Il carcinoma colorettale. La terapia della neoplasia colorettale: Il trattamento medico

Transcription

1 Il carcinoma colorettale. La terapia della neoplasia colorettale: Il trattamento medico Dott. Francesco Giuliani Dipartimento di Oncologia Medica U.O. Oncologia Medica e Sperimentale IRCCS Ospedale Oncologico Giovanni Paolo II - Bari

2 Advanced Colorectal Cancer 90 s BSC 5-FU FU+LV or CI FU Bolus/CI FU ~ 4 6 months 9 months months months Median overall survival (months)

3 New Drugs in CRC Irinotecan Oxaliplatin Oral Fluoropyrimidines (CAP-UFT) Bevacizumab Cetuximab Creative Chaos

4 First-Line: Questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drug doublet?/ sequential or combination? What s the role of biological agents?

5 Protocol GOIM 9901

6 GOIM Protocol 9901: Objective Response Entered Evaluable FOLFIRI FOLFOX Response: CR PR SD PD CR + PR ORR: Evaluable (95% C.I.) p ITT (95% C.I.) G.Colucci et al, JCO ( 4.8) 48 (29.2) 68 (41.6) 40 (24.4) ( 5.2) 53 (30.8) 66 (38.3) 44 (25.7) ( ) ( ) 31 ( ) 34 ( ) p 0,60

7 Kaplan-Meier Survival Estimates, by cdarm Colorectal Cancer Chi-Square = 1.17 p< 0.28 Arm - A Median = 14 Range (1-48) Arm - B Median = 15 Range (1-43) Arm - A Arm - B analysis time Evaluable pts

8 GOIM 9901: Second-Line 2nd-line therapy FOLFOX4 61% FOLFIRI 58% Median Duration OS Pts receiving 2 nd -line therapy 17 mos Pts not-receiving 2 nd -line therapy 10 mos P= Median Duration OS Pts receiving 3 drugs * 18 mos *: FU, OHP, CPT

9 FOLFOX-6 vs FOLFIRI: Clinical Efficacy First-line FOLFIRI (n=109) FOLFOX (n=111) Response rate 1st 56% 54% (NS) Response rate 2nd 15% (n=81) 4% (n=69) PFS, 1st-line 8.5 mth 8.1 mth TTP, 2nd-line 14.4 mth 11.5 mth (NS) Overall survival (OS) 20.4 mth 21.5 mth (NS) 2-year survival 41% 45% Tournigand C et al, JCO 2004

10 Incidence % of NCI-CTC grade 3-4 FOLFIRI FOLFOX Tournigand n=109 Colucci N=138 Tournigand n=111 Colucci N=167 Neutropenia Febrile neutropenia Diarrhoea Neurotoxicity** (grade 3) Alopecia (grade 2) Nausea/vomiting Stomatitis Cholinergic syndr (gr. 2) Hypersensivity Cardiac * *1 toxicity death; ** Specif. modified Levy-scale +19% neurotoxicity grade 3 with FOLFOX in first-line

11 Potential Determinants of the Choice Early vs delayed toxicity; Alopecia-asthenia vs neuro; Winter vs summer; Potential resection of liver mets; Molecular determinants; PERSONAL EXPERIENCE.

12 Folfox o Folfiri? First-Line: Questions Fluoropyrimidines? Doublet or triplet? Doublet or single-drug doublet?/ sequential or combination? What s the role of biological agents?

13 Randomized Phase III study of Capecitabine plus Oxaliplatincompared with Fluorouracil/foloinic acid plus Oxaliplatin as First-line therapy for Metastatic colorectal cancer 2-arm design protocol amendment 2x2 factorial design R 634 pts R 1401 pts XELOX (317) FOLFOX4 (317) XELOX FOLFOX4 +plb +Beva +plb +Beva No pts %RR PFS DOR OS FOLFOX XELOX J. Cassidy e al.,j Clin Oncol 2008; 26:

14 Protocollo GOIM 2406 XELOX bisettimanale nel trattamento di prima linea del carcinoma colo-rettale in fase avanzata. Studio multicentrico di fase II Ricercatore Responsabile: E. Maiello (S. Giovanni Rotondo) Coordinatori: G. Di Maggio (S. Giovanni Rotondo) F. Giuliani (Bari)

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16 Activity: Objective Response (N 82 pts evaluable) N pts % Objective Response Rate Complete Response (CR) 5 6 Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) Disease Control CR+PR+SD

17 Toxicity NCI criteria Toxicity G 1-2 % G 3-4 % Neutropenia Trombocytopenia Anaemia Nausea/ vomiting Diarrhea Stomatitis Asthenia Neurotoxicity Stipsi Abdominal Pain

18 Protocol GOIM 2405 FOLFIRI vs XELIRI in 1 st Line Treatment of Advanced Colorectal Cancer: a Randomized Phase II Study of GOIM Main Investigator: Coordinator: G. Colucci (Bari) F. Giuliani (Bari)

19 Response Rates: XELIRI Compares Favorably with 5-FU /LV/Irinotecan 60 Response (%) XELIRI (n=52) 1 XELIRI (n=68) 2 XELIRI (n=37) 3 IFL (n=231) 4 IFL (n=264) 5 FOLFIRI (n=145) 6 FOLFIRI (n=109) 7 1 Patt YZ et al. Proc ESMO Ann Onc. 2004;15:iii88 (238P); 2 Bajetta E et al. Cancer 2004;100:279 87; 3 Borner MM et al. Ann Onc.,2005;16:282 8; 4 Saltz LB et al. N Engl J Med 2000;343:905 14; 5 Goldberg R et al. J Clin Oncol 2004;22:23 30; 6 Douillard JY et al. Lancet 2000;355: Tournigand C et al. J Clin Oncol 2004;22:229 37

20 Folfox o Folfiri? First-Line: Questions Fluoropyrimidines? Doublet or triplet? Doublet or single-drug doublet?/ sequential or combination? What s the role of biological agents?

