Randomized phase 3 study of panitumumab with FOLFOX4 compared to FOLFOX4 alone as first-line treatment in patients with metastatic colorectal cancer: the PRIME trial S. Siena,1 J. Cassidy,2 J. Tabernero,3 R. Burkes,4 M.E. Barugel,5 Y. Humblet,6 D. Cunningham,7 F. Xu,8 J. Gansert,8 J.Y. Douillard9 1Ospedale Niguarda Ca’ Granda, Milan, Italy; 2The Beatson West Of Scotland Cancer Centre, Glasgow, United Kingdom; 3Vall d'Hebron University Hospital, Barcelona, Spain; 4Mount Sinai Hospital, Toronto, Canada; 5Hospital de Gastroenterología, Buenos Aires, Argentina; 6Centre du Cancer de l'Université Catholique de Louvain, Brussels, Belgium; 7The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8Amgen Inc., Thousand Oaks, California, 9Centre René Gauducheau, Nantes, France;

Introduction Panitumumab, a fully human monoclonal antibody targeting the EGFR, is approved for use as monotherapy for mCRC1,2 in patients with wild-type (WT) KRAS tumor status1 PRIME (20050203) is an open-label, randomized, global, phase 3 trial prospectively investigating panitumumab with FOLFOX4 vs FOLFOX4 alone as 1st-line treatment (tx) for mCRC among patients with WT KRAS tumors Originally designed to compare the tx effect in the all randomized population, the trial was amended, prior to any efficacy analysis and completion of enrollment, to focus on hypothesis testing in the WT KRAS subset 1Amgen Europe B.V. Vectibix® Summary of Product Characteristics. 2009 2Vectibix® Prescribing Information, Amgen Inc. Thousand Oaks, CA; 2009

Study Schema and Stratification END OF TREATMENT LONG TERM FOLLOW UP SCREENING ENROLLMENT Tx Arm 1: Panitumumab 6.0 mg/kg Q2W + FOLFOX4 Q2W Canada Mexico Costa Rica Tx Arm 2: FOLFOX4 Q2W Disease assessment every 8 weeks PRIME Study Countries South Africa Australia Brazil Chile Argentina United Kingdom Belgium France Spain Switzerland Italy Poland Czech Republic Hungary Latvia Enrollment Target: 1150 patients Randomization stratification: ECOG score: 0-1 vs. 2 Geographic Region: Western Europe, Canada, and Australia vs. Rest of the World

PRIME Study Timeline Final Primary SAP Amendment 10 Dec 2008 Protocol Amendment 10 Oct 2007 First Patient Enrolled 23 Aug 2006 Last Patient Enrolled 1 Feb 2008 KRAS Testing Feb-Apr 2009 2006 2007 2008 2009 Study Unblinding and PFS Primary Analysis 31 July 2009 KRAS SEQUENCE ANALYSIS (Selected Samples from CRC Phase 2 Studies) 20020408 KRAS ANALYSIS OS Primary Analysis Nov 2009 SAP = Statistical analysis plan

Study Objective and Endpoints Primary Objective: To assess the effect of panitumumab on progression-free survival (PFS) by KRAS status* Primary Endpoint: PFS (by blinded central radiology review) Other Key Endpoints: Overall survival (OS) Objective response rate (ORR) Time-to-response (TTR) Duration of response (DOR) Safety *KRAS status was determined by blinded, independent central testing

Key Eligibility Criteria Metastatic adenocarcinoma of the colon or rectum No prior tx for mCRC Adjuvant 5-FU-based therapy was allowed if disease recurrence occurred > 6 months after completion Prior oxaliplatin was not allowed No prior EGFR inhibitor therapy Measurable disease Paraffin-embedded tumor tissue available for central biomarker testing EGFR expression and KRAS status were not required at entry ECOG performance status 0-2 Adequate hematologic, renal, and hepatic function Signed informed consent

