ASCO 07, June 3rd.

ADVANCED PANCREATIC CANCER TREATMENT :

NOTHING NEW ??

Christophe LouvetHôpital St-Antoine

Paris, France

The Burris Study

Gemcitabinen=63

5-Fluorouraciln=63

Clinical Benefit

5.65 months ** 4.41 months Median Survival

** p = 0.0025

Burris H A, et al.: JCO 15: 2403, 1997

23.8% * 4.8%

* p = 0.0022

Randomized phases III in Pancreatic Cancer Study PFS/TTP(m) OS (m)

Gem ± Marimasmat (Bramhall, 2002) NA 5.5

Gem ± Pemetrexed (Richards, 2004) 3.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 3.4 6.3

Gem ± Tifarbinib (Van Cutsem, 2004) 3.7 6.4Gem ± Exatecan (O’Reilly, 2004) 3.7 6.7

Study PFS/TTP(m) OS (m)

Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7

Gem ± Capecitabine (Cunningham, 2005) - 7.4

Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4Gem ± 5FU/LV (Riess, 2005) 4.9 5.9

Gem ± Capecitabine

Median survival 12-month (months, 95%CI) survival

GEM 6.0 (5.4, 7.1) 19%GEM-CAP 7.4 (6.5, 8.5) 26%

Hazard Ratio:0.80 (95% CI: 0.65, 0.98)Log rank p=0.026; χ2

LR=4.93

Randomized phases III in Pancreatic Cancer Study PFS/TTP(m) OS (m)

Gem ± Marimasmat (Bramhall, 2002) NA 5.5

Gem ± Pemetrexed (Richards, 2004) 3.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 3.4 6.3

Gem ± Tifarbinib (Van Cutsem, 2004) 3.7 6.4Gem ± Exatecan (O’Reilly, 2004) 3.7 6.7

Gem ± Cisplatin (Heinemann, 2003) 5.3 7.5Gem ± Oxaliplatin (Louvet, 2004) 5.8 9.0Gem ± Oxaliplatin (Poplin, 2006) - 5.9

Study PFS/TTP(m) OS (m)

Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7

Gem ± Capecitabine (Cunningham, 2005) - 7.4

Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4Gem ± 5FU/LV (Riess, 2005) 4.9 5.9

GEM-GEMOX Study : Overall survival

Gem Gemox

median 7.1 m 9.0 m

6-mth 60.4% 68.0%8-mth 45.3% 56.5%9-mth 40.0% 48.1%1-yr 27.8% 34.7%

Overall Survival

0 26 52 78 104 130 1560.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0GemGemox

weeks

% s

urv

ival

p

0.13

Louvet C, et al. J Clin Oncol, 2005

GEM FDR GEMOX

Gem : median = 4.9 monthsGemox : median = 5.9 monthsGem FDR : median = 6.0 months

Gem vs Gemox : NSGem vs Gem FDR : NS

ECOG Study (2006)

Randomized phases III in Pancreatic Cancer Study PFS/TTP(m) OS (m)

Gem ± Marimasmat (Bramhall, 2002) NA 5.5

Gem ± Pemetrexed (Richards, 2004) 3.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 3.4 6.3

Gem ± Tifarbinib (Van Cutsem, 2004) 3.7 6.4Gem ± Exatecan (O’Reilly, 2004) 3.7 6.7

Gem ± Cisplatin (Heinemann, 2003) 5.3 7.5Gem ± Oxaliplatin (Louvet, 2004) 5.8 9.0Gem ± Oxaliplatin (Poplin, 2006) - 5.9

Gem ± Erlotinib (Moore, 2005) 3.7 6.4

Study PFS/TTP(m) OS (m)

Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7

Gem ± Capecitabine (Cunningham, 2005) - 7.4

Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4Gem ± 5FU/LV (Riess, 2005) 4.9 5.9

GEMCITABINE ± ERLOTINIB Phase III Study

A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus

bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic

cancer: A preliminary analysis of CALGB 80303

Hedy Lee Kindler, Donna Niedzwiecki, Donna Hollis, Ebele Oraefo, Deborah Schrag, Herbert

Hurwitz, Howard McLeod, Mary Mulcahy, Richard Schilsky, and Richard Goldberg

for the Cancer and Leukemia Group B

Advanced pancreatic

cancerN=590 Gemcitabine

Placebo

CALGB 80303 Trial design

GemcitabineBevacizumab

Stratification:•Performance status: 0/1 vs. 2•Extent of disease: metastatic vs. locally advanced•Prior radiation: yes/no

RANDOMIZE

CALGB 80303: Overall Survival by Treatment Arm

Bevacizumab 5.8 mo

Placebo 6.1 mo

HR = 1.03

P = 0.78

0 5 10 15 20 25

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g

BevacizumabPlacebo

Phase III Study Comparing Gemcitabine Phase III Study Comparing Gemcitabine plus Cetuximab versus Gemcitabine in plus Cetuximab versus Gemcitabine in

Patients with Locally Advanced or Patients with Locally Advanced or Metastatic Pancreatic AdenocarcinomaMetastatic Pancreatic Adenocarcinoma

Southwest Oncology Group Protocol S0205Southwest Oncology Group Protocol S0205

PA Philip, J Benedetti, C Fenoglio-Preiser, M Zalupski, H Lenz, B Goldman, E O’Reilly, R Wong,

J Atkins, J Abbruzzese, C Blanke

On behalf of SWOG, CALGB, NCIC, and the CTSU

S0205 Study SchemaS0205 Study Schema

Stratify

Locally advanced versus metastatic

Prior pancreatectomyYes versus No

Performance status0/1 versus 2

Gemcitabine +

Cetuximab

Gemcitabine +

Cetuximab

GemcitabineGemcitabine

RANDOMIZE

RANDOMIZE

Overall Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 12 24 36Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events338331

Medianin Months

66

P = 0.14

5.96.4

S0205: Primary EndpointS0205: Primary EndpointSurvival of All PatientsSurvival of All Patients

HR = 1.09 (95% CI: 0.93, 1.27)

ASCO 07, June 3rd.

