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This study was funded by Amgen Inc.

Panitumumab Efficacy and Patient-Reported Outcomes in Metastatic Colorectal Cancer Patients With Wild-Type KRAS Tumor Status.

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This study was funded by Amgen Inc.

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  1. Panitumumab Efficacy and Patient-Reported Outcomes in Metastatic ColorectalCancer Patients With Wild-Type KRAS Tumor Status Rafael G. Amado, MD;1 Michael Wolf, MS;1 Dan Freeman, PhD;1Marc Peeters, MD, PhD;2 Eric Van Cutsem, MD, PhD;3Salvatore Siena, MD;4 Sid Suggs, PhD;1 Giovanna Devercelli, PhD;1Michael Woolley, PhD;1 and David Chang, PhD1 1Amgen Inc., Thousand Oaks, CA, USA; 2Ghent University Hospital, Ghent, Belgium;3University Hospital Gasthuisberg, Leuven, Belgium; 4Ospedale Niguarda Ca’Granda, Milan, Italy This study was funded by Amgen Inc.

  2. Disclosures • This study was sponsored by Amgen Inc. • R.G. Amado, M. Wolf, D. Freeman, S. Suggs, S. Patterson, D. Chang, T. Juan, M. Reiner, and R. Radinsky are Amgen employees and own Amgen Inc. stock. • M. Peeters, Amgen advisory board and Amgen honoraria; E. Van Cutsem, Amgen advisory board and Amgen honoraria; N.J. Meropol, consultant for Amgen, Genentech, and Imclone; J. Berlin, advisory boards for Amgen, BMS, and Imclone.

  3. Introduction • Panitumumab, a fully human monoclonal antibody directed against EGFr, has demonstrated efficacy as monotherapy in patients with metastatic colorectal cancer (mCRC).1, 2 • Recent studies have suggested that the mutational status of the KRAS gene in tumors of patients with mCRC may impact response to anti-EGFr therapies.3 • A phase 3, randomized controlled trial demonstrated that panitumumab was well tolerated and significantly improved progression-free survival compared with best supportive care alone, in refractory mCRC patients.2 • Using tumor samples from that study,we correlated KRAS status with clinical and patient-reported outcomes. 1 Vectibix™ Prescribing Information; Amgen Inc. Thousand Oaks CA, 2007 2 Van Cutsem E, et al. J Clin Oncol 2007;25:1658–1664. 3 Benvenuti S, et al. Cancer Res. 2007;67:2643–2648.

  4. R A N D O M I Z E Panitumumab PD Follow-up 6.0 mg/kg Q2W + BSC BSC PD Follow-up Optional Panitumumab Crossover Study KRAS Analysis of a Phase 3, Randomized, Controlled Trial Comparing Panitumumab vs BSC in Colorectal Cancer Hypothesis: There would be a larger treatment effect in patients with wild-type KRAS compared to patients with mutant KRAS 1:1 • Randomization stratification • ECOG score (0-1 vs. 2) • Geographic region (Western EU vs. Central & Eastern EU vs. Rest of World) Van Cutsem E et al. J Clin Oncol 2007;25:1658–1664.

  5. Objectives and Analysis Methodology Primary Objective • To assess whether the effect of panitumumab on PFS was significantly greater in patients with wild-type KRAS compared with mutant KRAS Secondary Objectives • To assess whether panitumumab improves PFS compared with BSC alone in patients with wild-type KRAS • To assess whether panitumumab improves overall survival (OS) compared with BSC alone in patients with wild-type KRAS Test for a PFS effect among all randomized patients at a 5% level Test for quantitative PFS effect interaction, i.e., wild-type effect > mutant p ≤ 0.05 p > 0.05 Compare PFS in wild-type KRAS subset STOP p ≤ 0.05 p > 0.05 Compare OR & OS in wild-type KRAS subset STOP

  6. 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 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 Assay Used to Detect KRAS Mutational Status • Gly 12 Arg • Gly 12 Cys • Gly 13 Asp