Statistical Considerations Sample size calculation for PFS 380 events in WT KRAS stratum 90% power for the WT pts (Hazard Ratio [HR] = 0.71) by stratified log-rank test 1150 patients planned At the time of the primary PFS analysis, a 0.001 nominal significance level was used to compare OS in an interim analysis in the WT and MT KRAS subsets The primary OS analysis was planned when at least 50% of patients in each tx arm had died in the WT subset A significance level of 0.0499 was used This trial was overseen by an independent DMC

Treatment Assignment by KRAS Status: SCREENED FOR ELIGIBILITY (n = 1378) EXCLUDED (DID NOT MEET INCLUSION CRITERIA (n = 195) PATIENTS RANDOMIZED (n =1183) PANITUMUMAB 6.0 mg/kg + FOLFOX4 (n = 593) FOLFOX4 (n = 590) TUMOR SAMPLE AVAILABLE AND KRAS TESTING COMPLETED (n = 546) TUMOR SAMPLE AVAILABLE AND KRAS TESTING COMPLETED (n = 550) KRAS WT PANITUMUMAB + FOLFOX4 (n = 325) KRAS MT PANITUMUMAB + FOLFOX4 (n = 221) KRAS WT FOLFOX4 (n = 331) KRAS MT FOLFOX4 (n = 219) MT: mutant (KRAS status)

Results: KRAS Ascertainment Panitumumab + FOLFOX4 FOLFOX4 Total Patients randomized, n 593 590 1183 Patients included in KRAS analysis – % 92 93 WT KRAS – % 60 MT KRAS – % 40 Patients with KRAS unevaluable, % 8 7 KRAS tumor status was determined using the DxS kit (Manchester, UK) that tests the 7 most common KRAS mutations in codons 12 and 13.

Demographics and Disease Characteristics WT KRAS MT KRAS Panitumumab + FOLFOX4 (n = 325) FOLFOX4 (n = 331) Panitumumab+ FOLFOX4 (n =221) (n = 219) Sex – Men, % 67 62 66 58 Age – years, median (min, max) 62 (27, 85) 61 (24, 82) 63 (33, 83) 61 (27, 82) Race – White, % 91 93 89 ECOG performance status, % 0-1 94 941 96 2 6 5 4 42 Region, % Western EU, Canada, Australia 60 56 54 Primary Diagnosis, % Colon cancer 65 68 73 Rectal cancer 34 35 32 27 Prior adjuvant, % 16 17 12 Sites of metastatic disease, % Liver only 18 14 Liver + other sites 69 71 Median follow-up time, months 13.2 12.5 10.8 12.0 1One patient had an unknown ECOG PS at baseline 2One patient had an ECOG score of 4 at baseline

WT KRAS: Progression-Free Survival Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 199 (61) 9.6 (9.2–11.1) FOLFOX4 215 (65) 8.0 (7.5–9.3) HR = 0.80 (95% CI: 0.66–0.97) P-value = 0.02 Patients at risk: Panitumumab+FOLFOX4 325 313 294 284 254 243 204 187 156 145 111 94 73 57 39 28 22 14 10 4 1 FOLFOX4 alone 331 321 296 281 242 231 185 172 127 113 82 65 41 36 29 22 16 12 10 2 1 1 1

WT KRAS: Subgroup Analyses for PFS Factors N Favors: Pmab No Pmab HR 95% CI All Randomized 656 0.80 0.66-0.97 Primary: Colon 430 0.79 0.62-1.00 Primary: Rectal 226 0.83 0.59-1.16 Liver mets: Yes 566 0.78 0.64-0.96 Liver mets: No 90 0.91 0.54-1.54 Liver mets only: Yes 116 0.82 0.50-1.34 Liver mets only: No 540 0.81 0.65-1.00 Met sites: < 3 363 0.85 0.65-1.11 Met sites: ≥ 3 290 0.76 0.57-1.02 ECOG: 0 369 0.68 0.52-0.90 ECOG: 1 248 0.92 0.68-1.24 ECOG: 2 38 1.99 0.96-4.15 Age ≥ 65 261 1.02 0.75-1.38 Age < 65 395 0.70 0.54-0.89 Men 421 0.71 0.55-0.90 Women 235 1.00 0.73-1.39 0.10 1.00 10.00 Hazard Ratio (Pmab / No Pmab)

