Results From Panitumumab Regimen Evaluation in Colorectal Cancer to Estimate Primary Response to Treatment (PRECEPT): Second-Line Treatment With Panitumumab and FOLFIRI by Tumor KRAS Status Allen L. Cohn, 1 David A. Smith, 2 Marcus A. Neubauer, 3 Gerry Ann Houston, 4 Pankaj Khandelwal, 5 R. Glen Wiggans, 6 Kathy Zhang, 7 Mohamed Yassine 8 1 Rocky Mountain Cancer Centers, Denver, CO, USA; 2 Northwest Cancer Specialists, PC, Vancouver, WA, USA; 3 Kansas City Cancer Center, Overland Park, KS, USA; 4 Jackson Oncology Associates PLLC, Jackson, MS, USA; 5 West Texas Cancer Center, Odessa, TX, USA; 6 Northeast Georgia Cancer Care, LLC, Athens, GA, USA; 7 Amgen Inc., South San Francisco, CA, USA; 8 Amgen Inc., Mississauga, Ontario, Canada

Introduction Panitumumab, a fully human antibody to the epidermal growth factor receptor (EGFR), is approved in the US as monotherapy in patients with metastatic colorectal cancer (mCRC) after disease progression on standard chemotherapy and in the EU, Canada, and Australia as monotherapy in patients with wild-type tumor KRAS status 1,2 The status of the KRAS gene in tumors (wild-type or mutant) is a predictive biomarker of response to anti-EGFR antibody monotherapy in patients with mCRC 3-5 PRECEPT is the first study to prospectively estimate the efficacy of panitumumab plus folinic acid/ 5-fluorouracil/irinotecan (FOLFIRI) treatment according to tumor KRAS status in patients receiving second-line treatment for mCRC

Study Objectives To estimate the effect of tumor KRAS mutation status on efficacy endpoints in patients receiving panitumumab plus FOLFIRI treatment as second-line therapy in patients with mCRC To evaluate the safety profile of second-line panitumumab with FOLFIRI

Methods Study Design Phase 2, multicenter, open-label, single-arm, clinical trial conducted in the U.S. Patients received panitumumab (6 mg/kg) plus FOLFIRI until disease progression, panitumumab intolerability, death, or withdrawal from study Tumor tissue (paraffin block or slides) for KRAS testing was collected at screening Tumor response was assessed by the investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST) at week 8 and every 8 weeks thereafter

Methods Study Design (continued) Tumor response was assessed approximately every 12 weeks in patients who discontinued second-line treatment prior to disease progression Adverse events were described using MedDRA version 11.1 terms and graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 Patients who discontinued the study underwent a follow-up safety visit 4 weeks ± 7 days after the last dose of second-line treatment

Methods (continued) Study Schema a Patients who discontinued second-line treatment prior to disease progression had repeat radiographic tumor assessments once every 12 weeks for up to 52 weeks after the final patient was enrolled FOLFIRI, folinic acid/5-fluorouracil/irinotecan; Q2W, Every 2 weeks; CR, Complete response; PR, Partial response; SD, Stable disease

Study Endpoints Efficacy Endpoints (Investigator assessment) –Objective response rates –Best overall response rates –Progression-free survival –Time to disease progression –Time to treatment failure –Overall survival Safety Endpoints –Incidence and severity of adverse events –Changes in selected laboratory values

Key Eligibility Criteria ≥ 18 years of age Metastatic adenocarcinoma Prior treatment failures: –Disease progression following fluoropyrimidine and oxaliplatin- based chemotherapy with bevacizumab for mCRC (  4 therapeutic doses of bevacizumab and oxaliplatin) –Toxicity from fluoropyrimidine, oxaliplatin, and/or bevacizumab Measurable disease per modified RECIST Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate hematologic, renal, hepatic, and metabolic functions No prior irinotecan therapy No prior anti-EGFR therapy

KRAS Determinations DNA was isolated from fixed tumor samples Mutant KRAS was detected using a KRAS mutation kit (DxS Ltd, Manchester, UK) that used allele-specific, real- time polymerase chain reaction (PCR) –The kit can detect approximately 1% of mutant DNA in a background of wild-type genomic DNA –The test identifies 7 somatic mutations in codons 12 and 13: Gly 12 Asp Gly 12 Ala Gly 12 Val Gly 12 Ser Gly 12 Arg Gly 12 Cys Gly 13 Asp

