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1 Fighting a Smarter War On Colon Cancer: Value as a new endpoint? John L. Marshall, MD Tel: (202) Fax: (202)

2 Stakeholder Motivation Stakeholders FDA CMS/Payers NCI/CTEP PhRMA Community Onc Academic Onc Patients Priority/Agenda Safety and Efficacy Cost Control/Value Cure Cancer Markets, ROI Efficient/Quality Care Clinical Trial Accrual Cure/Benefit/Altruism

3 Gastrointestinal (GI) Cancers Facts GI cancers represent the most common and fatal cancers in the world 2009: 275,720 new diagnosis of GI Cancers and 135,830 deaths in the US alone Anal Cancer Colorectal Cancer Esophageal Cancer Gallbladder Cancer Liver Cancer Pancreatic Cancer Small Intestine Cancer Stomach/Gastric Cancer No two cancers are alike and treatments must be selected based on an individual s tumor characteristics, by personalized medicine

4 Breast Cancer Nation

5 Why Not Brown?

6 Our Current Model of Colon Cancer

7 The Laws from Mt Sinai: 2005 Agents that work in Stage IV colon cancer will work in Stage II and III Transitive math (AxB=BxA) Refractory stage IV = Front line stage IV FOLFOX = FOLFIRI Combining targeted agents would be our pathway to the promised land Dual antibody therapy EGFR receptor expression is valuable We would keep finding blockbuster drugs/targets

8 Advances in the Treatment of Colorectal Cancer ? Targeted therapies 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab Ziv-Aflibercept KRAS Regorafanib 8

9 Inconvenient Truths The majority of U. S. cancer patients are treated with practice guideline, evidencebased therapies. Fewer than 5 percent of cancer patients participate in clinical trials Evidence-based medicine highly effective medicine We both curse and cling to our health insurance

10 2012 ESMO Guidelines: Sequence of Treatment by Line Schmoll et al. Ann Oncol. 2012;23:

11 U S Oncology Network pathways preserve survival, reduce cost by 34% in metastatic colon cancer. Table 1: Impact of pathways in colon cancer Overall survival (mos) Chemo Cost ($) Total Cost ($) Pathway (limited types) Non-pathway (no limits) , , , ,020 P value 0.03 <0.001 <0.001 Hoverman R, et al. Am J Manag Care May;17 Suppl 5 Developing:SP45-52.

12 Study design PFS1 PFS2 observation SD or better after 6 cycles CAPOX- B R PD Re-introduction CAPOX-B PD capecitabine + bevacizumab

13 PFS1 Probability Time (mths) Maintenance PFS1 median PFS1 - Observation : 4.1 (95% CI: ) median PFS1 - Maintenance : 8.5 (95% CI: ) ITT, events/n ( 256 / / 279 ) Median PFS1 Observation 4.1 m [95%CI: ] Maintenance 8.5 m [95%CI: ] HR= 0.44 ( 95% CI: ) Stratified stratified log-rank HR p-value [95%CI: ] p value < adjusted HR 0.41, p < Observation Observation Maintenance

14 OS Probability Time (mths) Overall Survival median OS - Observation : 18.2 (95% CI: ) median OS - Maintenance : 21.7 (95% CI: ) ITT, events/n ( 204 / / 279 ) HR= 0.87 ( 95% CI: ) Maintenance stratified log-rank p-value Median OS Observation 18.2 m [95%CI: ] Maintenance 21.7 m [95%CI: ] Stratified HR 0.87 [95%CI: ] p value adjusted HR 0.80, p Observation preliminary survival analysis Observation Maintenance

15 ML18147 (TML) Study Design (Phase III) BEV + standard first-line CT (either oxaliplatin or irinotecan-based) (n = 820) PD Randomize 1:1 CT switch: Oxaliplatin Irinotecan Irinotecan Oxaliplatin Standard second-line CT (oxaliplatin or irinotecanbased) until PD BEV (2.5 mg/kg/wk) + standard second-line CT (oxali or irino-based) until PD Primary endpoint Secondary endpoints included OS from randomization PFS Best ORR Safety Stratification factors First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS ( 9 months, >9 months) Time from last BEV dose ( 42 days, >42 days) ECOG PS at baseline (0/1, 2) Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.

