Anticorpi monoclonali nel trattamento del carcinoma colorettale IL TRATTAMENTO DI PRIMA LINEA NELLA MALATTIA AVANZATA

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1 Anticorpi monoclonali nel trattamento del carcinoma colorettale IL TRATTAMENTO DI PRIMA LINEA NELLA MALATTIA AVANZATA

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

3 First-Line: Questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drugdoublet? Continuous or intermittent therapy? What s the role of biological agents?

4 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.) 8 ( 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 G.Colucci et al.,jco 2005

5 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

6 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

7 Incidence % of NCI-CTC grade 3-4 FOLFIRI FOLFOX Tournigand Colucci Tournigand Colucci n=109 N=138 n=111 N=167 Neutropaenia Febrile neutropaenia 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

8 First-Line: Questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drugdoublet? Continuous or intermittent therapy? What s the role of biological agents?

9 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

10 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

11 Phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*) 2x2 factorial, randomized phase III trial Previously untreated patients with MCRC (n=1920) 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

12 Randomized Phase III study of Capecitabine plus Oxaliplatincompared with Fluorouracil/foloinic acid plus Oxaliplatin as First-line therapy for Metastatic colorectal cancer J. Cassidy e al.,j Clin Oncol 2008; 26: 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 Xelox1-NO16966A

13 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)

14 CAPOX and CAPIRI: Similar High First-Line Efficacy CAPOX 1st line (n=80) CAPIRI 2nd line (n=34) CAPIRI 1st line (n=77) CAPOX 2nd line (n=31) Overall response rate (%) Median PFS (months) Median overall survival (months [95% CI]) 16.5 ( ) 18.8 ( ) Grothey A et al. J Clin Oncol Proc ASCO 2004;22 (Suppl. 14S) (Abst 3534)

15 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) Diarrhea Nausea Vomiting Infection Sensory neuropathy Hand-foot syndrome Bilirubin Grothey A et al. Eur J Cancer 2003;1 (Suppl 5):S90 (Abst 295)

16 First-Line: Questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drugdoublet? Continuous or intermittent therapy? What s the role of biological agents?

17 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

18 First-Line: Questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drugdoublet? Continuous or intermittent therapy? What s the role of biological agents?

19 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:

20 First-line: questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drugdoublet? Continuous or intermittent therapy? What s the role of biological agents?

21 Stop and Go R OPTIMOX1: FOLFOX7 x 6 LV5FU U.PD FOLFOX7 202 pts OPTIMOX2: FOLFOX7 x 6 REST at PRO, FOLFOX7 %RR mpfs mddc mcfi mos p 0.04 p Maintenance LV5FU therapy prolongs PFS and OS, especially in pts with poor prognosis (14.5 vs 20.9). CFI can be recommended only in selected pts without adverse prognostic factors F. Maindrault-Goebel et al., ASCO 2007; 25:4013

22 29 studi di fase III: pazienti PFS e RR sono significativamente correlate (p <0.0001) PFS (m)=0,1xrr% + 3,2 Correlazione più debole tra % di RO e OS OS (m)= 0,088 RR% + 10,45

23 Combination first-line Survival associated with use of 3 drugs % with 3 drugs Overall survival (months) Author IFL 5% 14.8 Saltz IFL 24% 14.8 Goldberg FOLFIRI 16% 17.4 Douillard FOLFOX 30% 16.2 DeGramont FOLFOX 58% 18 Colucci FOLFOX 60% 19.5 Goldberg FUciOX 60% 19.4 Giacchetti FOLFOX 62% 20.6 Tournigand FUFOX 68% 19.7 Grothey AIO/IRI 54% 20.1 Köhne FOLFIRI 74% 21.5 Tournigand

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25 First-Line: Questions Folfox o Folfiri? Fluoropyrimidines? Doublet or triplet? Doublet or single-drugdoublet? Continuous or intermittent therapy? What s the role of biological agents?

26 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

27 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

28 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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32 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

33 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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35 Efficacy by Subgroups All ITT subjects (n= 169 vs 168) 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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38 GOIM 2402 Patients polulation: 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%)

39 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

40 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

41 Targeting angiogenesis: Anti-VEGF MoA Inhibiting antibodies VEGF VEGF recept or 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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43 Phase III Trial: Efficacy Summary IFL + Placebo IFL + Avastin (n=412) (n=403) P value Median survival (mo) PFS (mo) < ORR (%) CR PR Duration of response (mo)

44 Phase III trial: XELOX ± Avastin versus FOLFOX4 ± Avastin (XELOX1*) 2x2 factorial, randomized phase III trial Previously untreated patients with MCRC (n=1920) 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

45 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:

46 Randomized Controlled Phase 3 Trial in mcrc R A N D O M I Z E 1:1 ENDPOINTS Primary Secondary Safety Panitumumab PD Follow-up 6.0 mg/kg Q2W + BSC Optional BSC PD Panitumumab Follow-up Crossover Study 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

47 Progression-Free Survival Event-free Probability Primary Analysis, All Randomized Analysis Set, Central Radiology 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

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

49 Biologicals as first-line therapy in advanced CRC: ORR from key randomised trials ORR (%) FOLFIRIFOLFOX AvastinPlacebo AvastinPlacebo CetuximabControl CetuximabControlPanitumumab 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

50 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

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