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Introduction

Interim results from PACCE: irinotecan (Iri)/bevacizumab (bev) ± panitumumab (pmab) as first-line treatment (tx) for metastatic colorectal cancer (mCRC).

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Introduction

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  1. Interim results from PACCE: irinotecan (Iri)/bevacizumab (bev) ± panitumumab (pmab) as first-line treatment (tx) for metastatic colorectal cancer (mCRC) J. Randolph Hecht,1 Edith Mitchell,2 Tarek Chidiac,3Carroll Scroggin,4 Christopher Hagenstad,5 David Spigel,6John Marshall,7 Allen Cohn,8 Sam Suzuki,9 Thomas Griffin9 1UCLA School of Medicine, Los Angeles, CA; 2Kimmel Cancer Center of Thomas Jefferson University, Philadelphia, PA; 3Mid Ohio Oncology/Hematology, Inc, Columbus, OH; 4NEA clinic, Jonesboro, AR; 5Suburban Hematology-Oncology Associates, Lawrenceville, GA; 6Sarah Cannon Research Institute, Nashville, TN;7Georgetown University Hospital, Washington, DC; 8Rocky Mountain Cancer Centers, Denver, CO;9Amgen Inc., Thousand Oaks, CA This study was funded by Amgen Inc.

  2. Introduction • Panitumumab is a fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFr) and is approved as monotherapy in the US for the treatment of refractory mCRC • Early studies have suggested that combining EGFr, VEGF inhibitors, and chemotherapy may improve efficacy1,2 • PACCE was a US, community-based study designed to compare the efficacy and safety of bevacizumab and chemotherapy +/- panitumumab as first-line treatment for mCRC • This is an interim analysis for data available as of May 31, 2007 describing the safety and efficacy for the Iri-CT based cohort from PACCE (trial discontinued only panitumumab therapy in March 2007 after a planned interim analysis of ~231 PFS events in the Ox-CT cohort) 1Shaheen et al. Brit J Cancer 2001;85:584-589 2Saltz LB et al. ASCO 2005. Abstract #3508 (BOND2)

  3. Study Schema PACCE: Panitumumab Advanced Colorectal Cancer Evaluation Randomized, Open-Label, Controlled Phase 3b Trial Panitumumab 6 mg/kg Q2W + Ox-CT Bevacizumab Ox-based CT (eg, FOLFOX) N = 800 Inv choice S C R E E N I N G R A N D O M I Z E 1:1 Ox-CT + Bevacizumab Panitumumab 6 mg/kg Q2W + Iri-CT + Bevacizumab Iri-basedCT (eg, FOLFIRI) N = 200 Inv choice 1:1 Iri-CT + Bevacizumab Stratification Factors: ECOG score, prior adjuvant tx, disease site,Ox doses/Iri regimen, number of metastatic organs Tumor assessments: Q12W until disease progression or intolerability

  4. Investigator Choice – Iri-CT Regimens

  5. Key Eligibility Criteria • Age ³ 18 years old • Measurable mCRC per modified RECIST criteria • ECOG status 0 or 1 • Adequate hematologic, renal, and hepatic function • No prior chemotherapy or biologic therapy for mCRC • No adjuvant chemotherapy within 6 months • No major surgery within 28 days of randomization or elective and/or planned major surgical procedures during the trial • No clinically significant cardiovascular disease within 1 year prior to randomization • No EGFr testing required

  6. Study Endpoints and Design Characteristics • Primary endpoint of the PACCE study:* • Progression-free survival (PFS) by central review in the Ox-CT cohort • To detect a 30% improvement in median PFS in the panitumumab plus bev/Ox-CT vs the bev/Ox-CT • Planned interim analysis at ~231 Ox-CT PFS events • Iri-CT cohort analyses were descriptive only • Safety • Efficacy including: • Overall response rate (central and local review) • PFS (central and local review), TTF, OS • Exploratory biomarker analyses (eg, KRAS) *Powered for oxaliplatin cohort only; descriptive for irinotecan cohort

  7. Treatment: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aOf those who received any first-line treatment

  8. Baseline Demographics and Characteristics: Iri-CT Cohort (Interim Analysis, May 2007 Data Cutoff)

  9. Summary of Adverse Events: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) Safety set included all patients who were dosed. Graded per NCI CTCAE v3.0 *As reported by investigator – does not include disease progression (ie, neoplasms); n/a= not applicable