21 FOLFOXIRI vs FOLFIRI Study Drug RR (%) TTP OS p Souglakos BJC 2006 Folfoxiri (n=137) Folfiri (n=146) ns Falcone JCO 2007 Folfoxiri (n=122) Folfiri (n=122) Sig.

22 Main Differences Dosage of drugs Age of the enrolled patients Performance status

23 Folfox o Folfiri? First-Line: Questions Fluoropyrimidines? Doublet or triplet? Doublet or single-drug doublet?/ sequential or combination? What s the role of biological agents?

24 DCCG 02-01/CKTO CAIRO Study Arm A Randomise Arm B 1 st line capecitabine capecitabine irinotecan 2 nd line 3 rd line irinotecan capecitabine oxaliplatin capecitabine oxaliplatin

25 MRC FOCUS Trial: 5-arm Randomised Trial in Advanced Colorectal Cancer A B C 5FU/LV 5FU/LV 5FU/LV irinotecan 5FU/LV oxaliplatin irinotecan 5FU/LV irinotecan 5FU/LV oxaliplatin Salvage therapy Salvage therapy

26 Survival (mo) A 13.9 FOCUS Lancet 2007 B B C C CAIRO Lancet 2007 S 16.3 C 17.4

27 But... Pts with metastases limited to liver and lung and potentially candidated for secondary surgery were excluded from Focus and under-represented in Cairo trial; Only 19-55% of patients received all three drugs

28 First-Line Therapy (Patients with 3 Drugs %) 22 Median OS (months) Infusional 5-FU/LV+irinotecan Infusional 5-FU/LV+oxaliplatin Bolus 5-FU/LV+irinotecan Irinotecan+Oxaliplatin Bolus 5-FU/LV LV5-FU % of Pts with 3 drugs Grothey et al, JCO 2005; 23:

29 Advanced Colorectal Cancer 90 s BSC 5-FU FU+LV or CI FU Bolus/CI FU ~ 4 6 months 9 months months months 2000 s FU (XEL) + IRI or OXA months FU (XEL) + IRI + OXA months Median overall survival (months)

30 Folfox o Folfiri? First-Line: Questions Fluoropyrimidines? Doublet or triplet? Doublet or single-drug doublet?/ sequential or combination? What s the role of biological agents?

31 Targeting angiogenesis: Anti-VEGF MoA Inhibiting antibodies VEGF VEGF recepto r Antibodies inhibiting VEGF Soluble VEGF receptors (VEGF-Trap) P P P P Small-molecules inhibiting VEGF receptors (TKIs) Angiogenesis P P TKIs = tyrosine kinase inhibitors

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33 Avastin in mcrc AVF2107 AVF2192 E3200 Data Avastin + IFL Avastin + 5-FU/LV Avastin + FOLFOX-4 Indication First-line First-line Second-line PFS 10.6 vs 6.2 (p<0.001) OS 20.3 vs 15.6 (p<0.001) 8.8 vs 5.6 (p<0.0001) 17.9 vs 14.6 (p=0.008) 7.3 vs 4.7 (p<0.0001) 12.9 vs 10.8 (p=0.0011) Avastin, in combination with intravenous 5-FU-based chemotherapy, is indicated for first- (global) and second-line (US) metastatic CRC IFL = bolus 5-fluorouracil (5-FU)/leucovorin (LV) + irinotecan FOLFOX = 5-FU/LV + oxaliplatin 1 Hurwitz, et al. NEJM 2004; 2 Kabbinavar, et al. JCO Giantonio, et al. JCO 2007

34 Bevacizumab Significantly Improves OS in First- and Second-line First-line 1 Second-line Median OS 15.6 vs 20.3 months (HR=0.66; p<0.001) 1.0 Median OS 10.8 vs 12.9 months (HR=0.75; p=0.0011) Estimated probability IFL + bevacizumab -IFL + placebo Estimated probability FOLFOX4 + bevacizumab -FOLFOX OS (months) OS (months) Figure reproduced with permission from: Hurwitz, et al. NEJM 350: Copyright 2004 Massachusetts Medical Society. All rights reserved; 2. Giantonio, et al. JCO 2007;25(12): Reprinted with permission American Society of Clinical Oncology.