16 OS Estimate PFS Estimate OS: ITT Population PFS: ITT Population CT (n = 410) BEV + CT (n = 409) Unstratified a HR: 0.81 (95% CI: ) P =.0062 (log-rank test) Stratified b HR: 0.83 (95% CI: ) P =.0211 (log-rank test) CT (n=410) BEV + CT (n=409) Unstratified a HR: 0.68 (95% CI: ( ) P<.0001 (log-rank test) Stratified b HR: 0.67 (95% CI: ) P<.0001 (log-rank test) mo 11.2 mo mo 5.7 mo Time, Months Time, Months No. at risk No. at risk CT CT BEV + CT BEV + CT Median follow-up: CT, 9.6 months (range ); BEV + CT, 11.1 months (range ) a Primary analysis method; b Stratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS ( 9 months, >9 months), time from last dose of BEV ( 42 days, >42 days), ECOG performance status at baseline (0, 1) Bennouna J, et al. Lancet Oncol. 2012;14(1):29-37.

17 Targeting EGFR Finding drivers in the rear view mirror

18 Irinotecan and 5-FU/FA +/- Cetuximab The CRYSTAL Trial EGFR-expressing Metastatic CRC Study Design R Cetuximab + FOLFIRI Cetuximab IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly + irinotecan (180 mg/m 2 ) +5-FU (400 mg/m 2 bolus mg/m 2 as 46-hr continuous infusion) +FA every 2 weeks Stratification factors: Regions ECOG PS Populations Randomized patients: n=1217 Safety population: n=1202 ITT population: n=1198 FOLFIRI irinotecan (180 mg/m 2 ) +5-FU (400 mg/m 2 bolus mg/m 2 as 46-hr continuous infusion) +FA every 2 weeks Van Cutsem E, et al. 43 rd ASCO; June 1-5, Abstract 4000.

19 CRYSTAL Trial PFS Van Cutsem E, et al. 43 rd ASCO; June 1-5, Abstract 4000.

20 The Nature of the Disease

21 EGFR: One of Many Signaling Modules in Cancer Cells Hanahan, Weinberg, Cell 100:57,

22 mabs Target Tumor Cell-Bound EGFR Ligand EGFR Extracellular PTEN PI3K Akt Ras Raf MEK Intracellular MAPK Cell survival Proliferation DNA Angiogenesis Cell Motility Metastasis

23 Pathway vs. Network signaling Pathway Network Newtonian Chaotic A. Friedman and N. Perrimon, Cell 128, January 26,

24 EGFR Shc PI3-K Grb2 Sos-1 AKT MEKK-1 Ras Raf Signaling Proteins mtor MKK-7 MEK JNK ERK Apoptosis Resistance Proliferation Angiogenesis Metastasis Cell Response to Signaling 24

25 Which Target? Shc PI3-K Grb2 Sos-1 AKT MEKK-1 Ras Raf mtor MKK-7 MEK JNK ERK 25

26 Shc Grb2 Sos-1 PI3-K Ras MEK MEKK-1 Raf JNK MKK-7 ERK AKT Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center 26

27 The EGF Receptor Interactome Where s the target? Sos-1 PI3-K Shc Grb2 Ras MEK MEKK-1 Raf JNK MKK-7 ERK AKT 638 Genes Courtesy of I. Serebriiskii and E. Golemis, Fox Chase Cancer Center 27

28 mabs Target Tumor Cell-Bound EGFR Ligand EGFR Extracellular PTEN PI3K Akt Ras Raf MEK Intracellular MAPK Cell survival Proliferation DNA Angiogenesis Cell Motility Metastasis

