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The KRAS Oncogene

Abstract 0007: Wild-type KRAS is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer: Results From a Randomized, Controlled Trial

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The KRAS Oncogene

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  1. Abstract 0007: Wild-type KRAS is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer: Results From a Randomized, Controlled Trial Rafael G. Amado, Michael Wolf, Dan Freeman, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Sid Suggs, Scott Patterson, David Chang Abstract 3014: Association of Somatic KRAS Gene Mutations and Clinical Outcome in Patients With Metastatic Colorectal Cancer Receiving Panitumumab Monotherapy Dan Freeman, Todd Juan, Neal J. Meropol, J. Randolph Hecht, Jordan Berlin, Eric Van Cutsem, Maureen Reiner, Robert Radinsky, Rafael G. Amado, Marc Peeters Analysis of KRAS Mutations in Patients With Metastatic Colorectal Cancer Receiving Panitumumab Monotherapy

  2. The KRAS gene encodes the human cellular homolog of the transforming gene Kirsten rat sarcoma-2 virus KRAS is a self-inactivating signal transducer It cycles from GDP bound (“off” state) to GTP bound (“on” state) in response to receptor activation This response is transient due to the intrinsic GTPase activity KRAS oncogenes harbor activating mutations yielding proteins with reduced GTPase activity These activating KRAS mutations are among the most common oncogenic alterations in cancer1 The KRAS Oncogene 1Malumbres and Barbacid. Nat Rev Cancer. 2003;3:459-465.

  3. EGFr Signal Transduction Ligand Ligand EGFRdimer Shc Signal Adapters and Enzymes Grb-2 STAT P13K SOS Ras Raf Akt PTEN MEK 1/2 Signal Cascade GSK-3 FKHR BAD mTOR TranscriptionFactors MAPK p27 Jun FOS Myc Cyclin D-1

  4. Single-Arm Studies Support the Hypothesis for KRAS as a Biomarker for EGFr Inhibitors WT, wild type; MT, mutant; cmab, cetuximab; CT, chemotherapy; pmab, panitumumab

  5. Patient samples from 3 Amgen panitumumab monotherapy, single-arm, phase 2 trials in metastatic colorectal cancer were obtained under an ancillary biomarker protocol The majority of patient samples were archived tumor samples from the primary resection KRAS mutational status was determined using cloning and sequencing of DNA isolated from paraffin-embedded tumor samples KRAS mutational status was correlated with clinical outcomes including response, progression-free survival, and overall survival KRAS Analysis of Single-Arm, Panitumumab Monotherapy Studies

  6. Objective Tumor Response PR partial response; SD, stable disease; PD, disease progression

  7. Median (95% CI) in Weeks _ Mutant: 7.4 (7.1–8.0) - - Wild-type: 16.2 (8.3–23.7) Progression-Free Survival for Panitumumab-Treated Patients by KRAS Status 1.0 Proportion with PFS 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Weeks From Enrollment Patients at Risk: Mutant 24 24 6 6 4 3 2 2 Wild-type 38 38 25 25 17 14 13 7 6 3 3

  8. 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 Best Supportive Care (BSC) in Colorectal Cancer Hypothesis: The treatment effect of panitumumab monotherapy is larger 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, Peeters et al. JCO. 2007;25:1658-1664.

  9. Objectives and Analysis Methodology • Primary Objective • To assess if the effect of panitumumab on progression-free survival (PFS) was significantly greater in patients with wild-type KRAS compared to patients 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 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

  10. 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

  11. Results: Prevalence of Mutant KRAS BSC, best supportive care

  12. Distribution of KRAS Mutations

  13. Baseline Disease Characteristics KRAS Evaluable Group ECOG, Eastern Cooperative Oncology Group; EGFr, epidermal growth factor receptor

  14. KRAS Evaluable Patients:PFS by Treatment Median In Weeks Mean In Weeks 1 . 0 Events/N (%) 0 . 9 Pmab + BSC 191/208 (92) 8.0 15.4 9.6 BSC Alone 209/219 (95) 7.3 0 . 8 0 . 7 HR = 0.59 (95% CI: 0.48–0.72) 0 . 6 Proportion with PFS 0 . 5 0 . 4 0 . 3 0 . 2 0 . 1 0 . 0 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 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 Weeks Patients at Risk Pmab + BSC 2 0 8 1 9 7 1 8 8 1 7 8 1 0 6 7 9 7 1 6 4 5 5 5 0 4 9 4 9 3 7 2 9 2 5 2 4 1 9 1 5 1 5 1 5 1 2 9 9 7 6 6 2 1 9 2 0 0 1 6 8 1 4 2 7 5 4 2 3 4 2 5 2 3 1 9 1 6 1 4 1 4 1 0 1 0 1 0 1 0 9 8 6 6 5 4 4 4 3 BSC Alone