35 NO16966: Progression-Free Survival Primary Endpoint Met 1.0 PFS estimate FOLFOX-4/XELOX + Avastin (n=699; 513 events) FOLFOX-4/XELOX + placebo (n=701; 547 events) HR=0.83 (97.5% CI: ) (ITT) p= Progression-free survival (months) Saltz, et al, JCO 2008, vol 26, no 12: HR = hazard ratio ITT = intent-to-treat CI = confidence interval

36 NO16966: Strong Benefit from Treatment Until Progression months FOLFOX-4/XELOX + Avastin FOLFOX-4/XELOX + placebo Probability of being progression-free ON TREATMENT: HR=0.63 (10.4 vs 7.9 months, p<0.0001) GENERAL: HR=0.83 (9.4 vs 8.0 months, p=0.0023) Months Saltz, et al, JCO 2008, vol 26, no 12:

37 NO16966: Overall Survival Proportion Patients Xelox/Folfox-4 + bevacizumab n=699 (420 events) -Xelox/Folfox-4 + placebo n=701 (455 events) HR=0.89 (97,5% CI P= Time (mo) Saltz, et al, JCO 2008, vol 26, no 12:

38 Significantly Improved Overall Survival in the Bevacizumab Era 1.0 Estimated probability Pre-bevacizumab ( ) Bevacizumab era (2006) p< Months Renouf et al. ASCO GI 2009

39 Overall survival estimate BRITE: Avastin Increases Survival Post First-Progression Post-progression therapy: No treatment n=253 No Avastin post PD n=531 Avastin post PD n= Overall survival (months) PD = progressive disease Grothey, et al, JCO 2008, vol 26, no 33:

40 Prot. GOIM 2601 Bevacizumab (Avastin) + Folfiri nel trattamento del carcinoma colorettale avanzato. Studio Multicentrico di fase II. F. Giuliani, E. Maiello, V. Lorusso, F. De Vita, I. Nugnes, S. Del Prete, S. Cinieri, R. Mattioli, S. Molica, M. Caruso, A. Tuveri, G. Colucci.

41 Prot 2601:Attività Arruolati 72 Valutabili 72 CR 7 (9.6%) PR 25 (34.8%) SD 33 (45.8%) PRO 7 (9.6%) ORR 32/72 (44.4%) 95%IC ( ) TGCR 65/72 (90.3%) 95%IC ( ) Risposta per sede: Fegato: 25/50 pts (50%) Polmone: 6/18 pts (33.3%) 2 pz trattamento sospeso dopo la 1ª valutazione per evento avverso: 1 evento tromboembolico venoso; 1 ischemia cardiaca

42 Tempo alla Progressione 100 TTP: 9 mesi Survival probability % Time

43 Sopravvivenza 100 Sopravvivenza : 22,2 Survival probability % Time

44 Analisi sottogruppo 26 pazienti in risposta o con malattia stazionaria hanno effettuato Avastin di mantenimento: Il TTP mediano di questo gruppo e stato di 14 mesi; La sopravvivenza mediana di 31 mesi

45 Folfiri in prima linea: Sopravvivenza Studio Sopravvivenza Avastin + FOLFIRI 22.2 (AVIRI) 1 Avastin + Folfiri (GOIM) Sobrero, et al. ASCO 2007

46 Folfiri in prima linea: Sopravvivenza Studio Sopravvivenza BRITE 31.8 (BBP) Avastin + Folfiri (Avastin mantenimento) 31.2

47 Efficacy Results for Selected Studies of 1st line Chemotherapy Study/regimen Endpoint TTP/PSS (mo) OS (mo) ORR (%) TREE (phase II) mfolfox mfolfox+bev bfol bfol+bev CapeOx CapeOx+bev NO16966 (phase III) FOLFOX or XELOX FOLFOX or XELOX+bev O Neil et al, The Oncologist 2008; 13:

48 Efficacy Results for Selected Studies of 1st line Chemotherapy Study/regimen Endpoint TTP/PSS (mo) OS (mo) ORR (%) BICC-C (phase III) FOLFIRI FOLFIRI+bev 9 not reached 63 mifl mifl+bev CapIRI CapIRI+bev nr nr nr O Neil et al, The Oncologist 2008; 13:

49 Cetuximab

50 CRYSTAL: Study Design Stratification by: -Region -ECOG PS EGFR-detectable mcrc R ERBITUX + FOLFIRI ERBITUX (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-h continuous infusion) + LV (every 2 weeks) Primary endpoint -Progression-free survival time (as assessed by blinded independent review) Secondary endpoints -ORR (independent review) -OS -Quality of life (EORTC QLQ-C30) -Safety FOLFIRI Irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus mg/m 2 as 46-h continuous infusion) + LV (every 2 weeks)

51 CRYSTAL trial: Primary endpoint PFS met ITT Population Independent Review 1.0 PFS estimate mo HR = 0.851; 95% CI = [ ] Stratified log-rank p-value = mo Cetuximab + FOLFIRI, n=599 FOLFIRI, n=599 1-year PFS rate 23% vs 34% Subjects at risk Progression-free survival time (months) FOLFIRI alone Cetuximab + FOLFIRI

52 CRYSTAL trial: Independent Assessment of Response p-value* = CR PR SD PD ORR FOLFIRI % Cetuximab + FOLFIRI % %CI [ [ ] 42.8] DCR** *Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate

