Updated results of STEPP, a phase 2, open‑label study of pre-emptive versus reactive skin toxicity treatment in metastatic colorectal cancer (mCRC) patients receiving panitumumab + FOLFIRI or irinotecan‑only chemotherapy as second-line treatment Edith P. Mitchell,1 Mario LaCouture,2 Heather Shearer,3 Nicholas Iannotti,4 Bilal Piperdi,5 Madhavan V. Pillai,6 Feng Xu,7 Mohamed Yassine7 1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; 2Northwestern University, Chicago, IL, USA; 3Piedmont Hematology Oncology Associates PLLC, Winston-Salem, NC, USA; 4Hematology Oncology Associates of Treasure Coast, Port Saint Lucie, FL, USA; 5University of Massachusetts Medical Center, University Campus, Worcester, MA, USA; 6Virginia Oncology Care PC, Richlands, VA, USA; 7Amgen Inc., Thousand Oaks, CA, USA STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

Introduction Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is approved in the US as monotherapy for mCRC after disease progression on standard chemotherapy and in the EU as monotherapy in patients with wild-type KRAS tumor status1,2 Skin toxicities are the most common treatment‑related side effects of anti‑EGFr therapy2,3 The STEPP study is first prospective study to examine differences between pre‑emptive and reactive skin treatment for skin toxicities associated with panitumumab in combination with FOLFIRI or single-agent irinotecan chemotherapy In addition, efficacy by KRAS mutational status was evaluated Reminder- this is an interim analysis of STEPP. It is the final analysis of the primary endpoint. Jakobovits A, et al. Nat Biotech. 2007; 25:1134-1143. Vectibix® Prescribing Information, Amgen Inc. Thousand Oaks, CA; 2007. Perez-Soler R, Saltz L. J Clin Oncol. 2005; 23:5235-5246. STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

Study Objectives, and Pre-Emptive Skin Treatment Regimen Primary objective: To estimate the difference in incidence rates of specific ≥ grade 2 skin toxicities of interest between patients in the pre-emptive and reactive skin treatment arms during the 6-week skin treatment period Other objectives: Safety and efficacy of panitumumab plus Q2W or Q3W chemotherapy by skin treatment and KRAS status Pre-emptive skin treatment regimen administered weeks 1 to 6: Skin moisturizer – apply to face, hands, feet, neck, back, and chest daily in the morning upon rising Sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection) – apply to exposed skin areas before going outdoors Topical steroid (1% hydrocortisone cream) – apply to face, hands, feet, neck, back, and chest at bedtime Doxycycline 100 mg BID STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

STEPP Study Schema n = 48 n = 47 n = 95 TUMOR SKIN OVER AL L TOXICITY RESPONSE EVALUATION SKIN TOXICITY EVALUATION OVER AL L SURVIVAL FOLLOW UP SAFETY FOLLOW UP RANDOMI ZAT I ON PROGRESS ION SCREEN I NG Pre-Emptive Skin Treatment n = 48 Reactive Skin Treatment Patients (planned N = 95) received either: FOLFIRI Q2W + pmab 6.0 mg/kg Q2W (n = 55), or Irinotecan Q3W + pmab 9.0 mg/kg Q3W (n = 40) Within each stratum, patients were randomized 1:1 to either: Pre‑emptive skin treatment during weeks 1 to 6 Reactive skin treatment Pre-emptive skin treatment included the administration of: Skin moisturizer Sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection) 1% hydrocortisone cream Doxycycline 100 mg BID n = 47 n = 95 Q8W or Q9W STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

Key Eligibility Criteria ≥ 18 years of age Unresectable metastatic adenocarcinoma of the colon or rectum that cannot, per investigator, be cured by surgical resection at the time of randomization Measurable disease per modified RECIST Failure of first-line treatment containing fluoropyrimidine and oxaliplatin-based chemotherapy with or without bevacizumab for mCRC Treatment failure was defined as toxicity-based from fluoropyrimidine, oxaliplatin, and/or bevacizumab or progression of disease ECOG performance status of 0 or 1 No prior irinotecan use for the treatment of mCRC STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