29 Probability of PFS CRYSTAL: FOLFIRI +/- Cetuximab PFS in Patients With KRAS Wildtype Tumors FOLFIRI (n = 350) FOLFIRI + Cetuximab (n = 316) No of events Median PFS 8.4 months 9.9 months [95% CI] [ ] [ ] HR [95% Cl] P value 0.70 [ ] Number of patients FOLFIRI FOLFIRI + cetuximab Time, Months FOLFIRI FOLFIRI + cetuximab Van Cutsem E, et al. J Clin Oncol. 2011;29(15):

30 Proportion Event-Free Proportion Event-Free PRIME (FOLFOX +/- Panitumumab) PFS by KRAS Mutation Status Final Analysis WT KRAS MT KRAS 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Months 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Months Panitumumab + FOLFOX4 Median, months (95% CI) 10.0 ( ) FOLFOX4 8.6 ( ) HR = 0.80 (95% CI: ) Log-rank P value =.01 Douillard J, et al. J Clin Oncol. 2011;29(Suppl): Abstract Panitumumab + FOLFOX4 Median, months (95% CI) 7.4 ( ) FOLFOX4 9.2 ( ) HR = 1.27 (95% CI: ) Log-rank P value =.02

31 Updated Analysis of PRIME Study RAS and BRAF Status Panitumumab + FOLFOX4 FOLFOX4 Alone Oliner KS, et al. J Clin Oncol. 2013;31(Suppl): Abstract Total KRAS exon 2 (codons 12/13) Wildtype Mutant Wildtype KRAS exon 2 tumors tested for RAS and BRAF N = 320 N = 321 N = (16) 57 (18) 108 (17) KRAS exon 3 (codon 61) n (%) WIldtype 308 (96) 306 (95) 614 (96) Mutant 10 (3) 14 (4) 24 (4) Failure 2 (1) 1 (0) 3 (0) KRAS exon 4 (codons 117/146) n (%) WIldtype 288 (90) 296 (92) 584 (91) Mutant 21 (7) 15 (5) 36 (6) Failure 11 (3) 10 (3) 21 (3) NRAS exon 2 (codons 12/13) n (%) WIldtype 308 (96) 307 (96) 615 (96) Mutant 8 (3) 14 (4) 22 (3) Failure 4 (1) 0 (0) 4 (1) NRAS exon 3 (codon 61) n (%) WIldtype 305 (95) 305 (95) 610 (95) Mutant 12(4) 14 (4) 26 (4) Failure 3 (1) 2 (1) 5 (1) NRAS exon 4 (codon 117/146) n (%) WIldtype 316 (99) 313 (98) 629 (98) Mutant 0 (0) 0 (0) 0 (0) Failure 4 (1) 8 (2) 12 (2) BRAF exon 15 (codon 600) n (%) WIldtype 286 (89) 280 (87) 566 (88) Mutant 24 (8) 29 (9) 53 (8) Failure 10 (3) 12 (4) 22 (3) KRAS exon 2 codon 12/13 KRAS exon 3 codon 61 KRAS exon 4 codon 117/146 NRAS exon 2 codon 12/13 NRAS exon 3 codon 61 BRAF exon 15 codon % 4% 6% 3% 4% 8% 17%

32 Proportion Alive Proportion Alive Proportion Alive Proportion Alive OS in Patients w/ WT KRAS Exon2 2 and WT RAS mcrc OS in Patients w/ MT RAS mcrc 100% - 90% - 80% - 70% - 60% - 50% - 40% - 30% - 20% - 10% - HR 0.83 (KRAS wildtype cod 12/13) 0% % - 90% - 80% - 70% - 60% - 50% - 40% - 30% - 20% - 10% - 0% - HR 0.78 (all RAS wildtype) Original WT KRAS Exon 2 Testing Panitumumab + FOLFOX4 FOLFOX4 alone WT RAS Events n/n (%) 165/325 (51) 190/331 (57) Median mos (95% CI) 23.9 ( ) 19.7 ( ) Hazard ratio = 0.83 (95% CI, ) P =.072 Panitumumab + FOLFOX4 FOLFOX4 alone Events n/n (%) 128/259 (49) 148/253 (58) Median mos (95% CI) 26.0 ( ) 20.2 ( ) Hazard ratio = 0.78 (95% CI, ) P = % - 90% - 80% - 70% - 60% - 50% - 40% - 30% - 20% - 10% - 0% - 100% - 90% - 80% - 70% - 60% - 50% - 40% - 30% - 20% - 10% - 0% - Detriment! MT RAS Panitumumab + FOLFOX4 FOLFOX4 alone OS in Patients w/ WT KRAS Exon 2/MT Other RAS mcrc WT KRAS Exon 2/ MT Other RAS Panitumumab + FOLFOX4 FOLFOX4 alone Events n/n (%) 187/272 (69) 175/276 (63) Events n/n (%) 35/51 (69) 33/57 (58) Median mos (95% CI) 15.6 ( ) 19.2 ( ) Hazard ratio = 1.25 (95% CI, ) P = Median mos (95% CI) 17.1 ( ) 18.3 ( ) Hazard ratio = 1.29 (95% CI, ) P = Oliner KS, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3511.