53 Bari S.Giovanni Rotondo Taranto Colucci Giuliani Maiello Pezzella Benevento Daniele Potenza Manzione Catanzaro Molica Palermo Gebbia N. Roma Lopez Roma Garufi Fano Mattioli Trieste Tuveri Prot. GOIM 2402 FOLFOX 4 + Cetuximab in untreated patients with advanced colorectal cancer. A phase II multicenter study of the Gruppo Oncologico dell Italia Meridionale. G. Colucci, F. Giuliani, C. Garufi, R. Mattioli, R. Mallamaci,L. Manzione, N. Gebbia, G. Pezzella, B. Daniele, N. Silvestris, S. Molica, A. Tuveri, M. Lopez and E. Maiello

54 Schedule of Treatment DAY 1 Cetuximab starting dose 400 mg/m then 250 mg/m 2 (iv 1-h infusion) weekly 2 (iv 2-h infusion) DAY 2 1-hr later FU 400 mg/m 2 iv bolus FU 400 mg/m 2 iv bolus Oxaliplatin 85 mg/m 2 Leucovorin* 100 mg/m 2 FU 600 mg/m 2 iv infusion Leucovorin* 100 mg/m 2 FU 600 mg/m 2 iv infusion 2 hours 22 hours 2 hours 22 hours ** l-isomer-form

55 Patients Population: 70 Unselected Enrolled : 70 Sex Male: 43 (61,4%) Female: 27 (38,6%) Age (yrs) Median: 62 Range: PS (Ecog) Median: 0 Range: 0-2 Primary tumor site: Colon: 48 (68.6%) Rectum: 22 (31,4%) Main sites: Liver: 53 (75.7%) Lung: 23 (32.9%) Lymphnodes: 9 (12.9%) Others: 19 (27.1%) Single site: 44 (63%) Multiple sites: 26 (37%) Sinchronous: 59 (84%) Metacronous: 11 (16%) Adjuvant therapy: yes: 7 (10%) no: 63(90%) Only liver metastases: 33 pts (47%); with bulky disease: 25/33 (76%)

56 Activity: Objective Response Enrolled/Screened 70/82 (85%) Evaluable 67 CR 4 (6%) PR 39 (58.2%) SD 20 (29.8%) PRO 4 (6%) ORR 43/67 (64%) 95%IC ( ) TGCR 63/67 (94%) 95%IC (88-99) ITT analysis OR 43/70 (61%) 95%IC (50-72) TGCR 63/70 (90%) 95%IC (83-97) 3 pts NED: 1 suicide; 1 refused treatment; 1 allergic reaction

57 Activity: Resecability Rate Response according to site: Liver: 32/53 pts (60%) Lung: 11/23 pts (48%) Resecability Rate: 10/67 (15%) Liver: 7/33 (21%) Lung: 3/6 (50%)

58 Efficacy Median number of cycles: 10 Median time to progression (mo): 10 Median overall survival (mo): 22

59 Toxicity NCI Criteria Toxicity G 1-2 % G 3-4 % Leukopenia 4 5,7 5 7,1 Neutropenia 3 4, Thrombocytopenia 9 12,9 1 1,4 Anemia 16 22,8 1 1,4 Nausea/vomiting 30 42,8 6 8,6 Diarrhea 24 34,3 6 8,6 Mucositis 11 15,7 6 8,6 Fever ,9 Loss of hair 11 15,7 - - Neurologic 26 37,1 2 2,9 Cutaneous 47 67, Astenia 15 21,4 - - Stipsi 6 8,6 - - Hepatic ,4 Allergic reactions ,4

60 Cutaneous Toxicity and Response G0 G1 G2 3/6 (50%) 7/16 (44%) 33/48 (69%)

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63 OS time CRYSTAL-Updated Efficacy Analysis in Patients by KRAS Mutation Status Data Cetuximab + Folfiri (n=316) KRAS wild-type Folfiri (n=350) Cetuximab + Folfiri (n=214) KRAS mutant Folfiri (n=183) Median OS (mo) HR (95%CI) ( ) ( ) p PFS time Median PFS (mo) HR (95%CI) ( ) ( ) p Best overall response OR rate (%) Odds ratio (95%CI) ( ) ( ) p < *Van Cutsem E, et al. ECCO/ESMO Congress 2009; Abstract No: 6077

64 Logrank test P= WT 22paz Mut 13 paz TTP Time - Kaplan-Meier cumulative PFS on the basis of KRAS mutational status. wt, wild type, mut mutated

65 1.0 OS Logrank test P= WT 22paz Mut 13 paz Time - Kaplan-Meier cumulative OS on the basis of KRAS mutational status. wt, wild type, mut mutated

66 PFS, OS and Objective Response Rate for K-ras Patients Randomized to IFL+Placebo or IFL+BV Efficacy variable IFL +placebo (n=67) Wild-type IFL + BV (n=85) p; HR (95%CI) IFL +placebo (n=67) Mutant IFL + BV (n=85) p; HR (95%CI) Median survival duration (mo) p=.04; HR 0.58 ( ) p=.26; HR 0.69 ( ) Median PFS duration during first-line therapy (mo) p<.0001; HR 0.44 ( ) p=.0008; HR 0.41 ( ) Objective response 25 (37.3%) 51 (60.0%) p= (41.2%) 19 (43.2%) Complete 2 (3.0%) 3 (3.5%) 0 (0.0%) 3 (6.8%) Partial 23 (34.3%) 48 (56.5%) 14 (41.2%) 16 (36.4%) p=.86 Hurwitz et al, The Oncologist, 2009; 14:22-28

