FOLFOX in Patients with Metastatic Colorectal Cancer (Mrc): A GERCOR Study
Maindrault-Goebel F, et al.

14. OPTIMOX Studies OPTIMOX-1: OPTIMOX-2: Maintenance therapy (N = 620)
FOLFOX 4 until progression
FOLFOX 7
sLV5FU2
OPTIMOX-2:
Chemotherapy-free interval
(N = 202)
mFOLFOX 7
Tournigand et al. J Clin Oncol. 2006;24:394.
Maindrault-Goebel et al. ASCO Abstract 4013.

15. Progression-free Survival10 20 30 40 50 60 70 80 90
100
0.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX1 median 36 weeks
OPTIMOX2 median 29 weeks
Weeks
Probability
P = 0.08

16. Overall Survival 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
OPTIMOX1 median 26 months
OPTIMOX2 median 19 months
P =
Months
Probability

17. ASCO 2008, Abstract 4010
Intermittent Oxaliplatin (Oxali) Administration and Time-to-Treatment-Failure (TTF) in Metastatic Colorectal Cancer (mCRC): Final Results of the Phase III CONcePT Trial
Grothey A., et al.

18. CONcePT Trial Design Patients with mCRC (N = 140)
Continuous Oxaliplatin*
mFOLFOX7 + bevacizumab +placebo
(N = 34)
mFOLFOX7 + bevacizumab +Ca2+/Mg2+
(N = 35)
Intermittent Oxaliplatin†
mFOLFOX7 + bevacizumab + placebo
(N = 36)
mFOLFOX7 + bevacizumab + Ca2+/Mg2+
*Treat to failure.
†8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin.
Grothey A, et al. ASCO Abstract 4010.

19. CONcePT: Kaplan-Meier Estimate of TTF
Proportion of Patients
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Months
N at risk
CO:
IO:
TTF (mos)
95% CI CO IO
4.2
5.6
3.7–5.5
4.7–7.0
Unstratified (IO relative to CO), P = .002*
Stratified by CaMg (IO relative to CO), P = .003*
* Log rank test
Continuous Oxaliplatin (CO)
Intermittent Oxaliplatin (IO)
Censored data
Grothey A, et al. ASCO Abstract 4010.

20. CONcePT: Kaplan-Meier Estimate of PFS
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Proportion of Patients
1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Months
N at risk
CO:
IO:
Unstratified (IO relative to CO), P = .044*
Stratified by CaMg (IO relative to CO), P = .030*
* Log rank test CO
PFS (mos)
95% CI IO
7.3
12.0
6.9–NE
8.2–NE
Continuous Oxaliplatin (CO)
Intermittent Oxaliplatin (IO)
Censored data
Grothey A, et al. ASCO Abstract 4010.

21. ASCO 2007, Abstract 4000
Randomized Phase III Study of Irinotecan and 5-FU/FA With or Without Cetuximab in the First-line Treatment of Patients with Metastatic Colorectal Cancer (mCRC): The CRYSTAL Trial
Van Cutsem E, et al.

22. Irinotecan and 5-FU/FA ± Cetuximab The CRYSTAL Trial
Study Design
Cetuximab + FOLFIRI
Cetuximab IV 400 mg/m2 on day 1,
then 250 mg/m2 weekly
+ irinotecan (180 mg/m2)
+ 5-FU (400 mg/m2 bolus +
2400 mg/m2 as 46-hr
continuous infusion)
+ FA every 2 weeks
EGFR-expressing
Metastatic CRC R
Stratification factors:
Regions
ECOG PS
Populations
Randomized patients: N = 1,217
Safety population: N = 1,202
ITT population: N = 1,198
FOLFIRI
Irinotecan (180 mg/m2)
+ 5-FU (400 mg/m2 bolus +
2400 mg/m2 as 46-hr
continuous infusion)
+ FA every 2 weeks
Van Cutsem E, et al. ASCO Abstract 4000.