  7. Patient Disposition Screened N = 1,040 Randomized N = 463 Randomized to BSC alone N = 232 Randomized to panitumumab + BSC N = 231 Excluded from KRAS analyses (missing or unevaluable) N = 36 KRAS mutant N = 84 KRAS mutant N = 100 WT KRAS N = 124 WT KRAS N = 119 Received P’mab in X-over protocol N = 77 Received P’mab in X-over protocol N = 90 r p r t o l n = 9 0 BSC = Best supportive care; WT = wild-type

  8. M e d ian M ean M e d ian M ean 1 . 0 0 1 1 . . 0 0 ( W ks) E v e n t s /N ( % ) ( W ks) ( W ks) E v e n t s /N ( % ) ( W ks) 0 . 9 9 0 0 . . 9 9 P P m m ab ab + + BS BS C C 76/84 76/84 ( ( 90) 90) 7.4 7.4 9.9 9.9 P m ab + BS C 115/124 ( 93) 12.3 19.0 0 . 8 8 10.2 10.2 BS BS C C A A l l one one 95/100 95/100 ( ( 95) 95) 7.3 7.3 0 0 . . 8 8 9.3 BS C A l one 114/119 ( 96) 7.3 0 . 7 7 0 0 . . 7 7 HR = 0.99 (95% CI: 0.73–1.36) HR = 0.45 (95% CI: 0.34–0.59) 0 . 6 6 0 0 . . 6 6 Proportion Event-free S t r at i f i ed l og - r a n k te s t , p < 0.00 0 1 0 . 5 5 0 0 . . 5 5 0 . 4 4 0 0 . . 4 4 0 . 3 3 0 0 . . 3 3 0 . 2 2 0 0 . . 2 2 0 . 1 1 0 0 . . 1 1 0 . 0 0 0 0 . . 0 0 0 2 4 6 8 10 12 14 16 18 2 0 2 2 2 4 2 6 2 8 3 0 3 2 3 4 3 6 3 8 4 0 4 2 4 4 4 6 4 8 5 0 5 2 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 W eek s W eek s P P a a t t i i e e n n t t s s a a t t R R i i s s k k P P m m a a b b + + B B SC SC 8 4 8 4 7 7 8 8 7 7 6 6 7 7 6 2 2 1 2 2 0 6 1 8 0 6 8 5 6 5 5 5 5 5 5 4 5 4 4 4 4 4 4 2 4 2 2 2 2 2 2 2 2 2 2 2 2 1 2 1 1 1 1 1 12 4 11 9 11 2 10 6 8 0 6 9 6 3 5 8 5 0 4 5 4 4 4 4 3 3 2 5 2 1 2 0 1 7 1 3 1 3 1 3 1 0 7 7 6 5 5 10 0 10 9 1 0 7 9 7 1 6 7 1 7 3 6 7 1 2 3 2 7 2 1 2 9 1 1 0 9 1 9 0 8 9 6 8 5 6 5 5 4 5 4 4 4 4 4 4 4 4 4 4 3 4 3 3 3 3 2 3 2 2 2 2 2 2 2 11 9 10 9 9 1 8 1 3 8 2 0 1 5 1 5 1 4 1 1 1 0 9 9 6 6 6 6 5 4 3 3 2 2 2 2 1 B B S S C C A A l l on on e e PFS by KRAS Status and Treatment Mutant KRAS WT KRAS • The relative effect of panitumumab versus BSC was significantly greater in patients with WT versus mutant KRAS. • The quantitative-interaction test comparing the magnitude of the relative treatment effect on PFS between WT and mutant KRAS was statistically significant (p < 0.0001). • PFS was significantly greater for panitumumab treatment compared with BSC in the WT KRAS group (stratified log-rank test p < 0.0001).

  9. P P m m ab ab + + BS BS C C BS BS C C A A l l one one PFS – Interval Censored (Sensitivity Analysis) by KRAS Status and Treatment Mutant KRAS WT KRAS M e d ian M e d ian E v e n t s /N ( % ) ( W ks) E v e n t s /N ( % ) ( W ks) 76/84 ( 90) 8 115/124 ( 93) 16 95/100 ( 95) 8 114/119 ( 96) 8 HR=0.49 (95% CI: 0.37-0.65) HR=1.07 (95% CI: 0.77-1.48) Weeks Weeks