  15. Mutant KRAS Subgroup:PFS by Treatment Median In Weeks Mean In Weeks 1.0 Events/N (%) 0.9 Pmab + BSC 76/84 (90) 7.4 9.9 0.8 10.2 BSC Alone 95/100 (95) 7.3 0.7 HR = 0.99 (95% CI: 0.73–1.36) 0.6 Proportion with PFS 0.5 0.4 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 36 38 40 42 44 46 48 50 52 Weeks Patients at Risk Pmab + BSC 84 78 76 72 26 10 8 6 5 5 5 5 4 4 4 4 2 2 2 2 2 2 2 1 1 1 100 91 77 61 37 22 19 10 9 8 6 5 5 4 4 4 4 4 4 3 3 3 2 2 2 2 BSC Alone

  16. Wild-type KRAS Subgroup: PFS by Treatment p < 0.0001 for quantitative-interaction test comparing PFS log-HR (pmab/BSC) between KRAS groups 1 1 . . 0 0 0 0 . . 9 9 Median In Weeks Mean In Weeks Events/N (%) 0 0 . . 8 8 Pmab + BSC 115/124 (93) 12.3 19.0 0 0 . . 7 7 9.3 BSC Alone 114/119 (96) 7.3 0 0 . . 6 6 HR = 0.45 (95% CI: 0.34–0.59) Stratified log-rank test, p < 0.0001 Proportion with PFS 0 0 . . 5 5 0 0 . . 4 4 0 0 . . 3 3 0 0 . . 2 2 0 0 . . 1 1 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 Weeks Patients at Risk 124 119 112 106 80 69 63 58 50 45 44 44 33 25 21 20 17 13 13 13 10 7 7 6 5 5 Pmab + BSC 6 10 9 9 6 6 6 5 4 3 3 2 2 2 2 1 119 109 91 81 38 20 15 15 14 11 BSC Alone

  17. Wild-Type KRAS Subgroup:Treatment Effect on PFS by Demographic/Disease Status Factors N HR 95% CI Favors: Pmab BSC All Randomized 243 0.45 0.34-0.59 Male 159 0.42 0.30-0.59 Female 84 0.46 0.29-0.73 Age: < 65 141 0.42 0.29-0.60 Age: 65+ 102 0.47 0.31-0.73 Primary: Colon 168 0.47 0.34-0.65 Primary: Rectal 75 0.36 0.21-0.61 ECOG: 0–1 211 0.47 0.35-0.62 ECOG: 2–3 32 0.35 0.15-0.82 Prior regimens: 2 142 0.54 0.38-0.76 Prior regimens: 3 90 0.28 0.17-0.47 Prior regimens: 3+ 100 0.27 0.17-0.44 Met. Sites: 1–2 172 0.42 0.30-0.59 Met. Sites: 3–5 69 0.52 0.30-0.89 EGFr: 1–< 10% 60 0.30 0.16-0.56 EGFr: 10–35% 101 0.49 0.31-0.75 EGFr: > 35% 81 0.34 0.20-0.58 EGFr: 1+ 69 0.33 0.18-0.63 EGFr: 2+ 127 0.41 0.28-0.60 EGFr: 3+ 47 0.37 0.18-0.75 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Hazard Ratio (Pmab/BSC) HR, hazard ratio; Pmab, panitumumab; BSC, best supportive care Adjusted for randomization factors (ECOG score, geographic region)

  18. Objective Tumor Response (Central Radiology) Pmab, panitumumab; BSC, best supportive care; CR, complete response; PR partial response; SD, stable disease; PD, disease progression

  19. Objective Tumor Response Extension Study 20030194(Investigator assessment) Pmab, panitumumab; CR, complete response; PR partial response; SD, stable disease; PD, disease progression

  20. 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

  21. Overall Survival by Treatment and KRAS 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–Wild-type 124 92 58 35 18 9 3 2 1 BSC–Wild-type 119 82 54 28 18 10 5 1 0 Pmab–Mutant 84 51 21 10 6 3 3 1 0 BSC–Mutant 100 55 30 18 11 3 0 0 0

  22. Overview of Safety From KRAS Analysis (Panitumumab-Treated Patients) AE, Adverse Event

  23. Conclusions • The efficacy of panitumumab monotherapy in metastatic CRC seems confined to patients with wild-type KRAS • KRAS genotyping of tumors should be strongly considered in patients with metastatic CRC 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 wild-type and mutant KRAS tumors • Future studies should investigate the role of KRAS mutational status in the adjuvant setting in colon cancer and in other indications

  24. Acknowledgments • We wish to thank the patients and their families for study participation • We also thank all investigators and study personnel 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.

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