Colorectal Cancer: New Approaches

Daniel G. Haller, MD Professor of Medicine Abramson Cancer Center at the University of Pennsylvania Philadelphia, PA USA St. Louis, MO 10/1/04

Incidence of colorectal cancer in the U.S. and Western Europe 2003 (n~300,000) Stage I 24% Stage IV 22% Stage II Stage III 29% 26% Initially eligible for systemic therapy n~60,000 Eligible for adjuvant chemotherapy n~160,000 (55%)

Environmental Associates for Colorectal Cancer

Dietary Factors: Dietary Fiber Dietary Fat Red Meat Alcohol Folate Methionine Calcium and vitamin D Non-Dietary Factors: Body Mass Index Physical Activity Smoking Aspirin Endoscopy Use

Old Paradigm for Colorectal Cancer Patients

Preclinical stage Localized disease Advanced disease Early diagnosis S Adjuvant Rx CT 1 st -line Cure CT 2 nd -line S = Surgery CT = Chemotherapy

Key Therapeutic Agents in CRC: Historical Perspective

~ 1960: 5-FU is the cornerstone of first-line therapy in MCRC ~ 1985: Addition of LV (biochemical modulator) to 5-FU bolus regimens 1998: Irinotecan as single agent approved as second-line in CRC 2000: Irinotecan approved as first-line in CRC in bolus regimen (IFL) 2001: Capecitabine approved as first-line in CRC 2002: Oxaliplatin approved as second-line agent 2004: Oxaliplatin approved as first-line agent 2004: Introduction of biologics

– –

bevacizumab cetuximab

5-FU = 5-fluorouracil; MCRC = metastatic CRC; LV = leucovorin; IFL = irinotecan/5-FU/LV;

5-Fluorouracil; 5-FU

Irinotecan (CPT-11, Camptosar ®) C H 3 C H 2 N N O C O N Irinotecan hydrochloride N O H O O O C H 2 C H 3

•Topoisomerase I inhibitor

Phase III Trial of First-Line Irinotecan + 5-

M I Z E R A N D O

n=231

FU/LV

IFL

n=226 n=226

5-FU/LV Irinotecan monotherapy

End points: PFS OS PFS = progression-free survival; OS = overall survival.

Saltz et al.

N Engl J Med

. 2000;343:905.

Phase III Trial of First-Line Irinotecan + 5-FU/LV: Efficacy

PFS (mo)

5-FU/LV

4.3

IFL

7.0

P Value*

.004

Irinotecan

4.2

ORR (%) OS (mo) 21 12.6

39 14.8

<.001

.04

18 12.0

*

P

values comparing IFL with 5-FU/LV.

ORR = objective response rate.

Saltz et al.

N Engl J Med

. 2000;343:905.

Chemical Structure of Platinum Analogues

NH 3 Cl Diaminocyclohexane (DACH) carrier ligand NH 2 NH 2 Pt O O C C OXALATE hydrolysable ligand NH 3 O Pt NH 3 CISPLATIN Cl O O C O C NH 3 trans-l-diaminocyclohexane oxalatoplatinum OXALIPLATIN, Eloxatin ® Pt O CARBOPLATIN

Preclinical Synergy of Oxaliplatin and 5-FU

300 250 200 HT-29 colon tumor xenograft 150 D13 - Treatment 100 Control 5-FU 50 mg/kg Oxali 10 mg/kg Oxali 10 mg/kg + 5-FU 50 mg/kg 50 0 10 13 16 20 24 27 33 Days post tumor graft 35 40 45 Raymond et al. Anti Cancer Drugs. 1997.

Infusional 5-FU/LV Regimens

Oxaliplatin Irinotecan 400 400 FOLFOX4 85 FOLFOX6 100 mFOLFOX6 85 x 400 600 LV5FU2 q2w 600 x 2400 sLV5FU2 q2w 400 x 2400 sLV5FU2 q2w “Douillard” 180 FOLFIRI 180 m FOLFOX7 130 (85) x 2400 vsLV5FU2 q2w

IFL Failures

Oxaliplatin Second-Line Registrational Trial

n=272

R A N D O M I Z E

n=270 n=274 Infusional LV5FU2 FOLFOX4 Oxaliplatin

Primary end point: OS Secondary end points: TTP, ORR, safety

Rothenberg et al.

