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, E O’Reilly, R Wong,

J Atkins, J Abbruzzese, C Blanke

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

Systemic Therapy of Systemic Therapy of Pancreas CancerPancreas Cancer

• Gemcitabine-based cytotoxic combination therapies have demonstrated no significant advantage over gemcitabine alone

• Combinations of gemcitabine with targeted agents have demonstrated no benefit over gemcitabine alone

• Gemcitabine plus erlotinib resulted in a marginal survival benefit that was statistically significant1

1Moore et al, J Clin Oncol in press

S0205: BackgroundS0205: Background

• The EGFR pathway is activated in a large proportion of human pancreatic cancers

• Pre-clinical studies have demonstrated anti-tumor activity of cetuximab in human pancreatic cancer animal models

• A pilot phase II trial suggested an improvement of one-year survival with the combination of gemcitabine and cetuximab

1Xiong et al, J Clin Oncol 22:2610, 2004

S0205:S0205: Study Schema Study Schema

Stratify

Locally advanced versus metastatic

Prior pancreatectomyYes versus No

Performance status0/1 versus 2

Gemcitabine +

Cetuximab

Gemcitabine +

Cetuximab

GemcitabineGemcitabine

RANDOMIZE

RANDOMIZE

S0205:S0205: Drug administration Drug administration

• Gemcitabine

– 1000 mg/m2 IV over 30 minutes weekly x 7 of 8, then

– 1000 mg/m2 IV over 30 minutes weekly 3 of 4

• Cetuximab

– 400 mg/m2 IV loading dose, then

– 250 mg/m2 IV weekly

S0205:S0205: Study Objectives Study Objectives

• Primary– Overall survival

• Secondary– Time to treatment failure

– Objective response

– Pain and quality of life (QoL)

– Toxicity

– EGFR expression and its correlation with outcome

S0205:S0205:EligibilityEligibility

• Histologically or cytologically confirmed pancreatic adenocarcinoma

• Incurable locally advanced or metastatic disease• Measurable or evaluable disease• No prior therapy for metastatic disease

– > 6 months from completion of adjuvant therapy

• ECOG PS 0-2• Adequate organ function• Submission of tumor tissue for EGFR assessment• Written informed consent

S0205:S0205:Statistical MethodsStatistical Methods

• Detect a 33% increase in median survival

– 92% power for the entire population– 90% power for the anticipated EGFR positive subset– One-sided 0.0125 significance level

• Designed to accrue 704 patients/ 5 years

S0205:S0205:Statistical MethodsStatistical Methods

• Actual accrual accomplished in three years (766 total; 735 eligible)

• Two interim analyses and a final analysis one year after closure of accrual

• DSMC recommended study continuation based on formal interim analyses

S0205: Patient CharacteristicsS0205: Patient Characteristics

Gem + Cetux

N =366

Gem

N = 369

Median Age (years) 63.7 64.3

Female 49% 46%

Performance Status

0/1 87% 87%

Locally Advanced 21% 22%

Measurable Disease 86.3% 88.3%

Prior Pancreatectomy 10% 11%

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 Endpoint:S0205 Primary Endpoint:Survival of all PatientsSurvival of all Patients

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

Progression-Free Survival by Treatment Arm

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events360351

Medianin Months

34

P = 0.058

3.03.5

S0205: S0205: Progression-Free SurvivalProgression-Free Survival

HR = 1.13 (95% CI: 0.97, 1.31)

Time to Treatment Failure by Treatment Arm

0%

20%

40%

60%

80%

100%

0 6 12 18 24Months After Registration

GemcitabineGemcitabine and Cetuximab

N369366

Events369363

Medianin Months

22

P = 0.0014

1.82.5

S0205: S0205: Time to Treatment FailureTime to Treatment Failure

HR = 1.25 (95% CI: 1.08, 1.45)

S0205: S0205: Objective Tumor ResponseObjective Tumor Response

Response Gem + Cetux (%)

N = 316

Gem (%)

N = 326

CR 0 1

PR 12 13

SD 38 30

CR + PR + SD 50 44

PD 40 47

S0205:S0205: Grade 3 or 4 Adverse Events Grade 3 or 4 Adverse Events

Toxicity

Gem + Cetux (%)

N = 353

Gem (%)

N = 353

Grade 3 Grade 4 Grade 3 Grade 4

Neutropenia 18.4 5.1 19.0 4.8

Fatigue 18.1 2.5 15.9 1.7

Nausea 8.5 0.6 5.9 0

Vomiting 6.5 0.3 2.3 0

Anemia 7.9 1.1 6.2 0

Rash 7.1 0 0 0

Anorexia 6.2 0 7.4 0

ALT 4.5 0 2.5 0

Thrombocytopenia 4.2 2.0 6.2 2.3

Allergic reaction 3.1 0.3 0 0

S0205: S0205: CONCLUSIONSCONCLUSIONS

• The addition of cetuximab to gemcitabine in patients with advanced pancreas cancer was well tolerated

• Cetuximab did not significantly improve the overall survival or time to disease progression

S0205: S0205: CONCLUSIONSCONCLUSIONS

• Ongoing analyses will determine the impact of cetuximab on pain and QoL and the contributions of EGFR expression and skin rash on outcome

• Future studies with targeted agents in pancreas cancer must focus on improving patient selection and/or the adoption of rationally designed multitargeted approaches

AcknowledgementsAcknowledgements

• Patients

• Investigators & clinical trials support personnel

• Patient advocacy & support groups

• SWOG operations, data operations, and statistical center personnel

• NCI• ImClone• Bristol Myers Squibb