Statistical Considerations and Analysis Set This is an interim analysis of STEPP consisting of: The final analysis of the primary endpoint (N = 95) Analysis sets from this interim analysis included: Primary analysis set: all randomized patients (N = 95) that had the opportunity to complete the first tumor response assessment at week 13 or week 14 KRAS primary analysis set: all patients who had known KRAS status from the primary analysis set (N = 87; 8 patients were excluded) Safety analysis set: all patients who received at least 1 dose of investigational drug (N = 95) This is an interim analysis of STEPP consisting of the final analysis of the primary endpoint as described earlier. Analysis sets from this interim analysis included: Primary analysis set…. KRAS primary analysis set STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

Pre-Emptive Skin Treatment Reactive Skin Treatment Patient Disposition Pre-Emptive Skin Treatment (n = 48) Reactive Skin Treatment (n = 47) Patients who ended second-line treatment – n (%) 47 (98) 41 (87) Reason for ending treatment – n (%) Disease progression 30 (63) 25 (53) Adverse event 5 (10) 5 (11) Patient request 4 (8) 4 (9) Death 3 (6) 2 (4) Other 5 (12) Median (Q1, Q3) follow-up time1, weeks 26.9 (13, 39.9) 30.6 (17.7, 51) 1 Follow-up time is calculated as the randomization date to the last on-study or long-term follow-up visit STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL

Baseline Demographics and Disease Characteristics Pre-Emptive Skin Treatment (n = 48) Reactive Skin Treatment (n = 47) Sex – n (%) Men 32 (67) 26 (55) Race – n (%) White or Caucasian 34 (71) 40 (85) Black or African American 6 (13) 5 (11) Hispanic or Latino 5 (10) 1 (2) Other 3 (6) Age – years, median (min, max) 60 (24, 84) 61 (40, 86) ECOG performance status – n (%) 30 (64) 1 12 (25) 17 (36) 2 2 (4) 0 (0) Primary tumor type – n (%) Colon 28 (60) Rectal 14 (29) 19 (40) Number of metastatic sites – n (%) 18 (38) > 1 30 (63)

Primary Endpoint: Incidence of Grade 2 or Higher Skin Toxicities1 in Pre-Emptive vs Reactive Skin Treatment Arms (During the Skin Treatment Period, Final Analysis) Pre-Emptive Skin Treatment (n = 48) Reactive Skin (n = 47) Patients with grade 2 or higher skin toxicity – n 14 29 Percentage (95% CL) 29 (16, 42) 62 (48, 76) Odds Ratio2 (95% CL) 0.3 (0.1, 0.6) Most Severe with grade 2 or higher skin toxicity3 Grade 2 – n 11 19 23 (11, 35) 40 (26, 54) Grade 3 – n 3 10 Percentage (95% CL) 6 (0, 13) 21 (10, 33) 1 Specific skin toxicities of interest per protocol 2 Odds ratio is estimated from a logistic regression model including treatment (pre-emptive vs reactive) that includes an adjustment for chemotherapy stratum (Q2W vs Q3W). 3 There were no grade 4 skin toxicities of interest during the skin treatment period. NR = not reached

Time to First Occurrence of Grade 2 or Higher Skin Toxicity (Kaplan-Meier Estimate) Events Median (95% CI) N (%) Weeks Pre-emptive 14 (29) NR Reactive 29 (62) 2.7 (2.1, 6.3) HR = 0.4 (95% CI: 0.2 - 0.7)

Investigator Assessment Interim Best Overall Response by Pre-Emptive and Reactive Skin Treatment Group Investigator Assessment Central Review Pre-Emptive (n = 48) Reactive (n = 47) Best overall response – n (%) 8 (17) 7 (15) 4 (9) Complete response 2 (4) 3 (6) 0 (0) Partial response 6 (13) Stable disease 23 (48) 25 (53) 24 (50) 26 (55) Disease control 31 (65) 32 (68) 30 (64) Disease progression 10 (21) 9 (19) Not done or unevaluable

