Systemic Treatment of Metastatic Colorectal Cancer: Living with a

Moving Landscape

Neal J. Meropol, MD

Fox Chase Cancer Center

May 16, 2005

History of Systemic Therapy for Colorectal Cancer

?

5-FU Modulation

1980’s

New Cytotoxics

1990’s

Biologics

2000’s

Pat

ien

t B

enef

it

5-FU/leucovorin

oxaliplatin

irinotecan

capecitabine/irinotecan

FOLFOX

capecitabine/oxaliplatin

capecitabine

FOLFIRI

IFL

bevacizumab

cetuximab

cetuximab/irinotecan

Treatment Summary: Front-Line

• Capecitabine = 5-fluorouracil• 2 drugs are better than 1

– Irinotecan doubles response rate and improves survival by a few months when added to 5-FU/LV

– Oxaliplatin doubles response rate and improves TTP by a few months when added to 5-FU/LV

• Irinotecan/FU/LV = oxaliplatin/FU/LV• Bevacizumab improves survival when added to

irinotecan/FU/LV; improves TTP with 5-FU/LV

Treatment Summary: 2nd-, 3rd-Line

• Irinotecan improves survival (vs. BSC) by a few months as second-line therapy

• Oxaliplatin+FU/LV improves RR and TTP over either alone

• Bevacizumab improves survival when added to oxaliplatin/FU/LV

• Cetuximab and panitumumab have modest single agent activity

• Cetuximab + irinotecan improves RR% over cetuximab alone

Grothey, A. et al. J Clin Oncol; 22:1209-1214 2004

Survival with Metastatic Colorectal Cancer: Chemotherapy

IFLIROX

FOLFIRIFOLFOX

With antibodies?

Some Practical Clinical Questions

• Capecitabine combinations?• Optimal second line?• Combinations of biologics?• Cetuximab front-line?• Cetuximab before irinotecan failure?• Non-irinotecan cetuximab combinations?• Bevacizumab for life?

Questions Addressed Today

• Capecitabine combinations?

• Optimal second line?

• Combinations of biologics?

Infusional 5-fluorouracil/folinic acid plus oxaliplatin (FUFOX) versus

capecitabine plus oxaliplatin (CAPOX) as first line treatment of metastatic

colorectal cancer: results of the safety and efficacy analysis

Arkenau et al. ASCO 2005, #3507

FUFOX vs. CAPOX: Results

• Similar toxicity profile; ~25% severe neuropathy• Equivalent PFS, 7.0 (C) vs. 8.0 (F) months

(HR=1.19, 95% CI 0.97–1.48, p=0.11)• Equivalent median S, 16.3 (C) vs. 17.2 (F)

months (HR=1.05, 95% CI 0.79-1.41, p=0.72)• Response rate ~50% in both arms

• Note: potential differences in tolerated doses in different populations (e.g. Cassidy JCO 2004, Shields Cancer 2004)

CAPOX vs. FUFOX Overall Survival

1.0

0.8

0.6

0.4

0.2

00 20 40 60 80 100 120 140

Weeks

Estimated probability Median

CAPOX (n=238) 16.3 monthsFUFOX (n=230) 17.2 months

HR = 1.05 (95% CI: 0.79–1.41)p=0.72 (Log-rank)

N9841: A randomized phase III equivalence trial of irinotecan (CPT-11) versus

oxaliplatin/5-fluorouracil /leucovorin (FOLFOX4) in patients with advanced

colorectal cancer previously treated with 5FU

Pitot et al. ASCO 2005, #3506

N9841 Results

• Equivalent overall survival, 14.7 (I) vs. 13.5 (FOLFOX) months (HR=1.05, 95% CI 0.9-1.3)

• FOLFOX less toxic (except neuropathy)

• Response rate higher with FOLFOX (27% vs 15%, p<0.01)

• TTP equivalent (trend favors FOLFOX, 5.2 vs. 4 months, p=0.10)

N9841: Overall Survival

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Months from Registration

% A

live

CPT-11 N = 245

FOLFOX N = 246

Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer

Saltz et al. ASCO 2005, #3508

Pao, W. et al. J Clin Oncol; 23:2556-2568 2005

EGFR Antibodies Block Ligand Binding and Downstream Signaling

Antibody

Rational Combinations EGFR and

VEGF Inhibitors

VEGF

Bevacizumab + Cetuximab in Colorectal Cancer

Cetux/Bev/Irinotecan

Partial Response 15/41 (37%)

Median TTP 7.9 months

Range (1+ to 16+ months)

Cetux/Bev

Partial Response 8/40 (20%)

Median TTP 5.6 months

Range ( 1+ to 12+ months)

Saltz et al. ASCO 2005

Rational Combinations

EGFR and RAS/Raf/MEK/

MAPK Inhibitors

EGFR + IGF-1R or HER2 Inhibitors

EGFR and AKT/mTOR Inhibitors

What have we learned?

1. For many patients, metastatic colorectal cancer is no longer an acute illness

2. There is more than one correct way to use drugs with modest activity in unselected populations

3. The selection of new combinations should no longer be based primarily upon avoidance of overlapping toxicities, but rather an appreciation of colorectal cancer as a network of interrelated processes

The Big Questions that Should Guide Future Clinical

Research:

How do these drugs work and who should get them?

Matchmaking is Science

Potential Sources of Variability

• The tumor– Target characteristics– Target relevance– Drug disposition– Resistance mechanisms

• The patient– Drug metabolism– Normal tissue sensitivity

How Can Clinical Investigators Deal with a Rapidly Changing Landscape?

(This is not 1995)

• Undertake in vivo pharmacodynamic assessment to ensure target acquisition and define mechanism of action during early clinical development

• Be forward-thinking in clinical trial design; this requires acceptance of risk

• Accept that toxicity evaluation will not be complete before phase III investigation

• Work with patient advocates; ensure relevance to those asked to participate

• Bank biologic material; there is now less redundancy and more potential for missed opportunities

Can Society Afford State-of-the-Art Cancer Treatment?

Neal J. Meropol, MD, Fox Chase Cancer Center, Chair

Sue Hellmann, MD, MPH, Genentech Inc.

Kevin A. Schulman, MD, MBA, Duke University

Barry Straube, M.D., CMS

Level 4, Valencia Room, 415A

12:00-1:15

May 16, 2005