A Report from ASCO-GI 2008 and ASCO 2007

Up-to-Date Review of the Treatment of Adjuvant Colorectal Cancer

Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

History of Adjuvant Therapy of Colon Cancer • 5-FU/lev superior to surgery alone • 5-FU/LV superior to surgery alone • 5-FU/LV superior to 5 FU/lev • 6- and 12-month treatment cycles equivalent • Lev unnecessary • LV5FU2 and monthly bolus equivalent • High-dose and low dose LV equivalent • Monthly and weekly treatment equivalent

1990 1994 1998 2002

Moertel et al.

Ann Intern Med.

1995;122:321.

Francini et al.

Gastroenterol.

1994;106:899.

Wolmark et al.

Proc Am Soc Clin Oncol.

1996;15:205. Abstract O’Connell et al.

J Clin Oncol.

1998;16:295.

Haller et al.

Proc Am Soc Clin Oncol.

1998;17:256a. Abstract 982.

Andre et al.

Proc Am Soc Clin Oncol.

2002. Abstract 529.

3 Year DFS vs 5 Year OS

0.8

0.75

May 05, 2004: ODAC recommends 3-yr DFS as new regulatory endpoint for FULL approval in adjuvant colon cancer 0.7

0.65

0.6

0.55

0.5

0.5

P

0.55

= 0.90

5-yr OS = 0.0002 + 0.998* 3-yr DFS 0.6

0.65

Disease Free Survival 0.7

0.75

0.8

Sargent, et al.

J Clin Oncol

2005;23:8664 –8670.

5-FU: Historical Standard in the Adjuvant Setting

Observation 1 5-FU/high-dose LV (Mayo) 2 6 months 5-FU/LV (Mayo) 1 5-FU/low-dose LV (Mayo) 3 LV5FU2 4 55 Stage II and III colon cancer patients 60 65 70 3-year disease-free survival (%) 75 1 IMPACT Investigators,

Lancet

1995;345:939 –44.

2 Wolmark N, et al.

J Clin Oncol

1993;11:1879 –87.

3 QUASAR Group.

Lancet

2000;355:1588 –96.

4 André T, et al.

J Clin Oncol

2003;21:2896 –903.

Beyond 5-FU in the Adjuvant Setting

Completed studies: • • Oxaliplatin (MOSAIC, NSABP C-07) Irinotecan (CALGB 89803, ACCORD-2, PETACC-3) • Capecitabine (X-ACT) Ongoing studies: • CAPOX (XELOXA) • Bevacizumab (NSABP C-08, AVANT, E5202) • Cetuximab (N0147, PETACC-8)

MOSAIC: Study Design

N = 2,246

Enrollment:Oct 1998 –Jan 2001 (146 centres; 20 countries)

• Completely resected colon cancer • Stage II, 40%; Stage III, 60% • Age 18–75 years • KPS ≥60 • No prior chemotherapy (N =1,123) FOLFOX4 (LV5FU2 + oxaliplatin 85 mg/m²)

R

(N =1,123) LV5FU2 Primary end-point: disease-free survival Secondary end-points: safety, overall survival LV5FU2, Leucovorin 200 mg/m 2 iv over 2 hours followed by 5-fluorouracil 400 mg/m 2 bolus and 5-fluorouracil 600 mg/m 2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1

Disease-free Survival: ITT

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 0 FOLFOX4 Events 304/1,123 (27.1%) LV5FU2 360/1,123 (32.1%) HR [95% CI]: 0.80 [0.68

–0.93] 6 Data cut-off: June 2006 12

5.3%

18 24 30 36 42 Disease-free survival (months) 48

P

= 0.003

FOLFOX4 LV5FU2 54 60 5.9% De Gramont A, et al. ASCO 2007. Abstract #4007.

1.0

Disease-free Survival: Stage II and Stage III Patients

P

= 0.258

0.9

0.8

P

= 0.005

0.7

3.8%

0.6

0.5

7.5%

0.4

0.3

0.2

0.1

HR [95% CI]

P

- value Stage II 0.84 [0.62

–1.14] 0.258

Stage III 0.78 [0.65

–0.93] 0.005

0 0 6 Data cut-off: June 2006 12 18 24 30 36 Months 42 48 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 54 60 66 72 De Gramont A, et al. ASCO 2007. Abstract #4007.