33 FIRE-3 Phase III Study Design FOLFIRI + Cetuximab mcrc first-line therapy KRAS wildtype N = 592 Randomize 1:1 Cetuximab: 400 mg/m 2 IV 120 min initial dose 250 mg/m 2 IV 60 min q 1 w FOLFIRI + Bevacizumab Bevacizumab: B e v a c i z u m a b : 5 mg/kg m g / k g i IV. v min m i n q 2 w FOLFIRI: 5FU: 400 mg/m 2 (IV bolus); folinic acid: 400 mg/m 2 irinotecan: 180 mg/m 2 5FU: 2400 mg/m 2 (IV 46h) Primary objective: ORR (investigator assessed) Designed to detect a difference of 12% in ORR induced by FOLFIRI + cetuximab (62%) as compared to FOLFIRI + bevacizumab (50%) 284 evaluable patients per arm needed to achieve 80% power for an one-sided Fisher s exact test at an alpha level of 2.5% Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

34 FIRE-3 ORR Primary Endpoint FOLFIRI + Cetuximab FOLFIRI + Bevacizumab ORR % 95%-CI % 95%-CI ITT population (N = 592) Odds ratio P.183 Assessable for response (N = 526) P = Fisher s exact test (one-sided) Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

35 Probability of Survival FIRE-3 PFS Events n/n (%) FOLFIRI + Cetuximab 250/297 (84.2%) FOLFIRI + Bevacizumab 242/295 (82.0%) Median (months) % CI HR 1.06 (95% CI ) Log-rank P = Number at risk Months Since Start of Treatment Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA

36 Probability of Survival FIRE-3 OS 1.0 Events n/n (%) Median (months) 95% CI FOLFIRI + Cetuximab 158/297 (53.2%) FOLFIRI + Bevacizumab 185/295 (62.7%) PFS HR 0.77 (95% CI: ) Log-rank P = Number at risk Split of curves Months Since Start of Treatment Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

37 Potential Reasons for OS Difference With Same PFS Imbalance in postprogression therapy No evidence for this imbalance! First-line therapy affects sensitivity of cancer cells to subsequent treatments Early clonal selection Is there an optimal sequence of treatment options? First-line therapy is highly effective in a subpopulation of CRC with long-lasting treatment benefit Failure to use VEGF agents across mulitple lines of therapy?

38 Q: Is More Always Better? 38

39 Correlation Between Survival and Percentage of Patients Receiving Three Drugs in Phase 3 Trials Median OS (months) Patients with three drugs (%) 3 drugs: 5-FU/LV, irinotecan, oxaliplatin. Grothey A, et al. J Clin Oncol. 2005;23:

40 FOLFOXIRI vs FOLFIRI JCO 2007

41 TRIBE Study Design 508 mcrc pts 1st line unresectable stratified by center PS 0/1-2 adjuvant CT R FOLFIRI+bev (up to 12 cycles) FOLFOXIRI+bev (up to 12 cycles) 5-FU/LV +Bev 5-FU/LV +Bev PD INDUCTION MAINTENANCE