WT KRAS: Overall Survival Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 165 (51) 23.9 (20.3-28.3) FOLFOX4 190 (57) 19.7 (17.6-22.6) HR = 0.83 (95% CI: 0.67–1.02) P-value = 0.07 Months Survival Probability 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Patients at risk: Panitumumab+FOLFOX4 325 315 310 288 266 242 227 217 207 189 164 135 104 74 55 29 9 2 FOLFOX4 alone 331 320 301 281 265 242 223 207 188 170 145 116 77 56 36 21 9 3

WT KRAS: Subgroup Analyses for OS Factors N Favors: Pmab No Pmab HR 95% CI All Randomized 656 0.83 0.67-1.02 Primary: Colon 430 0.82 0.64-1.05 Primary: Rectal 226 0.77 0.53-1.12 Liver mets: Yes 566 0.77 0.61-0.96 Liver mets: No 90 1.12 0.65-1.91 Liver mets only: Yes 116 0.93 0.51-1.69 Liver mets only: No 540 0.79 0.63-0.99 Met sites: <3 363 0.88 0.65-1.17 Met sites: ≥3 290 0.71 0.53-0.96 ECOG: 0 369 0.72 0.53-0.98 ECOG: 1 248 0.89 0.65-1.22 ECOG: ≥2 38 1.46 0.73-2.92 Age ≥65 261 0.81 0.59-1.11 Age <65 395 0.80 0.61-1.06 Men 421 0.77 0.59-1.00 Women 235 0.88 0.62-1.24 0.10 1.00 10.00 Hazard Ratio (Pmab / No Pmab)

WT KRAS: Objective Response Central Review Panitumumab + FOLFOX4 (n = 317)1 FOLFOX4 (n = 323)1 Objective response rate, % (95% CI)2 55 (50–61) 48 (42–53) Complete response, % 0.3 Partial response, % 55 47 Stable disease, % 30 36 Progressive disease, % 7 11 1Included only patients with baseline measurable disease per central review 2P = 0.068 (descriptive); exact test of stratified odds ratio All responses were confirmed no earlier than 28 days after the response criteria were first met

PFS by KRAS Mutation Status WT KRAS MT KRAS Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 199 (61) 9.6 (9.2–11.1) FOLFOX4 215 (65) 8.0 (7.5–9.3) Events n (%) Median (95% CI) months Panitumumab + FOLFOX4 167 (76) 7.3 (6.3–8.0) FOLFOX4 157 (72) 8.8 (7.7–9.4) HR = 0.80 (95% CI: 0.66–0.97) P-value = 0.02 HR = 1.29 (95% CI: 1.04–1.62) P-value = 0.02

OS by KRAS Status WT KRAS MT KRAS Events/n (%) Median months Survival Probability 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 100% 90% 80% 70% Survival Probability 60% 50% 40% 30% 20% 10% 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Months Months Events/n (%) Median months Panitumumab+ FOLFOX4 165 (51) 23.9 (20.3-28.3) FOLFOX4 190 (57) 19.7 (17.6-22.6) HR = 0.83 (95% CI: 0.67–1.02) P-value = 0.07 Events/n (%) Median months Panitumumab+ FOLFOX4 152 (69) 15.5 (13.1-17.6) FOLFOX4 142 (65) 19.3 (16.5-21.8) HR = 1.24 (95% CI: 0.98–1.57) P-value = 0.07 An interim analysis test at a 0.1% Haybittle-Peto boundary nominal level of the treatment difference was performed (p value would be required to be < 0.001 to achieve significance) Similar to PFS, OS was reduced in patients with MT tumors receiving pmab, though this approached but did not reach statistical significance since a p-value < 0.001 would have been required For mutant population EGFR mAB drop in rate 4.5% for pmab arm vs 12.3% for FOLFOX4 arm Amgen Confidential Information / Not for Public Disclosure