67 SWOG and CALGB Trial FOLFOX or FOLFIRI Patients with untreated metastatic CRC (planned n=2300) FOLFOX or FOLFIRI + Cetuximab FOLFOX or FOLFIRI + Avastin

68 Randomized Controlled Phase 3 Trial in mcrc Panitumumab PD Follow-up 6.0 mg/kg Q2W + BSC BSC PD Follow-up 1:1 ENDPOINTS Primary Secondary Safety Randomization stratification ECOG score: 0-1 vs 2 Geographic region: Western EU vs Central & Eastern EU vs Rest of World PFS OS, ORR, Duration of & time to response adverse events, antibody formation

69 Progression-Free Survival 1.0 Primary Analysis, All Randomized Analysis Set, Central Radiology Event-free Probability Panitumumab + BSC BSC alone Hazard ratio=0.54 (95% CI: 0.44, 0.66) Stratified log-rank test p < Patients at risk: Panitumumab BSC alone Weeks from Randomization

70 Progression-Free Survival for Panitumumab- Treated Patients by KRAS Status Proportion with PFS Patients at Risk: Mutant 24 Wild-type Median (95% CI) in Weeks _ Mutant: 7.4 ( ) Wild-type: 16.2 ( ) Weeks From Enrollment

71 Combination Anti-EGFR + Anti-VEGFR Trial Combination TTP/PFS OS BOND-2 Cetuximab+bevacizumab+Cpt vs Bevacizumab+Cpt 7.9 vs 5.6 NR CAIRO-2 Cetuximab+bevacizumab+Xelox vs Bevacizumab+Xelox PACCE Panitumumab+bevacizumab+Folfox vs Bevacizumab+Folfox 10.0 vs vs 24.5

72 Combination Anti-EGFR + Anti-VEGFR Trial Combination TTP/PFS BOND-2 Cetuximab+bevacizumab+Cpt vs Bevacizumab+Cpt p: Sig. CAIRO-2 Cetuximab+bevacizumab+Xelox vs Bevacizumab+Xelox p: ns PACCE Panitumumab+bevacizumab+Folfox vs Bevacizumab+Folfox p:ns

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74 Conclusioni Nell ultimo decennio l introduzione di farmaci quali l oxaliplatino, l irinotecano e le fluoropirimidine orali ha ampliato le possibilita di trattamento del carcinoma colorettale avanzato consentendo di ottenere evidenti miglioramenti nella sopravvivenza; L impiego dei farmaci biologici sembra poter offrire ulteriori chances terapeutiche; E di fondamentale importanza ampliare le conoscenze di biologia molecolare per offrire ad ogni paziente il trattamento ottimale.

75 grazie

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77 Cetuximab as Single Agent in 2 nd Line Treatment of Irinotecan-Refractory mcrc Saltz JCO 2004 Cunningham NEJM 2004* Lenz ASCO 2004 Mirtsching ASCO 2004 Pts RR Dis Con mttp ms 57 9% 37% 1.4 mths 6.4 mths % 34% 1.5 mths 6.9 mths 10,9% % 34% % 46% - - * ~ 40% of pts received Cetuximab as a 3 rd or higher line treatment IRN/OHP-refractory pts IRN/FU/OHP-refractory pts

78 Response Rate/TTP: IRC BOND-1 Combination Monotherapy p-value (N=218) [95% CI] (N=111) [95% CI] PR 22.9% [ ] 10.8% [ ] Disease control* 55.5% [ ] 32.4% [ ] Median TTP 4.1 months 1.5 months < *CR+PR+SD

79 CRYSTAL Trial: Study Design Cetuximab + FOLFIRI EGFR-expressing metastatic CRC R 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

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83 OPUS Study Design Cetuximab + FOLFOX-4 EGFR-expressing metastatic CRC Stratification factors: ECOG PS 0-1, 2 R 400 mg/m 2 initial IV infusion (day 1) then 250 mg/m 2 weekly + oxaliplatin 85 mg/m FU/FA every 2 weeks FOLFOX-4 oxaliplatin 85 mg/m FU/FA every 2 weeks Treatment until progression, symptomatic deterioration or unacceptable toxicity ASCO 2007

84 Efficacy: Response Rate All Patients and ECOG 0-1 Stratum Response rate, % Cetuximab + FOLFOX-4 All 45.6 (n=169) ECOG 0-1* 49.0 (n=153) FOLFOX (n=168) 36.8 (n=152) * p=0.032**, Odds ratio: [95% CI:1.043, 2.604] **Cochran-Mantel-Haenszel (CMH) test

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86 All ITT subjects (n= 169 vs 168) Efficacy by Subgroups OR [95% CI] [0.97, 2.35] Subgroup (number of patients) ECOG 0/ [1.043, 2.604] Age <65 years (96 vs 109) 65 years (73 vs 59) 1.82 [1.03, 3.21] 1.14 [0.57, 2.31] Leucocytes / mm 3 (124 vs 131) 2.00 [1.19, 3.35] Liver metastasis only One metastatic site Region LDH Yes (50 vs 39) 1 (74 vs 69) Western Europe (72 vs 75) Eastern Europe (97 vs 93) >upper normal limit (82 vs 63) 2.11 [0.88, 5.07] 2.00 [1.02, 3.93] 2.29 [1.18, 4.46] 1.12 [0.61, 2.04] 2.07 [1.03, 4.14] Alkaline phosphatase <300 U/L (128 vs 128) 2.04 [1.22, 3.42] Favors Cetuximab + FOLFOX Favors FOLFOX