JCO 6/03

.

Oxaliplatin Second-Line Registrational Trial: Efficacy

TTP (mo)

5-FU/LV

2.6

FOLFOX4

5.6

P Value*

<.0001

Oxaliplatin

1.9

OS (mo) ORR (%) 8.7

0.7

9.8

9.6

.07

<.0001

8.1

1.1

% Relief from tumor related symptoms *

P

values for FOLFOX4 vs 5-FU/LV.

Rothenberg et al.

JCO 6/03

15 28 <.002

10

N9741 Phase III Trial of

First-line IFL vs FOLFOX4 vs IROX

Schema

R A N D O M I Z A T I O N N=245 N=246 N=250 Bolus IFL (5-FU/LV + Irinotecan) FOLFOX4 (5-FU/LV + Oxaliplatin) IROX (Irinotecan/Oxaliplatin)

Goldberg RN et al.

JCO

1/1/04 .

N9741: Safety Profile

Grade 3/4 Adverse Events* 50 45 40 35 30 25 20 15 10 5 0 14 4 11 Febrile neutropenia 29 12 25 Diarrhea 15 6 19 Nausea

P

 .002 for all comparisons of IFL and IROX vs FOLFOX.

*Observed in >10% of patients in any treatment arm.

Goldberg et al.

J Clin Oncol

. 2004;22:23.

13 4 23 Vomiting 22 8 8 IFL FOLFOX4 IROX 2 19 7 Infections Overall neuropathies

N9741 Phase III Trial of First-line IFL vs FOLFOX

Results

RR

IFL

31%

FOLFOX

45%

p value

0.002

Median Time to Progression (mo) Overall Survival (mo) 6.9

14.8

8.7

19.5

0.0014

0.0001

FOLFOX: Second-line approval in US 8/02; First line approval 2/04

Goldberg RN et al.

JCO

1/1/04 .

XELOX international phase II trial: first-line metastatic colorectal cancer

• Regimen recommended from phase I trial 1 • Male/female 64%/36%; median age 64 years 2 • n=96 • Overall response rate: 55%

Oxaliplatin 130mg/m 2 d1 Day 1 8 15 21 Capecitabine 1,000mg/m 2 twice daily Day 1 (pm) –15 (am) Rest Repeat cycle at day 22 1 D íaz-Rubio E, et al. Ann Oncol 2002;13:558–65 2 Van Cutsem E, et al. Proc Am Soc Clin Oncol 2003;22:255 (abst 1023)

Is There an Optimal Sequence in Therapy of Metastatic CRC?

• 5-FU, oxaliplatin, and irinotecan all have activity in first- and second-line settings • No compelling data exist to choose one sequence unless there is comorbid illness

The Evolution of Chemotherapy for CRC

50 45 40 35 30 25 20 15 10 5 0 BSC 5FU FU/LV Cape CIFU IFL FOLFIRI FOLFOX FOLFOX RR % median survival:mos

Pericyte PDGFr Imatinib VEGFr-1 PTK Endothelial Cell VEGFr-2 PTK VEGFr-3 PTK EGFr Gefitinib/Erlotinib COX-2 Cetuximab Trastuzumab Gefitinib/Erlotinib EGFr HER-2 Tumor Cell Imatinib PDGFr

Bevacizumab (Avastin ™) • A recombinant humanized anti-VEGF MAb – human IgG1 framework with antigen-binding regions from a murine MAb • Binds all forms of VEGF and prevents receptor binding • Effectively depletes circulating VEGF • Targets angiogenic components of tumor, stroma, and endothelial cells – Effect on drug delivery • Terminal half-life, 17-21 days