23. CRYSTAL Trial Progression Free Survival
Van Cutsem E, et al. ASCO Abstract 4000.

24. Cell Response to Signaling
What is the Role of the Epidermal Growth Factor Receptor (EGFR) in Cancer?
Proliferation
Metastasis
Angiogenesis
Apoptosis Resistance
Shc
PI3-K
Raf
MEKK-1
MEK
MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Cell Membrane
EGFR
Signaling Proteins
Cell Response to Signaling

25. Pathway vs. Network Signaling
Network “Chaotic”
Pathway “Newtonian”
A. Friedman and N. Perrimon, Cell 128, January 26, 2007

26. ASCO 2008, Abstract 2
KRAS Status and Efficacy in the First-line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) Treated with FOLFIRI With or Without Cetuximab: The CRYSTAL Experience
Van Cutsem E, et al.

27. CRYSTAL PFS in Patients with KRAS Wild-type
0.0
0.2
0.4
0.6
0.8
1.0 4 8 12
Months
PFS Estimate 18
Cetuximab + FOLFIRI
FOLFIRI
KRAS wild-type (N = 348) HR = 0.68: P = .017 2 6 10 14
Median PFS Cetuximab + FOLIFIRI: 9.9 months
Median PFS FOLIFIRI: 8.7 months
0.1
0.3
0.5
0.7
0.9 16
1-year PFS rate: 43%
1-year PFS rate: 25%
Van Cutsem E, et al. ASCO Abstract 2. Reproduced with permission.

28. Relating KRAS Status to Efficacy Progression Free Survival
Cetuximab + FOLFIRI HR = 0.63; P = mPFS wild-type (N = 172): 9.9 months mPFS mutant (N = 105): 7.6 months
FOLFIRI HR = 0.97; P = mPFS wild-type (N = 176): 8.7 months mPFS mutant (N = 87): 8.1 months
0.5
1.0
0.4
0.3
0.2
0.1
0.0
0.6
0.7
0.8
0.9 8 2 4 6 10 16
PFS Estimate
Months
Cetuximab + FOLFIRI wild-type
Cetuximab + FOLFIRI mutant 12 14
FOLFIRI wild-type
FOLFIRI mutant

29. ASCO 2008, Abstract 4000
KRAS Status and Efficacy of First-line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) with FOLFOX With or Without Cetuximab: The OPUS Experience
Bokemeyer C. et al.

30. Cetuximab + CT in KRAS Wild-Type: Data Consistency
Response rate (%) 59 37 10 20 30 40 50 60 70
CRYSTAL
(N = 540)
OPUS1 (N = 233) 43 61
FOLFIRI
FOLFOX
Cetuximab
+ FOLFIRI
Cetuximab + FOLF0X
CRYSTAL - KRAS wild-type: HR = 0.68
P = 0.017
32% risk reduction for progression
OPUS - KRAS wild-type: HR = 0.57
P = 0.016
43% risk reduction for progression
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 2 4 6 8 12 14 16 18
Months
PFS estimate
1Bokemeyer C. et al, ASCO Abstract 4000.

31. ECCO 2007, Abstract 0007
Analysis of KRAS Mutations in Patients with Metastatic Colorectal Cancer Receiving Panitumumab Monotherapy
Amado RG, et al.

32. KRAS as a Biomarker for Panitumumab Response in mCRC
Pts with mutant KRAS receiving panitumumab had 0% RR and SD similar to BSC alone (12% vs 8%)
PFS log HR significantly different depending on K-ras status (P < .0001)
Percentage decrease in target lesion greater in patients with wild-type KRAS receiving panitumumab
Patients With Mutant KRAS
Mean in Wks
Stratified log rank test: P < .0001
115/124 (93)
Patients With Wild-type KRAS
1.0
0.9
Proportion With PFS
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1 2 4 6 8 10
Events/N (%)
Median in Wks
Pmab + BSC
BSC alone
114/119 (96)
12.3
7.3
19.0
9.3
HR: 0.45 (95% CI: ) 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Weeks
76/84 (90)
95/100 (95)
7.4
9.9
10.2
HR: 0.99 (95% CI: )
Amado RG, et al. ECCO Abstract 0007.

