Final analysis of a randomized phase II trial of bevacizumab and gemcitabine plus cetuximab or erlotinib in patients

with advanced pancreatic cancer

Hedy Lee Kindler, Tara Gangadhar, Theodore Karrison, Howard Hochster,

Malcolm Moore, Kenneth Micetich, Weijing Sun, Daniel Catenacci, Walter M Stadler, and Everett E Vokes for the University

of Chicago Phase II Consortium

Disclosures• Authors with no disclosures: Tara Gangadhar, Theodore Karrison, Kenneth

Micetich, Daniel Catenacci• Hedy Lee Kindler: Research funding: Lilly, Genentech;

Consultant/advisory: OSI, Roche• Howard Hochster: Research funding: Genentech, OSI, BMS;

Consultant/advisory: Lilly, Genentech, BMS, OSI, ImClone; Honoraria: Lilly, Genentech, OSI, BMS, ImClone

• Malcolm Moore: Consultant/advisory: OSI, Roche; Expert testimony: OSI; Honoraria: OSI, Roche

• Weijing Sun: Consultant/advisory: Genentech; Honoraria: Genentech, Roche; Research funding: Genentech

• Walter M Stadler: Consultant/advisory: Genentech; Research funding: Lilly, Genentech, BMS, ImClone

• Everett E Vokes: Consultant/advisory: Lilly, OSI, Genentech, BMS, ImClone, Roche; Honoraria: Lilly, OSI, Genentech, BMS, ImClone, Roche; Research funding: Lilly

Rationale for combining VEGF and EGFR inhibitors in pancreatic cancer

• Pancreatic cancer:– Highly resistant to treatment– Targeting several critical pathways may be more

effective than single pathway blockade

• Preclinical pancreatic cancer models: – Combining EGFR + VEGF targeted agents is

synergistic1

• Our hypothesis:– Combining EGFR + VEGF targeted agents is

synergistic in patients

1Bruns, Cancer Research, 2000

VEGF inhibitors for pancreatic cancer

• Preclinical models:– Inhibition of VEGF suppresses pancreatic cancer

growth

• Gemcitabine + bevacizumab– Phase II1:

• 21% response rate • Median survival 8.8 months

– Phase III2:• Bevacizumab does not improve survival

1Kindler JCO 2005 2Kindler Proc ASCO 2007

EGFR inhibitors for pancreatic cancer

• Gemcitabine + cetuximab– Phase II1: • 12% response rate, median survival 7.1 mo

– Phase III2: • Cetuximab does not improve survival

• Gemcitabine + erlotinib– Phase III3: • 8% response rate, median survival 6.2 mo• Modest improvement in survival

1Xiong, JCO 2004 2Philip, Proc ASCO 2007 3Moore, JCO 2007

R

Gemcitabine

Bevacizumab

Cetuximab

Trial Design

Gemcitabine

Bevacizumab

Erlotinib

This trial was designed in 2003, beforephase III data on EGFR or VEGF inhibitors

in pancreatic cancer were available

Stratification: •Performance status•Treatment center

ObjectivesPrimary:• Response rate

Secondary: • Toxicity• Progression-free survival• Overall survival

Laboratory:• Correlate baseline plasma VEGF and serum

VEGFR2 with outcome

Statistics• Randomized phase II trial at 16 sites• 2 parallel, Simon optimal 2-stage designs test, in each arm,

the null hypothesis that the true RR is 20% against the alternative that the RR is 35%

• For each arm: – 1st stage: 27 pts. If 6 responses, 36 more pts enroll. If

17 responses (27%), regimen is worthy of further study

• RR are also compared under a “play-the-winner” strategy: – 88% power to select the better treatment if the true

difference is at least 10%• Correlative studies:

– 2 sample t tests, Cox regression models

Key Eligibility Criteria• Histologically-confirmed, unresectable

pancreatic adenocarcinoma • Measurable disease (outside an RT port)• No prior chemotherapy for metastatic disease• No prior gemcitabine, VEGF or EGFR inhibitor• ECOG PS 0-2• Adequate hematologic, hepatic, renal function,

<1+ proteinuria• Warfarin anticoagulation permitted

– if therapeutic, INR target <3, no bleeding risk

• Written informed consent

Key exclusion criteria

• Increased risk of bleeding:

– tumor invasion into duodenum, esophageal varices, bleeding diathesis

• Major surgery <28 days, biopsy <7days

• Uncontrolled HTN, clinically significant CV disease

• No TIA, CVA, MI in prior 6 months

• Non-healing wound, ulcer, fracture

• Active infection requiring IV antibiotics

• Clinically active second malignancy

• Inability to take oral medications

R

A

N

D

O

M

I

Z

E

Gemcitabine 1000 mg/m2 D 1, 8, 15

Bevacizumab 10 mg/kg D 1, 15

Erlotinib 150 mg po QD

D1-5, 8-12, 15-26

Gemcitabine 1000 mg/m2 D 1, 8, 15

Bevacizumab 10 mg/kg D 1, 15

Cetuximab 400 mg/m2 1st dose

250 mg/m2 Q wk

Treatment

1 Cycle=28 Days CT scans: Q 2 cycles

Patient CharacteristicsGBC(N=68)

GBE(N=71)