MOSAIC: Disease-free Survival – Final Update

Data cut-off: June 2006 ITT (overall population) Stage III Stage II High-risk stage II N = 576 Low-risk stage II N = 323 5-year DFS % FOLFOX4 73.3

66.4

83.7

82.1

86.3

LV5FU2 67.4

58.9

79.9

74.9

89.1

HR [95% CI] 0.80

[0.68

– 0.93] 0.78

[0.65

– 0.93] 0.84

[0.62

– 1.14] 0.74

[0.52

– 1.06] 1.22

[0.66

–2.26]

P

- value 0.003

0.005

0.258

— — De Gramont A, et al. ASCO 2007. Abstract #4007.

“High-risk” Stage II Colon Cancer

• Clinico-pathological parameters (MOSAIC) - T4 tumors - Obstruction/perforation - Lymphatic or vascular invasion - Undifferentiated histology - Less than 10 (12) Ln examined • Molecular parameters - LOH 18q - MSS - Other?

De Gramont A, et al. ASCO 2007. Abstract #4007.

Second cancer

Long-term Safety

(% patients) FOLFOX 5.3

LV5FU2 5.7

Peripheral Sensory Neuropathy Data cut-off: January 2007

60 50 40 30 20 10 0 Grade 1 Grade 2 Grade 3 Evaluable patients

N = 811 Grade 0 Grade 1 Grade 2 Grade 3 84.3% 12.0% 2.8% 0.7%

During Tx 6 months 1-year 2-year 3-year 4-year

De Gramont A, et al. ASCO 2007. Abstract #4007.

Overall Survival: ITT

1.0

0.9

P

= 0.057

0.8

0.7

0.6

2.6%

6 yrs: 78.6% vs. 76.0% 0.5

0.4

0.3

0.2

Events FOLFOX4 243/1,123 (21.6%) LV5FU2 279/1,123 (24.8%) HR [95% CI]: 0.85 [0.72

–1.01] FOLFOX4 LV5FU2 0.1

0 0 6 12 18 24 30 36 42 48 54 60 66 Overall survival (months) Data cut-off: January 2007 72 78 84 90 96 De Gramont A, et al. ASCO 2007. Abstract #4007.

Overall Survival: Stage II and Stage III

1.0

0.9

0.8

0.7

0.6

P P

= 0.996

= 0.029

0.1% 4.4%

0.5

0.4

0.3

0.2

0.1

HR [95% CI] Stage II 1.00 [0.71

–1.42] Stage III 0.80 [0.66

–0.98] FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III 0 0 6 12 18 24 30 36 42 48 54 60 66 Overall survival (months) Data cut-off: January 2007 72 78 84 90 96 De Gramont A, et al. ASCO 2007. Abstract #4007.

Take-Home Messages MOSAIC

• • • DFS benefit for FOLFOX is maintained over 5 years Significant OS benefit for stage III, but NOT for unselected stage II patients • “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear • No increased rate of secondary cancers, but more deaths of cancer in FOLFOX group (21 vs. 11) Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)  FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

NSABP C-07

N = 2,407 FU 500 RP LV 500

x3

R

FU 500 LV 500 FLOX Endpoint 3yr DFS OHP 85 2hr Week 1 2 3 4 5 6 7 8 Accrual 02/00 - 11/02 Kuebler JP, et al.

J Clin Oncol

2007;25:2198 –2204.

1 0.9

C-07: DFS

Ev # 3yr DFS FLOX 272 76.5% FULV 332 71.6% 0.8

0.7

0.6

0.5

0

P < 0.004

HR: 0.79 [0.67 – 0.93]

1 2

21 % risk reduction

3 4

Kuebler JP, et al.

J Clin Oncol

2007;25:2198 –2204.

C-07 and MOSAIC - Oxaliplatin benefit 3y DFS Δ HR C-07 76.5 % 4.9 % 0.79

MOSAIC

77.9 % 5.1 % 0.77

De Gramont A, et al. ASCO 2007. Abstract #4007.