  10. Mutant Wild-Type 160 160 140 140 PR (0%) SD (12%) PD (70%) PR (17%) SD (34%) PD (36%) 120 120 100 100 80 80 60 60 Pmab + BSC % Change % Change 40 40 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 Patient Patient 160 160 140 140 PR (0%) SD (8%) PD (60%) PR (0%) SD (12%) PD (75%) 120 120 100 100 80 80 60 60 BSC Alone 40 40 % Change % Change 20 20 0 0 -20 -20 -40 -40 -60 -60 -80 -80 Patient Patient Maximum Percent Decrease in Target Lesions Final Analysis, KRAS Evaluable Group BSC = Best supportive care; Pmab = panitumumab

  11. Overall Survival by KRAS Status and Treatment Median In Months Events / N (%) 1.0 Pmab, Wild-type 107 / 124 (86) 8.1 0.9 BSC, Wild-type 110 / 119 (92) 7.6 0.8 Pmab, Mutant 79 / 84 (94) 4.9 0.7 BSC, Mutant 95 / 100 (95) 4.4 0.6 Survival Probability Wild-type vs. Mutant (treatment arms combined) 0.5 0.4 HR = 0.67 (95% CI: 0.55–0.82) adjusted for treatment and randomization factors (ECOG, region) 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Months Pmab WT, N 124 92 58 35 18 9 3 2 1 BSC WT, N 119 82 54 28 18 10 5 1 0 Pmab Mutant, N 84 51 21 10 6 3 3 1 0 BSC Mutant, N 100 55 30 18 11 3 0 0 0

  12. Treatment Difference (95% CI) for FACT/NCCN Colorectal Cancer Symptom Index (FCSI) Mutant KRAS WT KRAS Imputed - LVCF Panitumumab - BCS Imputed - LVCF Panitumumab - BCS 20.00 20.00 16.00 16.00 12.00 12.00 8.00 8.00 4.00 4.00 FCSI Difference 0.00 0.00 -4.00 -4.00 -8.00 -8.00 -12.00 -12.00 -16.00 -16.00 4 8 12 16 4 8 12 16 Week Week MCID= -4.0

  13. 14.00 14.00 12.00 12.00 10.00 10.00 8.00 8.00 6.00 6.00 4.00 4.00 2.00 2.00 0.00 0.00 EORTC Global Health -2.00 -2.00 -4.00 -4.00 -6.00 -6.00 -8.00 -8.00 -10.00 -10.00 -12.00 -12.00 -14.00 -14.00 -16.00 -16.00 4 8 12 16 4 8 12 16 Week Treatment Difference (95% CI) for EORTC-QLQ-C30 Global Health Status Mutant KRAS WT KRAS Imputed - LVCF Panitumumab - BCS Imputed - LVCF Panitumumab - BCS Week MCID = -7.07

  14. Median (Wks) Events / N (%) Median (Wks) Events / N (%) 52 / 54 (96) 7.6 18 / 18 (100) 7.4 84 / 90 (93) 22.4 ≤ 66.667 1.0 ≤ 66.667 > 66.667 18 / 18 (100) 7.4 > 66.667 0.9 0.8 0.7 0.6 Proportion Event-Free 0.5 0.4 0.3 0.2 0.1 0 10 20 30 40 50 60 70 80 90 100 0.0 Weeks from Randomization Weeks from Randomization 0 10 20 30 40 50 60 70 80 90 PFS by Minimum Post-Baseline mDLQI Score, Panitumumab Landmark Safety Seta Mutant KRAS WT KRAS aExcludes patients with progression-free survival < 28 days. By mDLQI scores, dichotomization of PFS for degree of being bothered was explored using all possible cut points of mDLQI (based on the effect size from a Cox model) to find the maximum difference by mDLQI score.

  15. Conclusions • In patients with chemotherapy-refractory mCRC, the clinical efficacy of panitumumab monotherapy appears to be restricted to patients with WT KRAS tumors • Results of QOL analyses by KRAS status are consistent with clinical outcomes • KRAS genotyping of tumors should be strongly considered in patients with mCRC being treated with panitumumab monotherapy • Ongoing studies in 1st and 2nd lines will prospectively examine the effect of panitumumab in combination with chemotherapy in patients with WT and mutant KRAS tumors

  16. Acknowledgments • We thank the patients and their families for study participation, investigators and study personnel

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