33. Q: Is More Always Better?

34. 3 Drugs: 5-FU/LV, irinotecan, oxaliplatin
Correlation Between Survival and Percentage of Patients Receiving Three Drugs in Phase III Trials
3 Drugs: 5-FU/LV, irinotecan, oxaliplatin .
Grothey A, et al. J Clin Oncol. 2005;23:

35. FOLFOXIRI vs. FOLFIRI
JCO 2007

36. Open-label, Phase II-III Trial of Irinotecan or
Oxaliplatin-based CTX + Bevacizumab ± Panitumumab in First-line mCRC: PACCE Trial
Discontinued 3/2007 due to significantly inferior PFS
in planned interim analysis
OS significantly inferior in unplanned analysis
ECOG score
Prior adjuvant TX
Disease site
Oxaliplatin doses/ Irinotecan regimen
Number of metastatic organs
Oxaliplatin-based CTXa
Irinotecan-based CTXa
Oxaliplatin/CTX + Bevacizumab + Panitumumab
N = 407
Oxaliplatin/CTX + Bevacizumab
N = 405
Irinotecan/CTX +
Bevacizumab +
Panitumumab
N = 68
Irinotecan/CTX + Bevacizumab
N = 67
Phase III
Phase II
RANDOM I Z A T I ON
aThe choice of either Ox/CTX or Irino/CTX was at the oncologist’s discretion
Hecht et al. World Congress on GI Cancer, 2007

37. ECCO 2007, Abstract 3000
Randomised Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) With or Without Cetuximab in Advanced Colorectal Cancer (ACC), The CAIRO-2 Study of the Dutch Colorectal Cancer Group (DCCG) an Interim Safety Analysis
Tol J, et al.

38. Capecitabine Oxaliplatin Bevacizumab
CAIRO-2 Study Design
Arm A
Arm B
Randomization
Capecitabine Oxaliplatin Bevacizumab
Capecitabine
Oxaliplatin
Bevacizumab
Cetuximab
Dutch Colorectal Cancer Group (DCCG)

39. CAIRO-2 Interim Safety Analysis
Adverse Event, %
Arm A:
Capecitabine, Oxaliplatin, Bevacizumab (N = 197)
Arm B:
Capecitabine, Oxaliplatin, Bevacizumab, Cetuximab (N= 192)
Gastrointestinal, grade 3/4
Diarrhea 20 23
Nausea 9 6
Vomiting 8
Cardiovascular, grade 3/4
Hypertension 7 4
Thromboembolic event
Grade 3/4 neurotoxicity
Grade 3/4 allergic reaction 3
Grade 3/4 bleeding 2 1
Tol J, et al. ECCO Abstract 3000.

40. Progression-free Survival
Arm A (without cetuximab) 10.7 months ( )
Arm B (with cetuximab) 9.6 months ( )
HR: 1.21
P = 0.018 6 12 18 24 30
Months from randomization
0.0
0.2
0.4
0.6
0.8
1.0
Progression free survival probability
Arm A (without cetuximab)
Arm B (with cetuximab)
Dutch Colorectal Cancer Group (DCCG)

41. KRAS Genotyping (N = 501) Wildtype N = 305 (61%) Mutation
P value
Arm A
152 (50%)
103 (53%)
Arm B
153 (50%)
93 (47%)
Median PFS (months)
10.7
12.5
0.92
10.5
8.6
0.47
0.10
0.043
Dutch Colorectal Cancer Group (DCCG)

42. CALGB/Intergroup Front-line Trial
FOLFOX or
FOLFIRI
Bevacizumab
Cetuximab
Bevacizumab/

43. Adjuvant Oxaliplatin Mosaic Trial (3-year Data)
FOLFOX-4 (1,100 pts)
LV5FU2 (1,100 pts)
T3, T4 N0 = 40% (87% vs 84%)
Tx, N1, N2 = 60% (72% vs 65%)
77.8%
72.9%
P < 0.01 R A N D
OM I Z A T I O
DFS Endpoint

46. ASCO 2008 Abstract LBA4005
A Phase III Trial Comparing FULV to FULV + Oxaliplatin in Stage II or III Carcinoma of The Colon: Survival Results of NSABP Protocol C-07
Wolmark N, et al.