Kuebler JP, et al.

J Clin Oncol

2007;25:2198 –2204.

Cross-Study Comparison Toxicity: MOSAIC / C-07

Gr 3-4 Neutropenia FOLFOX 4 (MOSAIC) 41% (2% neut. fever) 11% FLOX (C-07) 4% (?) 38% Gr 3-4 Diarrhea Gr 3 Neuro (cum oxali) All Cause Mortality 12.4% (1,020 mg/m 2 ) 0.5% 8% (765 mg/m 2 ) 1% De Gramont A, et al. ASCO 2007. Abstract #4007.

Kuebler JP, et al.

J Clin Oncol

2007;25:2198 –2204.

Abstract 347

Diabetes Mellitus and the Incidence and Time to Onset of Oxaliplatin-Induced Peripheral Sensory Neuropathy (PSN) in Patients with Colorectal Cancer: A Pooled Analysis of Three Randomized Studies Ramanathan RK, André T, Rothenberg ML, de Gramont A, Tournigand C, Goldberg RM, Gupta S

Pooled Analysis

• • Data from 3 randomized clinical trials including FOLFOX4 • EFC3313 (MOSAIC): 5-FU and LV (LV5 –FU2) + oxaliplatin as adjuvant therapy in CRC • EFC4584: Three-arm study of LV5 –FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC • EFC2962: Phase II/III study of LV5FU2 + oxaliplatin first-line PSN data from the overall study population with or without diabetes were analyzed for: • • Incidence and time to onset of PSN Trends indicating clinically relevant differences in the incidence and severity of PSN Ramanathan 2008 ASCO GI abstract # 347

Incidence and Severity of PSN

PSN Grade 1 Grade 2 Grade 3 All Patients (N = 1,585) 45.2

28.4

13.0

DM Patients (N = 135) 46.7

26.7

12.6

Ramanathan 2008 ASCO GI abstract # 347

Probability of PSN by Cumulative Dose

EFC3313: any grade EFC3313: grade ≥ 3 EFC4584: any grade EFC4584: grade ≥ 3 Ramanathan 2008 ASCO GI abstract # 347

Conclusions FOLFOX in Diabetics

• In CRC trials with FOLFOX4 no difference in: - the probability of developing PSN nor - the severity of grade between all treated patients and the subset with diabetes mellitus was observed • This data suggests patients with diabetes mellitus have no increased risk of developing cumulative neurotoxicity Ramanathan 2008 ASCO GI abstract # 347

CALGB 89803: DFS and OS Not Improved with IFL in Stage III Colon Cancer 1.0

1.0

0.8

0.6

0.8

0.6

0.4

0.4

0.2

FU/LV IFL 0.2

FU/LV IFL 0 0 1 2 3 Years 4 5 6 7 FU/LV IFL N 629 635 Events 227 248

P

(stratified) = 0.85 (1-sided) FU/LV IFL OS = overall survival; IFL = irinotecan, 5-FU plus leucovorin 0 0 1 2 3 Years 4 5 N 629 635 Events 171 181

P

(stratified) = 0.74 (1-sided) 6 7 Saltz L, et al.

J Clin Oncol

2007;25:3456 –61

ACCORD-02 Irinotecan in High-risk Stage III Colon Cancer • • • 400 patients with resected high risk stage III colon cancer (N2 or N1 with occlusion/perforation) Accrual completed in Spring 2002 Stratified: - Center - N stage - Delay to chemotherapy - Age R A N D O M I Z E FOLFIRI: • LV5FU2 • CPT-11 180 mg/m 2 on day 1 LV5FU2 12 cycles planned Ychou M, et al.

J Clin Oncol

2005;(Suppl. 16):246s (Abstract 3502)

1.0

0.8

0.6

0.4

0.2

0 0 ACCORD-02: DFS Not Improved with FOLFIRI in High-risk Colon Cancer LV5FU2 FOLFIRI 3-year DFS (%) 60 51 HR = 1.19 (95% CI: 0.90

–1.59)

P

= 0.22

1 2 3 Years 4 5 6 Ychou M, et al.