Phase III Study in Metastatic CRC: 5-FU/LV/CPT-11 +/- bevacizumab

• Previously untreated metastatic colorectal cancer • n=900

Previously untreated metastatic CRC 5-FU/LV/CPT-11 (Saltz regimen) 5-FU/LV/CPT-11/ bevacizumab Primary endpoint: survival Randomization 5-FU/LV/ bevacizumab

Bevacizumab (anti-VEGF) in First-line Therapy

• Phase III trial of irinotecan/5-FU/LV  in 815 CRC patients bevacizumab (BV)

IFL/Placebo IFL/BV

N ORR 412 35% Median Survival 15.6 mo PFS 6.3 mo 403 45% ( p=0.0029) 20.3 mo ( p=0.00003) 10.6 mo ( p=<0.00001) Hurwitz H et al.

Proc ASCO

. 2003;23 (abstr 3646).

Bevacizumab

• Approved by FDA 2.26.04

• 1 st line therapy with any IV 5-FU-based chemotherapy • 5 mg/kg Q2W dose • Safety – Hypertension – Perforation – Cardiovascular events

Cetuximab (C225, Erbitux ™)

• Chimeric monoclonal antibody to EGFR – ABX-EGF: fully humanized • Inhibits EGFR function and downstream signal transduction pathways, promoting apoptosis • Synergistic with chemotherapy and radiation O‘Dwyer PJ, Benson AB III.

Semin Oncol

. 2002;29(suppl 14):10.

“BOND” Trial

• Randomized Phase II trial in CPT 11-refractory CRC • Cetuximab+CPT-11 versus Cetuximab alone • 2:1 randomization, 300 pts • 1 o endpoint: response rate

Cetuximab in Irinotecan Refractory EGFR

+

Patients

Cetuximab Cetuximab + (n=111) Irinotecan (n=218)

11% 23% PR TTP 1.5 mo Overall Survival 6.9 mo 4.1 mo 8.6 mo Cunningham D et al.

NEJM 7/04

Van Laethem JL et al.

Proc ASCO

. 2003;23 (abstr 1058).

Cetuximab Approval

• 2/04 • For CPT-11 failures, in combination with CPT-11 • Monotherapy, for CPT-11 “intolerant” patients • EGFR status known ???

• Role in 1 st line therapy?

Phase III Trials

First-line Metastatic Disease

“Dealer’s choice” Chemotherapy

mFOLFOX6 FOLFIRI XELOX XELIRI ? US TRIAL 2004 A T I O N R A N D O M I Z Cetuximab Bevacizumab Bevacizumab + Cetuximab

The future of treatment of colon cancer

• Cost: Shrag, NEJM, 7/2004 – Average patient with 1 st line FOLFOX+ bevacizumab (8 months) followed by CPT 11 + cetuximab (4 months)= $161,000 USD

Adjuvant Therapy of Colon Cancer 1990 5-FU/lev better than surgery alone 1994 5-FU/LV better than surgery alone 1998 5-FU/LV better than 5-FU/lev 1998 6 months = 12 months 1998 Levamisole unnecessary 1998 HDLV = LDLV 1998 Weekly = monthly 2002 LV5FU2 = monthly bolus

Adjuvant Therapy of Colon Cancer 1990 5-FU/lev better than surgery alone 1994 5-FU/LV better than surgery alone 1998 5-FU/LV better than 5-FU/lev 1998 6 months = 12 months 1998 Levamisole unnecessary 1998 HDLV = LDLV 1998 Weekly = monthly 2002 LV5FU2 = monthly bolus

CRC: AJCC 6 th Edition Staging Guidelines

• The AJCC 6 th edition staging manual refined stages II and III of the TNM system: – Smooth nodules in fat are considered LNs – Stage II divided into IIA (T 3 ) and IIB (T 4 ) – Stage III divided into • IIIA (T 1-2 N 1 M 0 ) • IIIB (T 3-4 N 1 M 0 ) • IIIC (T Any N 2 M 0 ) – N 2 denotes metastases to 4 or more regional lymph nodes American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 6th Edition (2002).