Panitumumab + Irinotecan Interim Efficacy by Panitumumab Plus FOLFIRI or Irinotecan Chemotherapy Regimen Panitumumab + FOLFIRI (n = 55) Panitumumab + Irinotecan (n = 40) Investigator Review Central Review Central Review Best overall response – % (95% CI) 24 (12, 35) 16 (7, 26) 5 (0, 12) Progression free survival – months (95% CI) 6.1 (4.6, 7.4) 4.6 (3.1, 6.2) 3.5 (2.3, 5.2) 4.0 (2.3, 6.0) Overall survival – months (95% CI) 13.3 (10.9, -) 9.2 (7.0, 13.8)

Investigator Assessment Interim Best Overall Response by KRAS Status (KRAS Primary Analysis Set) Investigator Assessment Central Review Wild-Type KRAS (n = 49) Mutant KRAS (n = 47) Best overall response – n (%) 10 (20) 4 (11) 7 (14) 3 (8) Complete response 3 (6) 2 (5) 0 (0) Partial response Stable disease 27 (55) 19 (50) 21 (55) Disease control 37 (76) 23 (61) 34 (69) 24 (63) Disease progression 9 (24) 6 (16) Not done or unevaluable 5 (10) 8 (21)

Interim Progression-Free Survival by KRAS Status (KRAS Primary Analysis Set) Local Review Central Review Events Median (95% CI) N (%) Months Wild-type 36 (73) 6.3 (4.6, 8.2) Mutant 29 (76) 3.8 (2.3, 5.2) HR = 0.7 (95% CI: 0.4-1.1) Events Median (95% CI) N (%) Months Wild-type 34 (69) 5.7 (4.0, 6.8) Mutant 25 (66) 3.3 (2.8, 5.2) HR = 0.7 (95% CI: 0.4-1.2)

Summary of Adverse Events Pre-Emptive Skin Treatment (n = 48) Reactive (n = 47) Patients with any adverse event – n (%) 48 (100) 47 (100) Maximum grade 3 or higher 29 (60) 38 (81) Serious adverse events 13 (27) 23 (49) Skin treatment-related adverse events 10 (21) 3 (6) Panitumumab discontinued due to adverse events 9 (19) 11 (23) Ended second-line treatment due to adverse events 6 (13) 7 (15) All deaths on study1 17 (35) 18 (38) 1 No panitumumab-related deaths were reported within 30 days of the last panitumumab administration.

Adverse Events of Interest1 Pre-Emptive Skin Treatment (n = 48) Reactive Skin Treatment (n = 47) Any Grade Grade 3 Grade 4 Patients with any adverse event – n (%) 48 (100) 19 (40) 5 (10) 47 (100) 25 (53) 9 (19) Dermatitis acneiform 37 (77) 2 (4) 0 (0) 40 (85) 10 (21) Nausea 31 (65) 3 (6) 26 (55) 4 (9) Fatigue 29 (60) 27 (57) 5 (11) Diarrhea 27 (56) 7 (15) 15 (32) Vomiting 22 (46) 17 (36) Pustular rash 13 (27) 8 (17) Neutropenia 1 (2) 20 (43) Hypomagnesemia 13 (28) Dehydration 6 (13) 1 There were no grade 5 adverse events of interest.

Conclusions In this analysis of STEPP, the incidence of specific grade 2 or higher skin toxicities during the 6 week skin treatment period was reduced by more than 50% in the pre-emptive treatment group compared with the reactive treatment group Numerical differences in favor of the wild-type KRAS group were observed for all efficacy endpoints The combination of panitumumab and irinotecan based chemotherapy was well tolerated The STEPP study continues per protocol for safety and efficacy A phase 3 registrational study is currently ongoing to investigate panitumumab with FOLFIRI by KRAS mutational status in second-line mCRC STEPP ASCO GI 2008 - DRAFT - CONFIDENTIAL