Statistical Analyses Analysis sets: –Primary Analysis Set – all patients receiving ≥ 1 dose of panitumumab with valid baseline KRAS status available (N = 109) –Safety Analysis Set – all patients receiving ≥ 1 dose of panitumumab (N = 115) Efficacy data were stratified by KRAS mutation status Hazard ratios for progression-free survival, overall survival, and time to treatment failure were estimated from a Cox Proportional Hazards regression model with only KRAS effect (wild-type vs mutant)

Results Patient Disposition 109 patients have been enrolled, received ≥ 1 dose of panitumumab, and had known KRAS status –64 patients (59%) had wild-type KRAS –45 patients (41%) had mutant KRAS At the time of data cut-off (02 January 2009), 106 patients (97%) had discontinued second-line treatment –The most common reason was disease progression – 67 patients (61%) 35 patients (55%) had wild-type KRAS 32 patients (71%) had mutant KRAS 81 patients (74%) had ended the study –The most common reason was death – 70 patients (64%) 34 patients (53%) had wild-type KRAS 36 patients (80%) had mutant KRAS

Results Baseline Patient Demographics and Disease Characteristics (Primary Analysis Set) a Time from diagnosis to date of enrollment ECOG, Eastern Cooperative Oncology Group

Results Best Objective Response (Primary Analysis Set) CL, Confidence limit The odds ratio of the best objective response rate for wild-type vs mutant KRAS status was 1.57 (95% CL: 0.58, 4.26) in favor of wild-type KRAS status

Results Progression-Free Survival (Primary Analysis Set)

Results Overall Survival (Primary Analysis Set)

Results Time to Treatment Failure (Primary Analysis Set)

The median estimated time to disease progression was: –26 weeks (95% CL: 16, 34) in patients with wild-type KRAS –17 weeks (95% CL: 15, 25) in patients with mutant KRAS Results Other Efficacy Endpoints

Results Treatment Exposure (Safety Analysis Set) a Included 6 patients without known KRAS status RDI, Relative dose intensity

Results Summary of Adverse Events (Safety Analysis Set) a Included 6 patients without known KRAS status AE, Adverse event; SD, Standard deviation Premedication is not required for panitumumab treatment –2 patients had an investigator-reported infusion-related reaction; subsequent doses and administrations were not altered

Results Comparison of Safety Between KRAS Strata More patients with tumors with mutant KRAS –experienced serious adverse events (44%) vs those with wild-type KRAS (36%) –died during the study (80%) vs those with wild-type KRAS (53%) –died within 60 days of the first dose (7%) vs those with wild-type KRAS (2%)

Results Grade 5 Events 8 grade 5 events were reported on study –In patients with tumors with wild-type KRAS, events included: sepsis (n = 2; 1 death was deemed to be related to panitumumab by the investigator); metastatic colon cancer (n = 1); and respiratory failure (n = 1) –In patients with tumors with mutant KRAS, events included: cardiac arrest (n = 1); colon cancer (n = 1); and rectal cancer (n = 1) –In patients with tumors with unknown KRAS, 1 patient died of metastatic colon cancer

Results Adverse Events of Interest a (Safety Analysis Set) a Related and unrelated to panitumumab; MedDRA v11.1 preferred terms; grading based on NCI CTCAE v3.0 (with modification for panitumumab-related skin toxicities) b Included 6 patients without known KRAS status

Conclusions Panitumumab plus FOLFIRI as second-line treatment appeared to be well tolerated and had antitumor activity in patients with mCRC Numerical differences in favor of patients with wild-type KRAS were observed in efficacy endpoints in PRECEPT, consistent with results from previous panitumumab monotherapy studies 4,5 –The observed response rates, progression-free survival, and overall survival are encouraging in patients with tumors expressing wild-type KRAS Panitumumab had a safety profile consistent with other FOLFIRI panitumumab trials

References 1.Vectibix ® Prescribing Information, Amgen Inc. Thousand Oaks, CA; Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy refractory metastatic colorectal cancer. J Clin Oncol. 2007;25: Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007;67: Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26: Freeman DJ, Juan T, Reiner M, et al. Association of KRAS, BRAF, and PI3K mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab monotherapy. Clinical Colorectal Cancer. 2008;7: