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