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89 Protocol GOIM 2402: Patients population: 70 unselected Enrolled : 70 Sex Male: 43 (61,4%) Female: 27 (38,6%) Age (yrs) Median: 62 Range: PS (Ecog) Median: 0 Range: 0-2 Primary tumor site: Colon: 48 (68.6%) Rectum: 22 (31,4%) Main sites: Liver: 53 (75.7%) Lung: 23 (32.9%) Lymphnodes: 9 (12.9%) Others: 19 (27.1%) Single site: 44 (63%) Multiple sites: 26 (37%) Sinchronous: 59 (84%) Metacronous: 11 (16%) Adjuvant therapy: yes: 7 (10%) no: 63(90%) Only liver metastases: 33 pts (47%); with bulky disease: 25/33 (76%)

90 Protocol GOIM 2402: Objective Responses Enrolled/Screened 70/82 (85%) Evaluable 67 CR 4 (6%) PR 39 (58.2%) SD 20 (29.8%) PRO 4 (6%) ORR COR 43/67 (64%) 95%IC (51-74) 42/67 (62,7%) TGCR 63/67 (94%) 95%IC (88-99) ITT analysis OR 43/70 (61%) 95%IC (48-71) TGCR 63/70 (90%) 95%IC (83-97) 3 pts NED: 1 suicide; 1 refused treatment; 1 allergic reaction

91 Protocol GOIM 2402: Toxicity NCI criteria Toxicity G 1-2 % G 3-4 % Leukopenia 4 5,7 5 7,1 Neutropenia 3 4, Thrombocytopenia 9 12,9 1 1,4 Anemia 16 22,8 1 1,4 Nausea/vomiting 30 42,8 6 8,6 Diarrhea 24 34,3 6 8,6 Mucositis 11 15, Fever ,9 Loss of hair 11 15,7 - - Neurologic 26 37,1 2 2,9 Cutaneous 47 67, Astenia 15 21,4 1 1,4 Stipsi 6 8,6 - - Hepatic ,4

92 Cetuximab + Oxaliplatin Based Regimen Author Ev Pts RR (%) TGC (%) PFS (mo) OS (mo) G3-4 skin toxicity Tabernero, % Seufferlein, nr nr nr 17% Colucci, % Dakhil, nr 17% Venook, 2006* nr nr OPUS, ,6 81 * part of randomized phase II

93 Phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*) 2x2 factorial, randomized phase III trial Previously untreated patients with MCRC (n=1 920) FOLFOX4 (n=300) XELOX (n=300) Avastin 5mg/kg every 2 weeks (n=330) Placebo (n=330) Avastin 7.5mg/kg every 3 weeks (n=330) Placebo (n=330) PD PD PD PD Primary objectives at least equivalent TTP with XELOX (± Avastin) versus FOLFOX4 (± Avastin) superior TTP with Avastin + XELOX/FOLFOX versus XELOX/FOLFOX *Roche registration study

94 50 Biologicals as first-line therapy in advanced CRC: ORR from key randomised trials 40 ORR (%) FOLFIRI FOLFOX Avastin Placebo Avastin Placebo Cetuximab Control Cetuximab Control Panitumumab Avastin + Avastin Colucci et al. JCO 2005 IFL XELOX/FOLFOX FOLFOX FOLFIRI Irinotecan-based CTx p=0.60 p=0.004 p=0.99 p=0.064 p= n.s. Hurwitz et al. Saltz et al. Bokemeyer et Van Cutsem NEJM 2004 JCO. In press al. ECCO 2007 ASCO 2007 Hecht et al. ASCO GI 2008

95 Biologicals as second-line therapy in advanced CRC: Evidence from key randomised trials Avastin Cetuximab Trial E3200 EXPLORE BOND EPIC Phase III II (initial III) II III Line of therapy Second Second Second + Third Second Regimen FOLFOX ± Avastin FOLFOX ± cetuximab Cetuximab ± irinotecan Irinotecan ± cetuximab Patient (n) (1100) ORR (%) 22.7 vs vs vs vs 4 p< n.s. p= p< PFS (months) 7.3 vs vs vs vs 2.5 p< n.s. p<0.001 p< OS (months) 12.9 vs vs vs vs 9.99 p= n.s. n.s. n.s. Reference Giantonio et al. JCO 2007 Mitchell et al. ASCO GI 2008 Cunningham et al. NEJM 2004 Sobrero et al. JCO 2008

96 Guidelines: Current Treatment Algorithms in Advanced CRC Patients suitable for combination CTx 1stline FOLFIRI/(XELIRI) + Avastin FOLFOX/XELOX + Avastin 2ndline FOLFOX/ XELOX Irinotecan + ERBITUX Erbitux mono FOLFIRI (XELIRI) 3rdline Irinotecan + Erbitux FOLFOX/ XELOX Irinotecan + erbitux Adapted from NCCN Colon Cancer v2, 2007

97 Domani Ca colorettale: 1ª linea EGFR+ KRAS wt mut folfiri/folfox + Cetuximab folfiri/folfox + Bevacizumab/ dual inhibitors

