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Final analysis of a randomized phase II trial of bevacizumab and gemcitabine plus cetuximab or erlotinib in patients with advanced pancreatic cancer.

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  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Trial Design Gemcitabine Bevacizumab Cetuximab R • Stratification: • Performance status • Treatment center Gemcitabine Bevacizumab Erlotinib This trial was designed in 2003, before phase III data on EGFR or VEGF inhibitors in pancreatic cancer were available

  7. Objectives Primary: • Response rate Secondary: • Toxicity • Progression-free survival • Overall survival Laboratory: • Correlate baseline plasma VEGF and serum VEGFR2 with outcome

  8. 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

  9. 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

  10. 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

  11. Treatment Gemcitabine 1000 mg/m2 D 1, 8, 15 Bevacizumab10 mg/kg D 1, 15 Cetuximab 400 mg/m2 1st dose 250 mg/m2 Q wk R A N D O M I Z E Gemcitabine 1000 mg/m2 D 1, 8, 15 Bevacizumab10 mg/kg D 1, 15 Erlotinib 150 mg po QD D1-5, 8-12, 15-26 1 Cycle=28 Days CT scans: Q 2 cycles

  12. Patient Characteristics

  13. Drug Delivery

  14. Grade 3/4 hematologic toxicity

  15. Grade 3/4 non- hematologic toxicity attributable to bevacizumab *includes grade 5 toxicity

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

  17. Response

  18. Survival

  19. Progression-free survival GBC 5.0 months GBE 5.0 months

  20. Overall survival GBC 7.8 months GBE 7.2 months

  21. 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

  22. Overall survival by disease extent Locally advanced: 14.4 months Metastatic: 7.0 months P=0.075

  23. 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 cetuximabarm 1Xiong, JCO 20042Moore, JCO 2007 *defined as a rash which develops in the 1st 2 cycles

  24. 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

  25. 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

  26. A comparison of the current trial with phase III trials of EGFR and VEGF inhibitors 1Kindler, Proc ASCO 2007 2Philip, Proc ASCO 2007 3Moore, JCO 2007

  27. 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

  28. 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

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