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Introduction

Final skin toxicity and patient‑reported outcomes results from PRIME: A randomized phase 3 study of panitumumab + FOLFOX4 for 1 st ‑line metastatic colorectal cancer.

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Introduction

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  1. Final skin toxicity and patient‑reported outcomes results from PRIME: A randomized phase 3 study of panitumumab + FOLFOX4 for 1st‑line metastatic colorectal cancer Jean‑Yves Douillard,1 Salvatore Siena,2 JosepTabernero,3 Ronald Burkes,4 Mario E. Barugel,5 Yves Humblet,6 David Cunningham,7Feng Xu,8Zhongyun Zhao,8 Roger Sidhu8 1Centre René Gauducheau, Nantes, France; 2Ospedale Niguarda Ca’ Granda, Milan, Italy; 3Vall d'HebrónUniversityHospital, Barcelona, Spain; 4Mount SinaiHospital, Toronto, Canada; 5Hospital de Gastroenterología, Buenos Aires, Argentina; 6Centre du Cancer de l'UniversitéCatholique de Louvain, Brussels, Belgium; 7The Royal Marsden NHS Foundation Trust, London, United Kingdom; 8Amgen Inc., ThousandOaks, California;

  2. Introduction • Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR) • PRIME (20050203) was an open-label, randomized, global, phase 3 trial prospectively investigating panitumumab + FOLFOX4 vs FOLFOX4 alone as 1st-line treatment for metastatic colorectal cancer (mCRC) among patients with wild-type (WT) KRAS tumors • The results from the primary analysis of this study showed that panitumumab + FOLFOX4 was generally tolerable and significantly improved progression-free survival (PFS) in patients with WT KRAS mCRC vs FOLFOX4 alone1 • Efficacy and patient-reported outcomes (PRO) by skin toxicity (ST) severity from the final descriptive analysis of PRIME are presented

  3. Study Schema and Stratification LONG TERMFOLLOW UP END OF TREATMENT ENROLLMENT SCREENING Treatment Arm 1: Panitumumab 6.0-mg/kg Q2W + FOLFOX4 Q2W Canada Costa Rica Mexico Treatment Arm 2: FOLFOX4 Q2W Argentina Brazil Chile South Africa PRO assessments every 4 weeks Disease assessment every 8 weeks Australia Belgium Czech Republic France Hungary Italy Latvia Poland Spain Switzerland United Kingdom PRIME Study Countries • Enrollment target: • 1150 patients • Randomization stratification: • Eastern Cooperative Oncology Group (ECOG) performance status: 0–1 vs 2 • Geographic region: Western Europe, Canada, and Australia vs rest of the world • Q2W – Every 2 weeks

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

  5. Key Eligibility Criteria • Metastatic adenocarcinoma of the colon or rectum • No prior treatment for mCRC • Adjuvant 5-fluorouracil-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

  6. Statistical Considerations for the ST and PRO Analyses • The ST and PRO analyses were based on data from the final analysis that occurred 30 months after the last patient was enrolled • PRO were assessed using the EuroQolEQ‑5D Health State Index Score and the EQ‑5D Overall Health Rating • PRO data were analyzed using a mixed‑effect model repeated measure (MMRM) model to analyze longitudinal PRO data with missing values2,3 • All statistical tests were performed at a 2‑sided significance level of 5% without adjusting for multiple comparisons and are regarded as descriptive • The primary goal of this analysis was to evaluate the correlation between worst grade ST and efficacy and PRO endpoints • The ST analysis includes the primary endpoint of PFS, and secondary endpoints of OS, objective response, and safety • Landmark analysis was performed in the efficacy by ST analyses to reduce bias • A landmark of day 28 was selected because > 50% of patients had their maximum grade ST by day 28 • Patients who were alive without disease progression at day 28 were included in the ST analyses

  7. Demographics and Disease Characteristics *One patient had missing/unknown ECOG performance status score

  8. PFS WT KRAS and PFS ≥ 28 Days Worst Grade ST Severity WT KRAS - Final Analysis

  9. WT KRAS - Final Analysis OS WT KRAS and PFS ≥ 28 Days Worst Grade ST Severity

  10. Objective Response by Worst Grade ST Severity (Central Review) aIncluded only patients with baseline measurable disease per central review All responses were required to be confirmed at least 28 days after the response criteria were first met

  11. PRO Results Summary of EQ-5D Health State Index Score Through Treatment Discontinuation Overall Health Rating Change From Baseline Through Disease Progression and Impact of ST on PRO (Central Assessment - WT KRAS PRO Analysis Set) The minimal clinically important difference is 0.08 for the EQ-5D Health State Index Score and 7 for the EQ-5D Overall Health Rating4

  12. Grade 3/4 Adverse Events of Interest by Worst Grade ST Severity MedDRA: Medical Dictionary for Regulatory Activities

  13. In the final analysis of PRIME, results from the primary analysis were confirmed: Statistically significant improvement in PFS in patients with WT KRAS mCRC receiving panitumumab+FOLFOX4 vs FOLFOX4 alone Trend toward improved OS in patients with WT KRAS mCRC receiving panitumumab+FOLFOX4 vs FOLFOX4 alone Higher objective response in patients with WT KRAS mCRC receiving panitumumab+FOLFOX4 Patients with WT KRAS mCRC receiving 1st-line treatment with panitumumab who develop ST grade 2-4 had longer PFS and OS vs patients receiving chemotherapy alone No significant difference in PRO was observed using the EQ-5D instrument in patients with WT KRAS mCRC who received panitumumab+FOLFOX4 that developed high grade 2-4 ST vs low grade 0-1 ST The adverse event profile was as expected for patients receiving anti-EGFR antibodies Conclusions

  14. References • Douillard JY, et al. J ClinOncol. 2010;28:4697-4705. • SiddiquiO, et al. J Biopharm Stat. 2009;19:227-246. • Lane P. Pharm Stat. 2008;7:93-106. • Pickard AS, et al. Health Qual Life Outcomes. 2007;5:70.

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