42 Secondary endpoint: Response rate (updated) - ITT population Best Response, % FOLFIRI + bev N = 256 FOLFOXIRI + bev N = 252 p Complete Response 3% 5% Partial Response 50% 60% Response Rate 53% 65% Stable Disease 32% 25% Progressive Disease 11% 6% Not Assessed 4% 4%

43 Primary endpoint: PFS (updated) ITT population FOLFIRI + bev FOLFOXIRI + bev Progression-free survival probability Median follow up: 32.3 mos FOLFIRI + bev: N = 256 / Progressed = 226 FOLFOXIRI + bev: N = 252 / Progressed = 213 FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos Unstratified HR: 0.77 [ ] p=0.006 Stratified HR: 0.75 [ ] p=0.003 F-up time (months) FOLFIRI/bev FOLFOXIRI/bev

44 Secondary endpoint: OS (preliminary) ITT population FOLFIRI + bev FOLFOXIRI + bev Median follow up: 32.3 mos Overall survival probability FOLFIRI + bev: N = 256 / Died = 155 FOLFOXIRI + bev: N = 252 / Died = 131 FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 31.0 mos Unstratified HR: 0.83 [ ] p=0.125 Stratified HR: 0.79 [ ] p=0.054 F-up time (months) FOLFIRI/bev FOLFOXIRI/bev

45 Aflibercept Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹ Aflibercept Blocks all human VEGF-A isoforms, VEGF-B and placental growth factor (PlGF)² High affinity binds VEGF-A and PlGF more tightly than native receptors Contains human amino acid sequences¹ 1. Holash. Proc Natl Acad Sci. 2002;99: Tew. Clin Cancer Res. 2010;16:

46 VELOUR Study Design Metastatic Colorectal Cancer Stratification factors: - ECOG PS (0 vs 1 vs 2) - Prior bevacizumab (Y/N) R A N D O M I Z E 600 Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks 1:1 Disease Progression 600 Placebo IV, day 1 + FOLFIRI q2 weeks Death Primary endpoint: Overall survival Sample size: HR 0.8, 90% power and a 2-sided type I error 0.05 Final analysis of OS: Analyzed at 863 th death event using a 2-sided nominal significance level of (α spending function)

47 Proportion of Patients Proportion of Patients VELOUR: Efficacy Results (ITT Population) Adding aflibercept to FOLFIRI in patients with metastatic CRC previously treated with an oxaliplatin-based regimen resulted in significant OS and PFS benefits OS No. at Risk Stratified HR = (95.34% CI, ) Log-rank P = Placebo/FOLFIRI Median = months Time (months) Placebo AFL Aflibercept/FOLFIRI Median = months PFS Van Cutsem E et al. J Clin Oncol. 2012;30: Reprinted with permission American Society of Clinical Oncology. All rights reserved No. at Risk Stratified HR = (99.99% CI, ) Log-rank P = Placebo/FOLFIRI Median = 4.67 months Aflibercept/FOLFIRI Median = 6.90 months Time (months) Placebo AFL

48 Safety Anti-VEGF Associated Events By Prior Treatment with Bevacizumab *Systematic pre-dosing urine spot urinalysis Patients Receiving Aflibercept Safety population, % of patients No prior bevacizumab N = 424 Prior bevacizumab N = 187 Grouped Term, PT All Grade Grade 3/4 All Grade Grade 3/4 Proteinuria* Hypertension Haemorrhage Epistaxis GI origin Dysphonia (PT) Headache (PT) Venous thromboembolic event Pulmonary embolism Arterial thromboembolic event Fistula Compromized wound healing GI perforation

49 Multiple signaling pathways activated in CRC Multiple pathways implicated in CRC, including: 1 3 EGF / EGFR VEGF / VEGFR PDGF / PDGFR FGF / FGFR Downstream pathways: RAS RAF MEK ERK PI3K PTEN AKT mtor Figure adapted from Siena S et al Kopetz et al showed that several compensatory pathways are activated during therapy with bevacizumab + FOLFIRI 3 Provides rationale for using a multitargeted agent following progression 1. Macarulla T et al. Clin Colorectal Cancer Siena S et al. J Natl Cancer Inst Kopetz S et al. J Clin Oncol 2010

