Phase 2, Randomized, Open-label Study of Cetuximab and Bevacizumab Alone or in Combination with Fixed-dose Rate (FDR) Gemcitabine as First-line Therapy of Patients with Metastatic Adenocarcinoma of the Pancreas (MPC) Ko A1, Dicke K2, Gurtler J3, Keaton M4, Lenz H-J5, Firstenberg B2, Zhang Y6, Katz T6, Rowinsky E6, Youssoufian H6 1UCSF Comprehensive Cancer Center, San Francisco, CA 2Arlington Cancer Center, Arlington, TX 3Metairie Oncology, Metairie, LA 4Augusta Oncology Associates, Augusta, GA 5University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 6ImClone Systems, a Wholly-Owned Subsidiary of Eli Lilly and Company, Branchburg, NJ

Abstract Background: Gemcitabine, either alone or as part of combination therapy, remains the standard of care for MPC. Non-gemcitabine-based regimens have not been routinely tested in the front-line setting in clinical trial design. Cetuximab and bevacizumab mechanistically may have synergistic activity and have demonstrated promise when used in combination for other solid tumor types. We therefore tested a novel strategy using concurrent administration of these dual monoclonal antibodies either alone or in combination with gemcitabine for patients with MPC. Methods: Patients (pts) with previously untreated MPC and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were randomized to receive either: (Arm A) cetuximab (400 mg/m2 initial dose; 250 mg/m2 thereafter every week), bevacizumab (10 mg/kg every 2 weeks), and FDR gemcitabine (1000 mg/m2 weekly x 3 of 4 weeks); or (Arm B) cetuximab and bevacizumab at the same dosing schedule. Patients were evaluated for tumor response every 8 weeks. Study objectives included determination of progression-free survival (PFS), objective response rate (ORR) as determined by the Response Evaluation Criteria in Solid Tumors (RECIST), response by CA19-9 level, time to progression (TTP), and safety. Results: A total of 58 pts (55% male, 57% < 65 years of age) were treated (29 in each arm); 28 in Arm A and 29 in Arm B are evaluable for response. Median PFS was 3.5 months (95% CI, 1.7-6.5 months) and 1.8 months (95% CI, 0.9-2.0 months) for patients in Arm A and Arm B, respectively. ORR was 10.7% for Arm A (one complete response [CR], two partial responses [PR]) compared with 0% for Arm B, with rates of stable disease 29% and 14%, respectively. Safety analysis revealed Grade 3-4 treatment-associated toxicity occurring in 39.3% of pts in Arm A compared with 20.7% in Arm B. This included rates of Grade 3 or 4 hematological toxicity of 3.6% vs 0%; Grade 3-4 infusion reaction 7.1% vs 0%; Grade 3-4 pulmonary embolism 0% vs 3.4%; and overall cutaneous toxicity (all grades) 78.6% vs 58.6%. Seven patients (23.3%) in Arm A and one (3.2%) in Arm B discontinued treatment due to adverse events (AEs). Conclusions: A dual-antibody strategy alone is safe and can produce disease control in some patients. However, it appears to result in inferior outcomes when compared with combining these agents with gemcitabine. At present, a cytotoxic backbone appears necessary in clinical trial design for front-line MPC.

Background MPC is the fourth leading cause of cancer-related mortality in the United States. Surgical resection is appropriate for only 10%-15% of patients at diagnosis. Therapeutic options for patients with unresectable metastatic or recurrent disease are extremely limited, with combination chemotherapy extending survival to a median of under 7 months. Cetuximab is a chimeric IgG1 monoclonal antibody that blocks ligand binding to the epidermal growth factor receptor (EGFR), inhibiting the proliferation and survival of pancreatic cancer cells in vitro. In a multicenter Phase 2 study, the addition of cetuximab to gemcitabine in the treatment of MPC produced encouraging preliminary results in terms of 1-year survival, PFS, median TTP, and median overall survival.