J Clin Oncol

2005;(Suppl. 16):246s (Abstract 3502)

PETACC-3: Study Design

Stratification: • Stage II vs. III • Center

R A N D O M I Z A T I O N F IF Day 1 Day 1 Day 2 Day 2

LV5FU2 FA 200 mg/m 2 5-FU bolus 400 mg/m 2 5-FU CI 600 mg/m 2 Irinotecan 180 mg/m LV5FU2 as above 2 Repeat q 2 weeks for 12 Cycles 210 pts treated with AIO regimen ± irinotecan within given centers will be presented later.

Van Cutsem E, et al.

J Clin Oncol

2005; 23:(Suppl. 16):3s (Abstract LBA8)

DFS RFS

PETACC-3: Results Stage III

HR (95% CI) 0.89

(0.77-1.11) 0.86

(0.75-1.00)

P

-value 0.091

0.045

Van Cutsem E, et al.

J Clin Oncol

2005; 23:(Suppl. 16):3s (Abstract LBA8)

PETACC-3: DFS not significantly improved with FOLFIRI in stage III

1.0

0.9

0.8

FOLFIRI 5-FU/LV N 1,044 1,050 3-year DFS (%) 63.3

60.3

0.7

0.6

0.5

HR=0.89

(95% CI: 0.77

–1.11)

P

= 0.091

0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Months DFS = disease free survival HR = hazard ratio; CI = confidence interval Van Cutsem E, et al.

J Clin Oncol

2005; 23:(Suppl. 16):3s (Abstract LBA8)

X-ACT Trial - Design

Recruitment 1998 –2001 Capecitabine 1 250mg/m 2 twice daily, d1 –14, q21d N = 1,004 Chemo naïve stage III colon cancer, resection  8 weeks 24 weeks Bolus 5-FU / LV 5-FU 425mg/m 2 plus LV 20mg/m 2 , d1 –5, q28d N = 983 Endpoints - DFS - RFS - overall survival (OS) - tolerability (NCIC CTG) - pharmacoeconomics - quality of life (QoL) Twelves et al.,

N Engl J Med

2005

1.0

X-ACT: 5-year DFS

(median follow-up 6.8 years) Capecitabine 5-FU/LV N 1,004 983 5-year DFS (%) 60.8

56.7

0.8

0.6

0.4

0.2

HR = 0.88 (95% CI: 0.77

NI margin 1.20

–1.01) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Test of non-inferiority

P

< 0.0001

Test of superiority

P

= 0.0682

78 84 90 96 102 ITT population ITT (intent-to-treat) population; NI = non-inferiority Twelves C, et al.

Eur J Cancer Suppl

2007;5:1 (Abstract 1LB)

1.0

0.8

0.6

X-ACT: 5-year OS

(median follow-up 6.8 years) Capecitabine 5-FU/LV N 1,004 983 5-year OS (%) 71.4

68.4

0.4

0.2

HR = 0.86 (95% CI: 0.74

–1.01) NI margin 1.14

0 0 6 12 18 24 30 36 Test of non-inferiority

P

= 0.000116

Test of superiority

P

= 0.06

42 48 54 60 66 72 Months 78 84 90 96 102 ITT population Twelves C, et al.

Eur J Cancer Suppl

2007;5:1 (Abstract 1LB)

X-ACT: Improved Safety with Capecitabine 50 40 30 20 10 0

* *

Grade 3/4 adverse events Capecitabine (N = 993) 5-FU/LV (N = 974)

* *

*

P

< 0.001

HFS = hand foot syndrome Scheithauer W, et al.

Ann Oncol

2003;14:1735 –43

XELOXA: Phase III Trial of CAPOX in the Adjuvant Setting

Chemo/ radiotherapy-

naïve

stage III colon cancer R A N D O M I S A T I O N N = 944 CAPOX Capecitabine 1,000mg/m 2 Oxaliplatin 130mg/m 2 b.i.d. days 1 –15 day 1 q3w N = 942 Duration of therapy: 24 weeks Bolus 5-FU/LV Mayo Clinic or Roswell Park • Primary endpoint: disease-free survival Schmoll HJ, et al.

