1. North Central Cancer Treatment Group Randomized Phase II Trial of Panitumumab, Erlotinib, and Gemcitabine (PGE) versus Erlotinib-Gemcitabine (GE) in Patients with Untreated, Metastatic Pancreatic Adenocarcinoma Kim GP, Foster NR, Salim M, P. J. Flynn, Moore DF, Zon R, Mowat RB, Wiesenfeld M, McCullough AE, Alberts SR. North Central Cancer Treatment Group, Rochester MN; Genentech, Inc; Amgen, Inc. Background Inhibition of the epidermal growth factor receptor pathway in advanced pancreatic cancer results in improved outcomes- erlotinib 1 (NCI-C) 6.24 vs. 5.91, p=.038, HR 0.82 Combined EGFR blockade using monoclonal antibodies and tyrosine kinase inhibitors results in greater inhibition of the EGFR pathway and downstream targets (MAPK and Akt). Synergistic inhibition of cell proliferation and increased apoptosis is observed in pancreatic cancer cells. This approach has shown promise clinically in non-small cell lung cancer 2-4. An initial run-in phase design established the maximal tolerated doses of the PGE regimen. In pancreas cancer, challenges exist in collecting tissue for correlative studies. DNA in stool can be detected and analyzed for K-RAS status. Goals & Study Design Goals: Primary Endpoint: Overall Survival (OS) comparison between PGE vs. GE Secondary Endpoints: response rate, OS, progression-free survival (PFS), toxicity. KRAS status -prognostic and predictive roles Study Design: Randomized phase II study With 39 evaluable patients per arm, we have 80% power to detect a significant difference between the arms using a 1-sided log-rank test at alpha=0.20 (51 events needed for final analysis) Patient Characteristics Adverse Events (AEs) Patient Outcome Discussion CharacteristicFrequency (%) Median Age Range 61 years 37-81 years Gender Female Male 32 (35%) 60 (65%) ECOG PS 0 1 47 (51%) 45 (49%) Site of metastasis Liver Other Both Liver and Other 33 (36%) 20 (22%) 38 (42%) Smoking Status Current Former Never 27 (29%) 22 (24%) 43 (47%) 92 patients evaluable (46 per arm) Only AEs at least possibly related to treatment Grade 3 or worse hematologic rates were similar for PGE vs. GE (p=0.25) (Non-Hematologic) PGE vs. GE Grade 3-65% 33%: p=0.002 Grade 4- 13% 20%, p=0.397 Grade 5-1 patient** 0 patients **duodenal bleed Rash Grade 3 13 (28%) 4 (9%); p = 0.03 Grade 1-2 29 (63%) 28 (61%); p = 0.83 All 92 patients evaluable (46 per arm) Median follow-up: 8.7 months Clinical OutcomeStatistics* Survival (OS) 6-month K-M estimate Median (months) PGE vs. GE 62% 37% 8.4 4.2 (p=0.14) Progression-free survival (PFS) 6-month K-M estimate Median (months) PGE vs. GE 24% 17% 3.7 2.0 (p=0.21) Best Clinical Response Complete Response Partial Response Stable Disease Progression Not Evaluable PGE vs. GE 0 (0%) 0 (0%) 3 (7%) 4 (9%) 25 (54%) 14 (30%) 11 (24%) 24 (52%) 7 (15%) 4 (9%) Confirmed Response Rate PGE vs. GE 6.5% 8.7% *Frequency (%) or percentage alone, unless otherwise noted. Combined EGFR inhibition results in increased anti-cancer activity in preclinical pancreatic cancer models. A run-in design required only six patients to establish the maximally tolerated doses for PGE in metastatic pancreatic cancer patients. PGE arm had higher non-hematologic grade 3 toxicity (65 vs. 33%, p=0.002), mainly due to increased rash (PGE: 28% vs. GE: 9%, p=0.03). Grade 4 toxicity was similar. PGE has significantly improved OS and met the primary endpoint criteria per protocol for further study (Median OS: PGE: 8.4 months vs. GE: 4.2 months, p= 0.14). PGE also showed improved median PFS as compared to GE (3.7 vs. 2.0 months; p = 0.21) KRAS status can be defined using stool DNA. As reported previously, KRAS wild-type patients have better prognosis with improved OS compared to KRAS mutant patients (p=0.20). Similar results were observed for PFS. KRAS is not a predictive marker for OS (interaction p = 0.59) or PFS (interaction p = 0.81) One Cycle = 28 days AgentDoseDay Gemcitabine1000 mg/m 2 1, 8, 15 Panitumumab4 mg/kg1, 15 Erlotinib100 mg1-28 Patients evaluated for response every 2 cycles. Treatment continued until disease progression, toxicity, or patient refusal. Eligibility: Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas Pertinent laboratory values : Total bilirubin  2 x UNL, AST  2.5 x UNL, Magnesium > LNL ECOG performance status of 0 or 1. Prior adjuvant chemotherapy for completely resected disease or chemoradiotherapy for locally advanced disease allowed but must be >6 months prior. Contraindications included: Locally advanced disease. Prior cytotoxic chemotherapy for metastatic disease. Prior anti-EGFR antibody therapy (e.g., cetuximab) or small molecule EGFR inhibitors (e.g., gefitinib, erlotinib, lapatinib). Radiation therapy, immunotherapy, biologic therapy <4 months prior to registration. Significant coexistent medical condition. Methods Treatment & Evaluation Grade 3-4 AEs (at least possibly related to treatment): Adverse Event Frequency (%) (N=92, 46 per arm) PGEGE Hematologic Neutropenia Thrombocytopenia 5 (11%) 3 (7%) 12 (26%) 2 (4%) Gastrointestinal Nausea Vomiting Diarrhea 5 (11%) 3 (7%) 4 (9%) 2 (4%) 1 (2%) Constitutional Fatigue Hypersensitivity 6 (13%) 0 (0%) 1 (2%) 0 (0%) Metabolic/ Laboratory AST ALT Alk phos Bilirubin Hypomagnesemia 3 (7%) 5 (11%) 2 (4%) 4 (9%) 3 (7%) 0 (0%) 1 (2%) 3 (7%) 4 (9%) 0 (0%) Other Thrombosis Dyspnea Dehydration 5 (11%) 3 (7%) 4 (9%) 1 (2%) 3 (7%) References 1.Moore, Malcolm J., et al. (2007) Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the NCI-C Clinical Trials Group. JCO 25(15):1960-1966. 2.Matar, P., et al., (2004) Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting. Clin Cancer Res, 10(19): p. 6487-501. 3.Ramalingam, S., et al. (2008) Dual inhibition of EGFR with cetuximab and gefitinib, in patients with refractory NSCLC: phase I study. J Thorac Oncol 3(3):258-64. 4.Guarino, MJ., et al. (2009)Dual Inhibition of the EGFR Pathway with Cetuximab and Erlotinib: Phase I Study in Patients with Advanced Solid Malignancies. Oncologist 14(2):119-124. Treatment Information 91 pts completed treatment (99%; PGE - 46; GE - 45). Subsequent treatment rates similar between the treatment arms (PGE: 28 (61%), GE: 23 (51%), p=0.35) Reasons for going off treatment similar between arms (p=0.23) Disease progression: 67 (74%) Adverse events:11 (12%) Patient refusal: 8 (9%) Other reasons: 5 (5%)