Background Bevacizumab is a monoclonal antibody against the vascular endothelial growth factor (VEGF). Several Phase 2 studies evaluating the addition of bevacizumab to gemcitabine-based regimens in patients with MPC have demonstrated promising results in terms of response rate, TTP, and overall survival. EGFR and VEGFR signaling systems appear partially interdependent in pancreatic cancer. A dual inhibition strategy using both cetuximab and bevacizumab may result in greater tumor growth suppression than can be achieved with either class of agent independently.

Objectives PRIMARY SECONDARY (SELECTED) To determine the PFS of patients with MPC treated with dual monoclonal antibody therapy consisting of cetuximab and bevacizumab, either alone or in combination with gemcitabine chemotherapy SECONDARY (SELECTED) To determine overall survival and TTP To determine the ORR in the subset of patients with measurable disease To determine the CA19-9 response rate in the subset of patients with elevated values at baseline To assess safety and tolerability

Methods KEY ELIGIBILITY CRITERIA Age ≥ 18 years Measurable disease by RECIST or nonmeasurable disease with baseline CA19-9 at least two times the upper limit of normal ECOG PS 0-2 Adequate hematologic, hepatic, and renal function, and either adequate coagulation function or use of stable full-dose anticoagulation with no active bleeding No prior chemotherapy, hormonal therapy, or radiation therapy for MPC; adjuvant therapy allowed if last dose was more than 6 months prior to randomization No prior EGFR or VEGF inhibitors No prior arterial thrombotic events, significant bleeding, or GI bleeding within 9 months prior to entry, and no history of uncontrolled hypertension unless on a stable antihypertensive regimen

Methods STUDY DESIGN Multicenter, open-label, randomized, Phase 2 study in patients with chemotherapy-naïve MPC. 114 patients (57 in each arm) were initially planned. Patients were randomized on a 1:1 basis to Arm A (cetuximab-bevacizumab) and Arm B (cetuximab-bevacizumab-gemcitabine).

Methods SCHEMA

Patient Population DISPOSITION Arm A (n=30) Arm B (n=31) All (N=61) Treated 29 (96.7%) 29 (93.5%) 58 (95.1%) In Study 4 (13.3%) 2 (6.5%) 6 (9.8%) Discontinued Adverse Event Death PD Withdrew Consent Other 26 (86.7%) 7 (23.3%) 1 (3.3%) 15 (50.0%) 3 (10.0%) 1 (3.2%) 3 (9.7%) 20 (64.5%) 55 (90.2%) 8 (13.1%) 4 (6.6%) 35 (57.4%) 2 (3.3%)

Patient Population DEMOGRAPHICS Arm A (n=29) Arm B (n=29) All (N=58) Sex Male Female 18 (62.1%) 11 (37.9%) 14 (48.3%) 15 (51.7%) 32 (55.2%) 26 (44.8%) Age < 65 years ≥ 65 years Median (years) Range (years) 17 (58.6%) 12 (41.4%) 64.0 33 – 84 16 (55.2%) 13 (44.8%) 63.3 36 – 78 33 (56.9%) 25 (43.1%) 63.8 Race White Black Hispanic Asian 24 (82.8%) 2 (6.9%) 3 (10.3%) 22 (75.9%) 1 (3.4%) 46 (79.3%) 5 (8.6%) 4 (6.9%) 3 (5.2%) ECOG PS 1 2 24 (41.4%) 31 (53.4%)

Results (Efficacy) ANTITUMOR EFFICACY Arm A (n=28) Arm B (n=29) All (n=57) Best Overall Response CR PR SD PD Not Evaluable Best Status Not Available 1 (3.6%) 2 (7.1%) 8 (28.6%) 6 (21.4%) 3 (10.7%) 4 (13.8%) 13 (44.8%) 8 (27.6%) 1 (1.8%) 2 (3.5%) 12 (21.1%) 21 (36.8%) 14 (24.6%) 7 (12.3%) Objective Response Rate (CR + PR) 10.7% 0% 5.3% Disease Control Rate (CR + PR + SD) 39.3% 13.8% 26.3% Progression-free Survival Median (months) Range (months) 95% CI of the median (months) 3.5 0.03 – 13.24 (1.7, 6.5) 1.8 0.03 – 5.55 (0.9, 2.0) 1.9 (1.7, 3.5)