47. Survival Results of NSABP C-07
FULV
5-FU 500 m2 IV bolus weekly x 6;
LV 500 mg/m2 IV weekly x 6, each
8-week cycle x 3
(N = 1,209)
FLOX
FULV + oxaliplatin 85 mg/m2 IV on
Weeks 1, 3, and 5 of each 8-week
cycle x 3
(N = 1,200)
Patients with stage II
or III carcinoma of the colon
stratified by number
of positive lymph nodes
N = 2,409
Primary endpoint: DFS
Wolmark N, et al. ASCO Abstract LBA4005.

48. C-07: Disease-Free Survival20 40 60 80
100 2 4 6
3-years 5-years 1 3 5 7 10 30 50 70 90
P = .002
HR: 0.81 [ ]
FLOX 76.1% 69.4%
FULV 71.5% 64.2%
∆ 4.6% 5.2%
FLOX (N = 1,200)
FULV (N = 1,209)
Years
Proportion of Patients (%)
Wolmark N, et al. ASCO Abstract LBA4005.

49. C-07: Overall Survival P = .06 HR: 0.85 [0.72-1.01] FLOX (N = 1,200)20 40 60 80
100 2 4 6
D(n) 3y 5y 1 3 5 7 10 30 50 70 90
FLOX % 77.7%
FULV % 73.5%
∆ % 4.2%
P = .06
HR: 0.85 [ ]
FLOX (N = 1,200)
FULV (N = 1,209)
Years
Proportion of Patients (%)
Wolmark N, et al. ASCO Abstract LBA4005.

50. C-07: Overall Survival Hazard Ratios
FLOX Better
FULV Better
0.5
0.75 1
1.25
1.5
1.75
Overall
< 65 yr
≥ 65 yr
Stage II
Stage III
Wolmark N, et al. ASCO Abstract LBA4005.

51. ASCO 2008 Abstract 4008
Confirmation of Deficient Mismatch Repair (Dmmr) as a Predictive Marker for Lack of Benefit from 5-FU Based Chemotherapy in Stage II and III Colon Cancer (CC): A Pooled Molecular Reanalysis of Randomized Chemotherapy Trials
Sargent D. J., et al.

52. MSI-H and Adjuvant 5-FU Sargent, ASCO 2008

53. MSI-H and Adjuvant 5FU Sargent, ASCO 2008

54. E5202: Stage II Colon Cancer
mFOLFOX6
vs.
mFOLFOX6 +
bevacizumab qow
Tumor block risk assessed based on biology (18q/MSI)
High risk (MSS and 18q LOH)
Low risk (MSI + or no loss 18q)
Observation
Surgery
Accrual goal: 3,125

55. Where We Are Today Adjuvant First-line Second-line Third-line 5-FU/LV
FOLFOX
Capecitabine
First-line
CPT-11
Oxaliplatin
Bevacizumab
Second-line
Cetuximab
Third-line
Cetuximab/ CPT-11
Panitumumab

56. Colon Cancer is More than One Disease
50-60%
40-50%
KRAS Wild Type
KRAS mutant
+ EGFR Agents
15-20%
– EGFR Agents
80-85%
MSI-High
MSS
? No 5-FU

57. Clinical Review of Current Treatment Strategies for Colorectal Cancer
Oncology Journal Club
Clinical Review of Current Treatment Strategies for Colorectal Cancer
Closing Comments