How to move on ?

1- Better knowledege on :

pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients

hopefully resulting in new drugs and new strategies

2- Optimize the available tools :

Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients

Prophylactic anticoagulation ?

Gemcitabine-free regimens ?

Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between

irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth

factor receptor (EGF-r) : an Eastern Cooperative Oncology Group Study (E8200)

B. A. Burtness, M. Powell, J. Berlin, D. Liles, A. Chapman, E. Mitchell, A. B. Benson, Eastern Cooperative Oncology Group

Fox Chase Cancer Center, Philadelphia; Dana-Farber Cancer Institute, Boston; Vanderbilt University, Nashville; East Carolina University School of Medicine ,

Greenville; Thomas Jefferson University, Philadelphia; Northwestern University, Chicago

#4519

E8200 Study Design

• Dexamethasone premedication• Docetaxel 35 mg/m2 followed by irinotecan 50 mg/m2

weekly x 4, q 6 weeks• Randomized phase II, 2 arms:

– Irinotecan/docetaxel– Irinotecan/docetaxel + cetuximab loading dose of 400 mg/m2

followed by 250 mg/m2 weekly

• All pts receive prophylactic enoxaparin if not on therapeutic anticoagulation

Treatment Arm ALIVEDEAD MEDIANTOTAL

A 43 37 6 6.5B 43 40 3 5.3

Sur

viva

l Pro

babi

lity

Overall Survival by Treatment Arm - E8200

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Overall Survival Time in Months

0 5 10 15 20 25 30 35

RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN

AND OXALIPLATIN) VS GEMCITABINEAS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC

ADENOCARCINOMA

FIRST RESULTS OF THE ACCORD 11/0402 TRIAL M. Ychou1, F. Desseigne2, R. Guimbaud3, M. Ducreux4, O. Bouché5,

Y. Bécouarn6, A. Adenis7, C. Montoto-Grillot8, E. Luporsi9, T. Conroy9

1. Centre Val d'Aurelle, Montpellier 2. Centre Léon Bérard, Lyon

3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif

5. Centre Hospitalier R. Debré, Reims 6. Institut Bergonié, Bordeaux

7. Centre Oscar Lambret, Lille 8. FNCLCC, Paris

9. Centre Alexis Vautrin, Nancy, FRANCE

#4516

Treatments

1 h 30

2 h

2 h 46 h

L-OHP85 mg/m2

CPT-11180 mg/m2

Leucovorin400 mg/m2

Continuous 5-FU 2.400 mg/m2

Bolus 5-FU 400 mg/m2

Arm A : FOLFIRINOX (D1 = D14)

Arm B : Gemcitabine (1000 mg/m² 30’ weekly 7 / 8, then 3 / 4 )

Results – Efficacy

FOLFIRINOX (A)n = 44

Gemcitabine (B)n = 44

Complete Response (CR) 0 0

Partial Response (PR)[ 95 % IC ]

14 (31.8 %)[18.6-47.6 %]

5 (11.4 %) [3.8-24.6 %]

Stable Disease (SD)

Progressive Disease (PD)

Non Evaluable (NE)**

* Panel confirmed 15 PR in arm A and 2 in arm B** 2 non treated and 4 ineligible

12 (27.3 %)

15 (34.1 %)

3 (6.8 %)

9 (20.4 %)

27 (61.4 %)

3 (6.8 %)

Investigators Response Rate* (ITT Population)

ASCO 07, June 3rd.

How to move on ?

1- Better knowledege on :

pancreatic cancer cellsrelationship between tumoral, endothelial and stroma cellspancreatic cancer patients

hopefully resulting in new drugs and new strategies

2- Optimize the available tools :

Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients

Prophylactic anticoagulation ?

Gemcitabine-free regimens ?

Genomics and proteomics for individualized strategies ?

ASCO 07, June 3rd.

K-ras mutation and EGF-r expression(Moore and coll, # 4521)

Samples from 117 pts (out of the 569 included in the PA3 study)

Only « trends » on survival, since sample size limits the conclusions.

K-ras mutant (79% of pts) better than K-ras WT unexpected

Among K-ras mutant : gem > or = to gem + TAmong K-ras WT: gem + T > or = to gem

expectedexpected

Fish neg (53% of pts) better than Fish pos expected

Among Fish pos, gem + T = gemAmong Fish neg, gem + T > gem

unexpectedunexpected

#4521

ASCO 07, June 3rd.SUMMARY / TAKE HOME MESSAGES

Gem-free regimens

Gem single agent still as standard treatment Bevacizumab EGF-r inhibitors

Separate strategies for LA and M tumors

New drugs

Genomics, proteomics and individualized treatments

Basic science

Preclinical studies

New early clinical trial designs