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108 CRYSTAL trial: Subgroup Analysis of PFS Time by On-Study Skin Reactions: Cetuximab + FOLFIRI 1.00 Skin reaction grade 3*, n=112 Skin reaction grade 2, n= Skin reaction grade 0 or 1, n=244 PFS estimate mo 9.4 mo 11.3 m *There were no grade 4 skin reactions Progression-free survival time (months)

109 CRYSTAL Trial: Safety: Grade 3/4 AE FOLFIRI n=602, % Cetuximab + FOLFIRI n=600, % Any Neutropenia Febrile neutropenia Diarrhea Vomiting Fatigue Skin reactions a Infusion-related reactions a There were no grade 4 skin reactions Magnesium levels were measured in only 20% of the patients (0.2% vs. 1.8%)

110 Is There a Better First-Line? Folfox o Folfiri? Doublet or triplet? Doublet or single-drug doublet? Fluoropyrimidines? How long to treat patients? Continuous or intermittent therapy? What s the role of biological agents?

111 GOIM 9901: Main Toxicities NCI Criteria % Grade 3-4 FOLFIRI FOLFOX

112 GOIM 9901: Second-Line 2nd-line therapy FOLFOX4 61% FOLFIRI 58% Median Duration OS Pts receiving 2 nd -line therapy 17 mos Pts not-receiving 2 nd -line therapy 10 mos P= Median Duration OS Pts receiving 3 drugs * 18 mos *: FU, OHP, CPT

113 FOLFOXIRI vs FOLFIRI Study Drug RR (%) TTP OS p Souglakos BJC 2006 Folfoxiri (n=137) Folfiri (n=146) ns Falcone JCO 2007 Folfoxiri (n=122) Folfiri (n=122) signif.

114 XELIRI in Advanced CRC 80 Response (%) Xeliri (n=52) Xeliri (n=68) Xeliri (n=37) IFL (n=23) IFL (n=264) FOLFIRI (n=145) FOLFIRI (n=109) Schmoll et al, The Oncologist 2006;11:

115 Safety of XELIRI is Similar to that of FOLFIRI Toxicities Grade 3-4 adverse events (% patients) XELIRI XELIRI FOLFIRI IFL Neutropenia Febrile neutropenia 4 NR 7 15 Diarrhea Nausea/vomiting Hand-foot syndrome 6 8 NR NR Thromboembolic events NR 1 DVT NR NR Schmoll et al, The Oncologist 2006;11:

116 Response Rates of Capecitabine in Combination in Randomized Trials Study Pts RR PFS OS Grothey CapOx 80 51% 7.2 mo >17 mo CapIri 77 41% 7.1 mo 18.8 mo Tree-1 study FOLFOX % 8.4 mo 17.6 mo bfol 50 32% 6.9 mo 17.9 mo CapOx 48 38% 17.2 mo 17.2 mo AIO study FUFOX % 8.0 mo 18.2 mo CapOx % 7.0 mo 16.6 mo TTD study FUFOX % 9.6 mo too early XELOX % 8.8 mo too early Schmoll et al, The Oncologist 2006;11:

117 Advanced Colorectal Cancer 90 s BSC 5-FU FU+LV or CI FU Bolus/CI FU ~ 4 6 months 9 months months months 2000 s FU (XEL) + IRI or OXA months FU (XEL) + IRI + OXA months Median overall survival (months)

118 Overall Survival: First-Line Combination Regimens 5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de Gramont) IFL (Goldberg) IFL (Saltz) FOLFIRI (Douillard) FOLFOX (de Gramont) FOLFOX (Goldberg) FUFOX (Schmoll) Capecitabine 1 Xeliri 2 Xelox 3 FOLF + biological? Median OS (months) 1 Van Cutsem E et al. Br J Cancer 2004;90: Patt YZ et al. Ann Oncol 2004;15(Suppl. 3):iii88 (Abst 238P) 3Cassidy J et al. J Clin Oncol 2004;22:

119 Safety: XELIRI vs 5-FU /LV/Irinotecan Historical Comparison Toxicity Grade 3-4 AEs (% pts) Xeliri 1 Xeliri 2 Xeliri 3 Folfiri 4 IFL 5 Neutropenia Febrile neutropenia NR 4 NR 7 15 Diarrhea Nausea/vomiting Hand-foot syndrome NR 6 8 NR NR Thromboembolic events NR NR 1DVT NR NR 1 Bajetta E et al. Cancer 2004;2 Patt et al. Proc ESMO Annals Oncol 2004; 3 Borner M et al. Ann Oncol 2005; 4 Douillard JY et al. Lancet 2000; 5 Goldberg R et al. J Clin Oncol 2004

120 Data from OPTIMOX Chemotherapy-free interval 8.0 months Good. Prog. N=30 med. 35 weeks Poor Prog. N=57 med.20 weeks 4.6 months Probability PS 2 LDH Alk Ph >3ULN > 1 site p= weeks 40 Saltz, Seminars in Oncology, 2006

121 Lessons from FUCUS LIFE Sequential: valuable defensive strategy ; OK for non pot. resectable, but good PS; Fewer pts will receive 2nd and 3rd line CT; Lower RR and Shorter PFS; Hint about folfiri better than iri as second line.