Revised, node-positive TNM classification for Stage III CRC (n=50,042) IIIA: T1/2, N1 Observed 5-year survival (%) 70 59.8% 60 50 40 30 20 10 0 IIIA IIIB: T3/4, N1 p<0.0001

42.0% IIIB Node-positive subgroups IIIC: Any T, N2 27.3% IIIC Greene et al (2002)

Model-Derived Estimates of 5 year DFS (%) with Surgery plus Adjuvant Therapy T stage Low Grade High Grade Nodal Status 0 nodes 1-4 nodes > 5 nodes T4 T1-T2 T3 T4 T1-T2 T3 T4 S 63 71 53 37 51 27 13 +AT 82 74 81 66 53 64 44 27 S 57 67 46 30 44 21 9 +AT 79 70 77 61 46 59 37 21

Adjuvant Therapy for Stage II Colon Cancer

?

CPT-11 , Oxalii FU/LV Surgery

Adjuvant Therapy for Stage II Colon Cancer: Cancer Care Ontario Metaanalysis

• Data: 62 randomized trials; 11 metaanalysis – Primary analysis based on subset of 3586 pts in whom deaths in pts with stage II disease were provided – OR: 0.82 (95% CI 0.67-1.01; p=0.07) • ASCO Guidelines : 8/15/04

JCO

Adjuvant Therapy for Stage III Colon Cancer

?

?

?

CPT-11 OXALI FU/LV Surgery

Extending Benefit in

over

Stage II/III colon cancer

• Do combination therapies offer advantages 5-FU alone?

– oxaliplatin-based regimens: MOSAIC, NSABP C0-7 – irinotecan-based regimens: CALGB, PETACC-3/V-307, FFCD/FNCLCC • Can convenience of administration be improved?

– replace 5-FU with capecitabine • Can we further improve results? The role of biologics: – anti-EGFR (cetuximab) – anti-VEGF (bevacizumab)

R

MOSAIC: Treatment arms

FOLFOX4 : LV5FU2 + Oxaliplatin 85mg/m² LV5FU2 Endpoints

 

Primary:

–

3-yr Disease Free Survival (DFS) Secondary:

– –

Safety (including long-term) Overall Survival (OS)

Probability 1

DFS by treatment arm (ITT)

3-year FOLFOX4 (n=1123) 77.8% LV5FU2 (n=1123) 72.9% 0,9 0,8 0,7 0,6 Hazard ratio: 0.77 [0.65 – 0.92] p < 0.01

0,5 0 10 20 30 DFS (months) 40 50 23% risk reduction in the FOLFOX4 arm

Probability 1 0,9

Disease-Free Survival Stage III patients

3-year FOLFOX4 (n=672) 71.8% LV5FU2 (n=675) 65.5% 0,8 0,7 0,6 Hazard ratio: 0.76 [0.62-0.92] 0,5 0 10 20 DFS (months) 30 40 24% risk reduction for stage III patients in the FOLFOX4 arm 50

0.8

0.75

0.7

0.65

0.6

0.55

0.5

0.5

3 Year DFS vs 5 Year OS: Approved by ODAC

r

=0.90

0.55

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

0.65

0.7

Disease Free Survival 0.75

0.8

Adjuvant therapy for colon

NO16968 (complete 10/04)

cancer

XELOX vs. FU/LV INT NO147 (open 2/04; 151/4800 pts) mFOLFOX6 vs. FOLFIRI vs. mFOLFOX6/FOLFIRI ± cetuximab NSABP C-07 (completed) 5-FU/LV (Roswell Park) ± oxaliplatin (FLOX) X-ACT Trial/C-06(ASCO 2004) Capecitabine vs FU/LV (Mayo) UFT/LV vs RPMI NSABP C-08 mFOLFOX6 ± bevacizumab (12 mo?) MOSAIC (completed) LV5FU2 vs. FOLFOX4