Results (Efficacy) RESPONSE BY CA19-9 A total of 17 patients, including nine in Arm A and eight in Arm B, had CA19-9 levels that were elevated at baseline. CA19-9 response was defined as a decrease in baseline CA19-9, no change to baseline, or an increase of < 10% from baseline. Of these 17 patients with elevated baseline values, four (23.5%) experienced a CA19-9 response (three [33.3%] in Arm A and one [12.5%] in Arm B). When CA19-9 response is considered along with CR and PR in the calculation of the response rate, the modified response rate is 17.9% for Arm A and 3.4% for Arm B.

Results (Safety) EXTENT OF EXPOSURE The 28 patients in Arm A received a median of 9.0 weeks (8.0 doses) of cetuximab, a median of 8.6 weeks (4.0 doses) of bevacizumab, and a median of 7.1 weeks (6.0 doses) of gemcitabine. The 29 patients in Arm B received a median of 7.9 weeks (7.0 doses) of cetuximab and a median of 8.0 weeks (4.0 doses) of bevacizumab.

Results (Safety) ADVERSE EVENTS Adverse events have been reported for 53 of 57 (93.0%) patients receiving at least one dose of study therapy; 40 of 57 (70.2%) experienced at least one AE of Grade ≥ 3. Grade ≥ 3 adverse events were more common in Arm A (89.3%) than in Arm B (51.7%). The most common AEs of any grade were nausea (50.9%), dermatitis acneiform (49.1%), fatigue (42.1%), vomiting (35.1%), constipation (28.1%), and anorexia (28.1%).

Results (Safety) TREATMENT-RELATED ADVERSE EVENTS Treatment-related AEs were reported for 44 (77.2%) patients. Common related AEs included (Arm A vs Arm B): dermatitis acneiform (57.1% vs 41.4%); fatigue (25.0% vs 17.2%); rash (21.4% vs 20.7%); and nausea (17.9% vs 17.2%). Overall, cutaneous toxicity affected 78.6% of patients in Arm A and 58.6% of patients in Arm B. Eight patients discontinued at least one study drug due to AE(s): seven in Arm A (pyrexia, flu-like symptoms, GI bleed, asthenia and diarrhea, infusion-related reaction, and pulmonary embolism) and one in Arm B (nausea and vomiting). Of these events, only three (asthenia, diarrhea, and infusion-related reaction) were considered at least possibly related to treatment. Grade ≥ 3 treatment-related AEs affected a total of 17 patients (29.8%), including 11 patients (39.3%) in Arm A and 6 patients (20.7%) in Arm B.

Results (Safety) RELATED GRADE 3-4 AEs Arm A (n=28) Arm B (n=29) All (N=57) Anorexia Asthenia Dermatitis Acneiform Diarrhea Dyspnoea Groin Infection Headache Hypomagnesaemia Hypotension Infusion-Related Reaction Neutropenia Pulmonary Embolism Rash 1 (3.6%) 3 (10.7%) 2 (7.1%) 1 (3.4%) 2 (3.5%) 1 (1.8%) 3 (5.3%)

A wholly-owned subsidiary of Eli Lilly and Company Conclusions A dual-antibody strategy employing cetuximab and bevacizumab is well-tolerated, with mild skin toxicity, fatigue, and nausea the most significant related adverse events. Treatment of MPC with cetuximab-bevacizumab alone was associated with modest disease stabilization, but no objective tumor regression and only one response as measured by CA19-9. The efficacy outcomes observed with cetuximab-bevacizumab alone appeared to be inferior to those obtained by combining these agents with gemcitabine. At present, a cytotoxic backbone appears necessary in clinical trial design for front-line MPC. Data on overall survival and TTP will be reported when available. ImClone Systems A wholly-owned subsidiary of Eli Lilly and Company