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
28
Embed
Final analysis of a randomized phase II trial of bevacizumab and gemcitabine plus cetuximab or erlotinib in patients with advanced pancreatic cancer Hedy.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
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;
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
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.