AVANT

FOLFOX4 ± bevacizumab vs. XELOX + bevacizumab

Surveillance

• Chau, et. al. ECCO 2003 • 550 pts with st II and III CRC treated with bolus or PVI; median f/U • CEA each visit, CT C/A/P at 12 and 24 months; non-randomized • 154 pts detected by – Sx (65), CEA (31), CT (49) • OS better in pts who had CT-detected tumor • 33 pts proceeded to potentially curative surgery

Salvage Surgery

Total patients Recurred

INT-0035 (colon)

1247 548 (43%)

INT-0114

1792 715(42%)

(rectal)

Salvage surgery 222 (41%) --- Curative intent surgery/ recurrences 5-yr 109 (20%) DFS: 23% (25 pts) 173 (34%) OS: 27% (46 pts)

· therefore, 71 potential cures in 3039 patients= 2.3%

INT-0035: Goldberg, et al, Ann Intern Med 1998 INT-0114: Tepper, J Clin Oncol 2003

Liver metastases from colorectal cancer

 Liver is the most common site of metastases from CRC  - 50 to 75% of patients with advanced CRC will develop liver metastases (1)  - 15 to 25% of patients have liver metastases at presentation (1, 2)  - 20 to 35% of patients will have metastatic disease confined to the liver (3)  Improving the outlook of advanced colorectal cancer necessitates better management of liver metastases •

1 - N. Kemeny, F. Fata, J. Hepatobiliary Pancreas Surg., 1999; 6: 39-49 2 - JK. Seifert, J. R. Coll. Surg. Edinb., 1998; 43: 141-54 3 - MM. Borner, Ann. Oncol., 1999; 10, 6: 623-26

Advances in surgery of liver metastases

Scheele, 1995 (1) Period 1960-1979 1980-1992 1989-1992 N. of patients Operative mortality 52 11.5% 382 3.4% 114 1.8% Doci, 1995 (2) Period N. of patients Operative mortality Operative morbidity Transfusions

1 - J. Scheele,

et al.,

2 - R. Doci,

et al.,

World J. Surg., 1995; 19: 59-71 Br. J. Surgery, 1995; 82: 377-81

1980-1986 78 5.1% 53% 450 ml 1987-1992 130 0.8% 24% 150 ml

Results of liver surgery for metastatic CRC (N > 100)

Adson, 1984 (1) Hughes, 1988 (2) Doci, 1991 (3) Scheele, 1991 (4) Rosen, 1992 (5) Nordlinger, 1992 (6) Gayowski, 1994 (7) Rees, 1997 (8) N. of patients Operative mort 5-yr survival 141 859 100 219 280 1818 204 114 2.8% 5% 6% 4% 2.4% 0% 1% 23% 33% 30% 39% 25% 26% 32% 37%

1 - MA. Adson

et al.,

Arch. Surg., 1984; 119: 647-51 2 - KS. Hugues, Surgery, 1988; 103: 278-88 141-59 3 - R. Doci

et al.,

Br. J. Surg., 1991; 78: 797-801 4 - J. Scheele

et al.,

Surgery, 1991; 110: 13-29 5 - CB. Rosen

et al.,

Ann. Surg., 1992; 216: 493-505 6 - B. Nordlinger

et coll.,

Ed. Paris Springer-Verlag, 1992; 7 - TJ. Gayowski

et al.,

8 - M. Rees

et al.,

Surgery, 1994; 116: 703-11 Br. J. Surg., 1997; 84: 1136-40

Ongoing Trials in Patients With Liver Metastases

• • •

EORTC Study 40983

– FOLFOX + surgery vs surgery alone – Primary endpoint: 3-yr RFS; also resectability – 350 patients, completed accrual (started 10/01)

CLOCC Trial

– FOLFOX +/- RFA for unresectable disease

NCCTG/NSABP

– Is HAI necessary with optimal SYS therapy?