122 OPTIMOX-1 No of patients Folfox4 -Folfox7 Patients who received each cycle No of patients Folfox4 -Folfox7 % of patients with grade 3-4 toxicity 0 6 cycles cycles No of patients Folfox4 -Folfox7 % of patients with neurologic grade 3 toxicity 0 6 cycles Saltz, Seminars in Oncology,

123 OPTIMOX-2: Study Design FOLFOX-7 for 6 cycles De Gramont Until PRO Reintroduction FOLFOX7 R FOLFOX7 for 6 cycles Stop Reintroduction FOLFOX7

124 Responses in OPTIMOX-2 Trial Response to initial FOLFOX-7 therapy Response param. Arm A* Arm B CR 3% 3% PR 58% 58% CR+PR 61% 61% SD 27% 32% Progressio n 11% 6% NE 0 1% Too early 11 pts 12 pts Response param. Response to FOLFOX-7 reintroduction Arm A* (n=30) Arm B (n=45) CR 0% 0% PR 13% 531% SD 43% 24% Progressio n 40% 40% NE 3% 5% Too early 1 pt 6 pts *Maintenance CFI Saltz, Seminars in Oncology, 2006

125 Results Arm A FOLFIRI FOLFOX6 Arm B FOLFOX6 FOLFIRI n RR 56% 15% 54% 4% Median PFS (months) Median PFS (months) for sequence Median overall survival (months) FOLFIRI vs FOLFOX: no difference in first-line efficacy Tournigand et al, JCO 2004;22:229 37

126 XELIRI / XELOX Drugs No. % TTP OS 3-4 gr Pts OR Tox % Patt 04 CPT 250, 1 + CAP 1000 bid x 14 / 3 w XELIRI N 25 HF 6 Schoffski 04 OXA 130, 1 + CAP 1000 bid x 14 / 3 w XELOX N 7 D 16 HF 3 NE 17 Grothey 04 CAPIRI CAPOX

127 Phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*) 2x2 factorial, randomized phase III trial Previously untreated patients with MCRC (n=1 920) FOLFOX4 (n=300) XELOX (n=300) Avastin 5mg/kg every 2 weeks (n=330) Placebo (n=330) Avastin 7.5mg/kg every 3 weeks (n=330) Placebo (n=330) PD PD PD PD Primary objectives at least equivalent TTP with XELOX (± Avastin) versus FOLFOX4 (± Avastin) superior TTP with Avastin + XELOX/FOLFOX versus XELOX/FOLFOX *Roche registration study

128 First-Line CAPIRI and CAPOX: Both Regimens Well Tolerated Patients (%) Most common (>2.5%) grade 3/4 clinical adverse events CAPIRI (n=79) CAPOX (n=80) Grothey A et al. Eur J Cancer 2003;1 (Suppl 5):S90 (Abst 295)

129 FOLFOXIRI IN ACC FOLFOXIRI FOLFIRI P OR PR < Resecability (244) Only liver (81) mpfs mos Falcone A. et al., JCO 2006; 24 (18S):3513 abs

130 Randomized Phase II Trial: CAPIRI vs CAPOX (Predefined Crossover in Second-Line) R A N D O M I Z A T I O N n=79 n=82 CAPIRI Xeloda 1000mg/m 2 twice daily, d1 14, q21d Irinotecan 80mg/m 2 d1, 8 CAPOX Xeloda 1000mg/m 2 twice daily, d1 14, q21d Oxaliplatin 70mg/m 2 d1, 8 Disease progression C R O S S O V E R n=33 n=35 CAPOX CAPIRI Age years; ECOG PS 2; no prior chemotherapy for MCRC (adjuvant therapy 6 months earlier) Grothey A et al. J Clin Oncol Proc ASCO 2004;22 (Suppl. 14S) (Abst 3534)

131 CAPOX and CAPIRI: Similar High First-Line Efficacy Grothey A et al. J Clin Oncol Proc ASCO 2004;22 (Suppl. 14S) (Abst 3534)

132 MRC FOCUS Trial: 5-arm Randomised Trial in Advanced Colorectal Cancer A B C D E 5FU/LV 5FU/LV 5FU/LV irinotecan 5FU/LV 5FU/LV oxaliplatin irinotecan 5FU/LV irinotecan 5FU/LV oxaliplatin At discretion of investigator, usually supportive care oxaliplatin + capecitabine or 5FU/LV irinotecan + capecitabine or 5FU/LV

133 Sequential Compared to Combination Chemotherapy R CAP 2500 IRI 350 CAPOX PTS R / T 820 / 803 CAPIRI CAPOX 410/ /402 All-cause-60-day mortality = 3% vs 4.5% (=30 pts) Treatment-related death 11 pts: 8A and 3B! mos 16.3 vs 17.4 (p 0.32, HR: 0.92) Koopmann M et al. Lancet 2007, 370:

134 OPTIMOX 1: Oxaliplatin Stop and Go R A N D O M I S A T I O N FOLFOX4 until progression or unacceptable toxicity FOLFOX7 x 6 cycles slv5fu2 x 12 cycles FOLFOX7 x 6 cycles Oxaliplatin can be safely stopped after 6 cycles; Reintroduction is feasible N=623 patients 56 hospital 5 country Tourningand C, JCO 2006:24, 396