Age MedianRange

6336-83

6339-86

ECOG PS 012

35%57%8%

48%46%6%

Prior adjuvant treatment 9% 7%

Metastatic disease 93% 90%

Sites of disease

LiverLung

Peritoneum

74%13%21%

73%14%24%

Anti-coagulated at baseline 4% 8%

Drug Delivery

GBC GBE

# Cycles 353 387

Median 4 4

Range 1-18 1-18

Grade 3/4 hematologic toxicity

GBCN=68

GBEN=71

P

Neutropenia 25% 31% NS

Anemia 6% 8% NS

Thrombocytopenia 13% 22% NS

Neutropenic fever 3% 1% NS

Grade 3/4 non- hematologic toxicity attributable to bevacizumab

GBC GBE P

CVA 1%* 1% NS

Epistaxis 0% 1% NS

GI bleeding 3% 6% NS

Hypertension 15% 11% NS

MI 1%* 4%* NS

Perforation 0% 1%* NS

Proteinuria 1% 6% NS

Thrombosis 9% 6% NS

*includes grade 5 toxicity

Grade 3/4 non- hematologic toxicity attributable to EGFR inhibitors

GBC GBE P

Diarrhea 3% 7% NS

Hypersensitivity 3% 0% NS

Hypomagnesemia 4% 0% NS

Pneumonitis 0% 3% NS

Rash 9% 7% NS

ALT 4% 11% NS

AST 4% 8% NS

Response

GBC GBEComplete Response

1% 3%

Partial Response

22% 15%

Stable Disease

50% 45%

Disease control: CR + PR + SD

73% 63%

Survival

GBC GBEMedian

overall survival(95% CI)

7.8 mo

(5.5,9.6)

7.2 mo

(5.6,8.8)

1-year survival 27% 25%

Progression-free survival

(95% CI)

5.0 mo

(3.7,5.8)

5.0 mo

(3.4, 5.5)

1-year PFS 14% 17%

Progression-free survival

GBC 5.0 months

GBE 5.0 months

Overall survivalGBC 7.8 months

GBE 7.2 months

Overall survival by performance status

PS 0 6.1 months

PS 1 8.4 months

PS 2 2.3 months

PS 0/1 vs. 2: p< 0.001

Overall survival by disease extent

Locally advanced: 14.4 months

Metastatic: 7.0 months

P=0.075

Rash as a predictor of outcome

• In prior trials of cetuximab1 and erlotinib2 in PC, grade of rash correlated with overall survival

• In this trial, there was a trend for improved overall survival in GBE pts with early rash* > grade 2 – median survival 9.1 vs. 6.1 mo, p=0.058

• There was also an improved PFS in GBE pts with early rash of any grade – median PFS 5.3 vs. 3.0 mo, p=0.015

• This was not observed in the cetuximab arm 1Xiong, JCO 2004 2Moore, JCO 2007

*defined as a rash which develops in the 1st 2 cycles

Early hypertension as a potential biomarker for response

• Early hypertension1:– Defined as ≥grade 2 HTN in 1st 2 cycles

• Phase II trial, gemcitabine + bevacizumab2: – Early HTN correlated with survival

• Interim analysis, current trial3:– 100% (6/6) pts with early HTN responded

• Final analysis: – 44% of pts with early HTN responded

– 18% of pts without early HTN responded

– p=0.04

– No correlation with OS (p=0.67) or PFS (p=0.75) 1Friberg, Proc ASCO 2005 2Kindler, JCO 2005, 3Kindler, Proc ASCO 2006

VEGF and VEGFR2

• Median pretreatment levels:– VEGF: 65 pg/ml– VEGFR2: 4897 pg/ml

• In each arm, there was no significant association between log VEGF or log VEGFR2 and: – response– overall survival– progression-free survival– early hypertension

A comparison of the current trial with phase III trials of EGFR and VEGF inhibitors

Trial Regimen N RR PFS(mo)

OS(mo)

UC GBC 68 23% 5.0 7.8

UC GBE 71 18% 5.0 7.2

CALGB

803031

GB 302 11% 4.9 5.8

SWOG

S02052

GC 366 4% 3.5 6.4

NCIC PA33 GE 285 8.6% 3.75 6.24

1Kindler, Proc ASCO 2007 2Philip, Proc ASCO 2007 3Moore, JCO 2007

Conclusions• The response rate, progression-free survival, and overall

survival for GBC and GBE are superior to historical controls of gemcitabine-targeted agent doublets– However, both regimens have insufficient activity to

merit phase III evaluation in PC pts • The 2 regimens have similar toxicity profiles• PS2 and LA pts have significantly different outcomes

from PS 0/1 and metastatic pts• Pretreatment VEGF, VEGFR2 did not correlate with

outcome• Early HTN and rash may be pharmacodynamic markers

of activity

Acknowledgments The patients who participated in this studyOur co-investigators: University of Chicago: Tara Gangadhar, TedKarrison, Lolita Douglas, Blase Polite, Pamela Lofton, Sarah Barbeau,Sunita Malhotra, Gregory Friberg, Kathryn Bylow, Walter Stadler,Everett Vokes. Central Illinois Hematology/Oncology: Edem Agamah.Cornell University: Allyson Ocean. Decatur Memorial Hospital: JamesWade. Duke University Medical Center: Herbert Hurwitz. EvanstonHospital: Gershon Locker. Fort Wayne Oncology/Hematology:Sreenivasa Nattam. Ingalls Hospital: Mark Kozloff. Joliet OncologyHematology Associates: Sanjiv Modi. Loyola University MedicalCenter: Kenneth Micetich. University of Maryland: Robert Fenton.Montefiore Medical Center: Andreas Kaubisch. New York UniversityMedical Center: Howard Hochster. Northern Indiana Cancer ResearchConsortium: David Taber. Oncology Care Associates: Eric Lester.Oncology/Hematology Associates of Peoria: James Knost. PrincessMargaret Hospital: Malcolm Moore. University of Pennsylvania CancerCenter: Weijing Sun. National Cancer Institute: Helen Chen.

Supported by NCI N01-CM-17102