J Clin Oncol

2007;25:4217 –23

50

Adjuvant CAPOX: Toxicity Compared with FOLFOX and FLOX

Grade 3/4 Adverse Events 40 30 CAPOX 1 (N = 938) FOLFOX4 2 (N = 1,108) FLOX 3 (N = 1,200) 20 10 0

* * *

Cross-trial comparison *Not reported 1 Schmiegel WH, et al.

J Clin Oncol

2 2007;25(Suppl. 18):172s (Abstract 4034) André T, et al.

N Engl J Med

2004;350:2343 –51 3 Wolmark N, et al.

J Clin Oncol

2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)

Ongoing US Cooperative Group Trials Adjuvant Therapy of Colon Cancer

Intergroup N0147 Stage III colon cancer (N = 2,300) mFOLFOX6 6m mFOLFOX6 6m + Cetuximab 6m NSABP C-08 Stage II/III colon cancer (N = 2,400) mFOLFOX6 6m mFOLFOX6 6m + Bevacizumab 12m Accrual completed

Should Patients with Stage II Colon Cancer Receive Adjuvant Therapy?

• Direct evidence of randomized trials • Meta-analyses • Identification of “high-risk” patients

Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit*

Dukes’ B Dukes’ C No. of No. of Survival ARR Patients Survival ARR Patients At 3-years 85% 2.5% 8,000 65% 5.2% 3,400 At 4-years 80% 3.3% 5,800 58% 6.0% 2,800 At 5-years 75% 4.0% 4,700 50% 6.6% 2,400 Abbreviation: ARR = absolute risk reduction • For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C.

Buyse, Piedbois, 2001

QUASAR: Study Design

Clear indication for chemotherapy (N = 4,320) Colon or rectal cancer • Stage I-III • Complete resection with no evidence of residual disease No clear indication for chemotherapy (mainly stage II) (N = 3,239) * Prior to 10/1997 chemotherapy patients were randomized as in clear indication arm; after 10/1997 patients received 5-FU/low-dose LV.

R A N D O M I Z E 2 x 2 randomization to 5-FU with low- or high-dose LV and Lev or placebo Observation (N = 1,617) Chemotherapy (N = 1,622)* QUASAR Group,

Lancet

2007

QUASAR: Overall Survival in Patients with “no clear indication for chemo”

100 80 Observation (N = 1,622) Chemotherapy (N = 1,617) 60 5-yr OS difference: 2.9% 40 20 0 0

P

= .02

5-year OS, Observation = 77.4% vs Chemotherapy = 80.3% Relative risk = 0.83 (95% CI, 0.71-0.97) 1 2 3 4 5 Years 6 7 8 9 10 QUSAR group,

Lancet

2007

ASCO Guidelines 2004

• Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. • Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. • The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. • Patients with stage II disease should be encouraged to participate in randomized trials.

Benson et al.

J Clin Oncol

. 2004

“High-risk” Stage II Colon Cancer

• Clinico-pathological parameters • • • • • T4 tumors Obstruction/perforation Lymphatic or vascular invasion Undifferentiated histology Less than 10 (12) Ln examined • Molecular parameters • • • LOH 18q MSS Other?

Analysis of Molecular Markers in Patients with Stage III Colon Cancer Watanbe T, et al.

N Engl J Med

344(16);1196-1206, 2001

Colon Stage II – Adjuvant E5202: High Risk Stage II R e g is t e r Expect 2 weeks for tissue review High Risk • MSS + 18q LOH • MSI-L + 18q LOH Tumor block assessment for 18q/MSI N = 3,610 Low Risk • MSS, no 18q LOH • MSI-L, no 18q LOH • MSI-H +/- 18q LOH R mFOLFOX6 mFOLFOX6 + bevacizumab Observation

What is the Standard Adjuvant Therapy in Colon Cancer ?

• FOLFOX is the standard adjuvant therapy in stage III and high-risk stage II colon cancer • • • • Capecitabine (UFT,S1?) for patients who are not considered candidates for oxaliplatin Irinotecan-based adjuvant setting combinations are NOT options in the XELOX data eagerly awaited Bevacizumab and Cetuximab are under investigation