  10. Grade 3 or 4 Adverse Events of Interest: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) MedDRA v 9.0 preferred terms; graded per NCI CTCAE v 3.0 aSkin toxicity included multiple terms from the skin and subcutaneous and infections system organ class (SOC) bGrade 5 infections occurred in 2 (2%) pmab + bev/Iri-CT pts cGrade 5 pulmonary embolism occurred in 1 (1%) pmab + bev/Iri-CT pts Grade 5 gastrointestinal perforations occurred in 2 (2%) pmab + bev/Iri-CT pts

  11. Overall Response Rate: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aCT scans performed Q12W; responses did not require confirmationbCentral review unable to evaluate clinical disease progression (ie, non-radiographic PD); central review unable to accurately evaluate PD after surgical resectionscIncluded missing and unreadable scans

  12. 100% 80% 100% 80% 60% 40% 60% 20% 40% 20% 0% 0 5 10 15 20 25 0% Months 0 5 10 15 20 25 Interim PFS – Iri-CT Cohort (May 2007 Data Cutoff) Local Reviewb Central Reviewa Pmab+bev/Iri-CT Bev/Iri-CT HR= 1.21 (95% CI: 0.80, 1.82)* HR= 0.92 (95% CI: 0. (0.63, 1.34)* *Descriptive only *Descriptive only Months Pmab 115 74 23 7 1 0 115 86 33 7 2 0 Censored 0 19 32 6 4 0 0 9 31 11 1 1 No Pmab 115 76 23 6 1 0 115 85 27 6 0 0 0 29 34 7 2 0 0 14 34 11 3 0 Censored bCensoring based on last day of patient contact or visit Q2W aCensoring based on last available scan read centrally Q12W • Differences in censoring rules; more early censoring in central review and in bev/Iri-CT cohort • Central review unable to assess clinical disease progression • Central review unable to accurately evaluate PD after surgical resections • Investigator bias Central vs Local Review

  13. PFS - Differences Between Central vs Local Review • Differences in censoring rules • Central censoring: if endpoint not reached, pt was censored back to their last scan date (Q12W) • Local censoring: if endpoint not reached, pt was censored back to their last investigator contact (Q2W on treatment, Q12W post-treatment follow-up) • More early censoring in central review and in bev/Iri-CT cohort • Central review unable to assess clinical disease progression • Per protocol, central review defined as single radiologist read, no oncologist review • Central review unable to accurately evaluate PD after surgical resections • Potential investigator bias for local review

  14. Other Efficacy Endpoints: Iri-CT Cohort (Interim Analysis, May 2007 Data Cutoff) aDeaths at any time including long-term follow-up (post-study treatment) NE= not evaluable

  15. Reasons for First-Line Treatment Discontinuation: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aOf those who discontinued first-line treatment bOther included end of first-line treatment without progression, requirement for alternative therapy, administrative, lost to follow-up, and other

  16. Treatment Exposure: Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff) aBolus 5-FUbInfusional 5-FU n/a=not applicable

  17. Prevalence of Mutant KRAS:Iri-CT Cohort(Interim Analysis, May 2007 Data Cutoff)

  18. Overall Response Rate By KRAS Status(Interim Analysis, May 2007 Data Cutoff) aOdds ratio for pmab:control (greater than 1.0 favors pmab+bev/Iri-CT). Descriptive only

  19. SUMMARY • This is a descriptive interim analysis of bev/Iri-CT +/- panitumumab in the PACCE study • Response rates were higher in the panitumumab + bev/Iri-CT cohort; no significant differences in PFS and OS between cohorts were observed • Most patients withdrew due to non-progressive events (59% on panitumumab + bev/Iri-CT arm, 71% on bev/Iri-CT arm), similar to the Ox-CT cohort, limiting the utility of PFS as a valid endpoint in this study • Increased response rates with panitumumab + bev/Iri-CT were seen only in wild-type KRAS patients; these findings are consistent with previously reported data on KRAS analyses in the monotherapy setting1-3 • Further data collection and analyses are ongoing 1Amado RG et al. JCO 2008, Manuscript in press 2Khambata-Ford S et al. JCO 2007; 25: 3230-3237 3Lievre A et al. Cancer Res 2006;66: 3992-3995

  20. SUMMARY (cont.) • Phase 3 registrational studies are currently ongoing to investigate panitumumab with chemotherapy alone in first- line and second-line mCRC • Study 20050181 investigates FOLFIRI +/- panitumumab in second-line mCRC (Peeters et al., Abstract #335, Poster #A56) • PRIME/Study 20050203 investigates FOLFOX +/- panitumumab in first-line mCRC (Douillard et al., Abstract #443, Poster #A63) • Independent data monitoring committees for these studies have recommended continuation per protocol

  21. ACKNOWLEDGEMENTS • Patients who participated in this study and their families • All investigators, co-investigators, and study staffs at 194 sites across the US • The Amgen study team

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