50 CORRECT study design mcrc after standard therapy R A N D O M I Z AT I O N 2 : 1 Regorafenib + BSC 160 mg orally once daily 3 weeks on, 1 week off Placebo + BSC 3 weeks on, 1 week off Primary Endpoint: OS 90% power to detect 33.3% increase (HR=0.75), with 1-sided overall a=0.025 Multicenter, randomized, double-blind, placebo-controlled, phase III 2:1 randomization Strat. factors: prior anti-vegf therapy, time from diagnosis of mcrc, geographical region Global trial: 16 countries, 114 active centers 1,052 patients screened, 760 patients randomized within 10 months Secondary endpoints: PFS, ORR, DCR

51 Survival Distribution Function CORRECT Primary Endpoint: Overall Survival Regorafenib Placebo Median 6.4 months 5.0 months 95% CI Hazard ratio: 0.77 (95% CI, ) 1-sided P = Placebo (n = 255) Regorafenib (n = 505) Days From Randomization Primary endpoint met prespecified stopping criteria at interim analysis. (1-sided P< at approximately 74% of events required for final analysis). Grothey A et al. Lancet. 2013;381: Reprinted with permission from Elsevier.

52 Survival Distribution Function CORRECT Secondary Endpoint: Progression-Free Survival 1.00 Regorafenib Placebo Median 1.9 months 1.7 months 95% CI Hazard ratio: 0.49 (95% CI, ) 1-sided P< Placebo (n = 255) Regorafenib (n = 505) Days From Randomization Grothey A et al. Lancet. 2013;381: Reprinted with permission from Elsevier.

53 Antoni van Leeuwenhoek ( ) Invented the microscope around

54 What can we predict?

55 Contrast of Appearance vs. Expression Phenotyping Microscope Low Grade High Grade Treatment Advice Microarray Low Risk High Risk 55

56 Cancer is driven by hyperactive or defective protein circuits The components of these circuits contain the drug targets of the future. Patient A Patient B Each patient s cancer is different. A drug that works for one patient may not work for another patient with the same cancer.

57 Colon Cancer is more than one disease 50-60% 40-50% kras Wild Type kras mutant + EGFR Agents 15-20% - EGFR Agents 80-85% MSI-High MSS? No 5FU And of course it is very many more than the 4 sub-groups above 57

58

59 Regulatory Approval vs Payer Approval FDA CMS Safety and Efficacy Pay for it somehow

60 Safety and Efficacy Hundreds to thousands of patients Incredible cost Incredible risk p < 0.05 OS = 1.4 months Approved (and paid for)

61 A war should be fought together Our healthcare system is fragmented, with each component making individual and discrete decisions and with its own lobby What we need is an interconnected system in which the various components are complementary

62

63 Regulatory Approval vs Payer Approval Great Britain Regulatory Approval Cash NICE Value Metric Access PHS Approved NO

64 Poorer Countries Their patients do our trials Limited access to the drugs they helped test

65 Crowded Closets

66 Clinical Research 2.0

67 Finding Value Come together Listen to each other Respect what we hear Find the common threads Weave a new fabric - provide global healthcare with value

68 Engaging the 97% Better education/information Incentives for patients and providers No added incentives for delivering SOC Honor our soldiers in the war on cancer Recognized the shared investment in research Docs, hospitals, NCI, Industry, Payers, Patients Target substantial therapeutic benefit Breakthrough Designation Reduce concept to approval time line Embrace the emerging markets

69

70 Fundamental Shifts In Cancer Care Yesterday Consumption Individual Practices Rich Countries Microscope Safety and Efficacy Large trials 1.4 months QOL Patient as a Subject Chaotic Data Collection Institutional IRBs National Approvals Tomorrow Outcomes Healthcare Systems All Countries Gene Profile Value Small trials Substantial Improvement Patient Reported Outcomes Patient as a Partner Standard Data Collection Central/National IRBs Global Approvals

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