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
Trial Design
R
Stratification:
•Performance status
•Treatment center
Gemcitabine
Bevacizumab
Cetuximab
Gemcitabine
Bevacizumab
Erlotinib
This trial was designed in 2003, before
phase III data on EGFR or VEGF inhibitors
in pancreatic cancer were available
Objectives
Primary:
• 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
Treatment
R
A
N
Gemcitabine
Bevacizumab
Cetuximab
1000 mg/m2 D 1, 8, 15
Gemcitabine
Bevacizumab
Erlotinib
1000 mg/m2 D 1, 8, 15
D
10 mg/kg D 1, 15
400 mg/m2 1st dose
250 mg/m2 Q wk
O
M
I
Z
10 mg/kg D 1, 15
150 mg po QD
D1-5, 8-12, 15-26
E
1 Cycle=28 Days
CT scans: Q 2 cycles
Patient Characteristics
Age
Median
Range
ECOG PS
0
1
2
Prior adjuvant treatment
Metastatic disease
Sites of
Liver
disease
Lung
Peritoneum
Anti-coagulated at baseline
GBC
GBE
(N=68)
(N=71)
63
36-83
35%
57%
8%
9%
63
39-86
48%
46%
6%
7%
93%
74%
13%
21%
4%
90%
73%
14%
24%
8%
Drug Delivery
GBC
GBE
# Cycles
353
387
Median
4
4
Range
1-18
1-18
Grade 3/4 hematologic toxicity
GBC GBE
P
N=68
N=71
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
CVA
Epistaxis
GI bleeding
GBC
1%*
0%
3%
GBE
1%
1%
6%
P
NS
NS
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
Complete
Response
Partial
Response
Stable
Disease
Disease control:
CR + PR + SD
GBC
GBE
1%
3%
22%
15%
50%
45%
73%
63%
Survival
GBC
GBE
Median
overall survival
7.8 mo
7.2 mo
(95% CI)
(5.5,9.6)
(5.6,8.8)
1-year survival
27%
25%
Progression-free
survival
5.0 mo
5.0 mo
(95% CI)
(3.7,5.8)
(3.4, 5.5)
1-year PFS
14%
17%
Progression-free survival
GBC 5.0 months
GBE 5.0 months
Overall survival
GBC 7.8 months
GBE 7.2 months
Overall survival
by performance status
PS 0
PS 1
PS 2
6.1 months
8.4 months
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
OS
(mo)
(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 study
Our co-investigators: University of Chicago: Tara Gangadhar, Ted
Karrison, 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: James
Wade. Duke University Medical Center: Herbert Hurwitz. Evanston
Hospital: Gershon Locker. Fort Wayne Oncology/Hematology:
Sreenivasa Nattam. Ingalls Hospital: Mark Kozloff. Joliet Oncology
Hematology Associates: Sanjiv Modi. Loyola University Medical
Center: Kenneth Micetich. University of Maryland: Robert Fenton.
Montefiore Medical Center: Andreas Kaubisch. New York University
Medical Center: Howard Hochster. Northern Indiana Cancer Research
Consortium: David Taber. Oncology Care Associates: Eric Lester.
Oncology/Hematology Associates of Peoria: James Knost. Princess
Margaret Hospital: Malcolm Moore. University of Pennsylvania Cancer
Center: Weijing Sun. National Cancer Institute: Helen Chen.
Supported by NCI N01-CM-17102