– Adjuvant XELOX ± HAI FUdR

Portion of Rectum Upper 1/3 Cm. from anal verge

Rectal Cancer

Left upper valve of Houston Right middle valve of Houston 15 Peritoneum Middle 1/3 11 Ampulla of Rectum Left lower valve of Houston Lower 1/3 7 2 Anal verge Cohen AM, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997, p. 1197

Rectal Cancer

• OBJECTIVES OF TREATMENT – Cure – Quality of Life •

sphincter preservation vs colostomy (distal lesions)

•

anorectal function

–

acute and late toxicity of treatment

Management of Early Rectal Cancer

• SURGERY (TME) • RADIATION – reduce locoregional failure – reduce distant failure (± chemotherapy) • CHEMOTHERAPY – reduce distant failure – reduce locoregional failure (± radiation)

Local failure: 1980s –2000s

35 30 Norway Mayo-NCCTG NSABP-R02 Ulsan NSABP-R01 GITSG-2 INT-PVI GITSG-1 INT-0114 Dutch TME 25 20 15 10 5 0 Surgery only Surgery



RT Surgery



CTRT TME + RT/CTRT

Distant metastases: 1980s –2000s

40 35 30 25 20 15 10 5 0 Surgery only NSABP-R02 GITSG-1 INT-PVI Ulsan Surgery



RT INT-0114 NSABP-R01 GITSG-2 Norway Mayo-NCCTG Dutch TME Surgery



CTRT TME +RT/CTRT

Adjuvant Therapy of Rectal Cancer

•

Postoperative

–

pathologic staging

•

EUS, MRI

–

immediate surgery

• • •

patient bias physician bias referral patterns

–

Positive adjuvant trials in US in postoperative setting

•

Preoperative

–

improved resectability

–

sphincter preservation

–

reduced damage to normal tissue

–

Only positive trial from Swedish study (2500 cGy/5 fx)

Pre-operative adjuvant therapy in rectal cancer: recent advances

• Emphasis on curative resection in addition to sphincter preservation – pre-operative staging (CRM unsafe) – pre-operative tumor down-staging – surgical technique (TME) – accurate pathological staging (R0)

CRM = circumferential resection margin; TME = total mesorectal excision

Preoperative vs Postoperative Chemoradiation

• INT-0147 – terminated prematurely secondary to low accrual • NSABP R-03 – terminated prematurely secondary to low accrual • German Trial – completed accrual!

Sphincter Preserving Surgery ITT Analysis Pre randomization: “APR Necessary“ Postoper. RCT n= 394 85 Sphincter preserved 17/85 (20%) Preoper. RCT p = 0.004

n = 405 109 43/109 (39%)

Cumulative Incidence of Local Relapses Intent-to-treat Analysis (Med. Follow-up: 40 mts)

.14

.12

.10

.08

.06

.04

.02

0.00

0

Postop CRT 12% 6%

10

Preop CRT

20 30 40

p = 0.006

50 60 Months

The Univ. Of Pennsylvania Trial in Rectal Cancer XELOX x2 cycles + cetuximab RT RT RT RT RT CAPE CAPE CAPE CAPE CAPE OXA OXA OXA cetuximab OXA OXA 45 Gy 825 x 2/d (Mon –Fri) 50/weekly CORE SURGERY CT

A New Paradigm for Colorectal Cancer Patients

Preclinical stage Localized disease Advanced disease S S Screening S Adjuvant Rx CT 1 st -line

Prevention

S = Surgery CT = Chemotherapy CT 2 nd -line biological agents CT 3 rd -line

CURE

• • • • • • •

The future of treatment of colon cancer

Improve efficacy Improve convenience Reduce duration Reduce toxicity Individualize treatment –Patient selection (anatomic staging, prognostic markers) –Drug selection (proteinomics, pharmacogenomics, SNPs) Cost/benefit Confusion…

Therapy for Colorectal Cancer

“There are only two tragedies in life: one is not getting what one wants, and the other is getting it.”

Oscar Wilde