MT KRAS: Objective Response Central Review Panitumumab + FOLFOX4 (n = 215)1 FOLFOX4 (n = 211)1 Objective tumor response, % (95% CI)2 40 (33 - 46) 40 (34 - 47) Complete response Partial response 40 Stable disease 38 43 Progressive disease 13 11 aIncluded only patients with baseline measurable disease per central review bP = 0.98 (descriptive); exact test of stratified odds ratio All responses were confirmed no earlier than 28 days after the response criteria were first met

Panitumumab + FOLFOX4 (n = 322) Panitumumab + FOLFOX4 (n = 217) Treatment Exposure WT KRAS MT KRAS   Panitumumab + FOLFOX4 (n = 322) FOLFOX4 (n = 327) Panitumumab + FOLFOX4 (n = 217) FOLFOX4 (n = 218) Median number of cycles received Panitumumab 11 - 10 Oxaliplatin 5-FU (bolus) 12 5-FU (continuous infusion) Relative dose intensity - % 81 83 77 79 80 78 Median cumulative total dose Panitumumab - mg/kg 62 57 Oxaliplatin – mg/m2 859 865 824 856 5-FU (bolus) – mg/m2 8627 8618 8294 8711 5-FU (continuous infusion) – mg/m2 13483 13229 12878 13109 Results presented only for patients that received study therapy

Grade 3/4 Adverse Events of Interest WT KRAS MT KRAS Adverse Event by MedDRA - % Panitumumab + FOLFOX4 (n = 322) FOLFOX4 (n = 327) Panitumumab + FOLFOX4 (n = 217) FOLFOX4 (n = 218) Patients with any event 84 69 80 73 Skin toxicity 36 2 30 1 Neutropenias 42 41 37 47 Diarrhea 18 9 20 10 Neurologic toxicity 16 17 Stomatitis/ Oral mucositis 6 3 Hypomagnesemia <1 Paronychia Pulmonary embolism1 4 Febrile neutropenia2 Infusion-related reaction3 (panitumumab) - Fatal adverse events4 - % 5 8 1There were 2 grade 5 events of pulmonary embolism in the panitumumab arm (1 each in the WT and MT KRAS group) 2There was 1 grade 5 febrile neutropenia in the panitumumab arm (MT KRAS group) 3There were no grade 4 infusion-related reactions (panitumumab) 4Includes cases in which primary cause of death was reported to be disease progression; 2 were reported to be related to panitumumab - pneumonia and pnemonitis (both KRAS WT) MedDRA = Medical Dictionary for Regulatory Activities

Conclusions In this large randomized phase 3 trial, results were prospectively analyzed according to tumor KRAS status – an important predictive biomarker for EGFR tx in 1st-line mCRC In patients with WT KRAS tumors: panitumumab significantly improved PFS when added to FOLFOX4 (median 9.6 vs 8.0 mo; HR = 0.80, p = 0.02) A favorable effect on OS was observed, although it did not reach statistical significance (median 23.9 vs 19.7 mo; HR = 0.83, p = 0.072). Response rates were higher in patients who received panitumumab (55% vs 48%) In patients with MT KRAS tumors, outcomes were inferior for panitumumab + FOLFOX4 vs FOLFOX4 alone (mechanism unknown) Panitumumab was well-tolerated when administered with FOLFOX4 The AE profile was as expected for an anti-EGFR antibody Grade 3/4 panitumumab-related infusion reactions were rare: (n = 2/539)

Acknowledgements The authors wish to thank: The patients and their families that participated in this trial The investigators and their study staff worldwide for their participation in the conduct and reporting of this study The study team at Amgen