1 O n c o l o Together for y LOncologia insieme per L*Aquila G Bruera, D Di Giacomo & E Ricevuto Medical Oncology Department Experimental Medicine University of LAquila Mediterranean School of Oncology Chieti, april 21 st 2010 COLORECTAL CANCER COLORECTAL CANCER Round Table TOWARD A PERSONALIZED THERAPY Economic Implications of k-ras testing

2 K-ras genotype in Colorectal Cancer Structural alterationPoint mutations Prevalence of mutations40% Hot-spot sites34, 35, 37, 38 Functional relevanceGain of function Diagnostic strategy Direct Sequencing Scanning for known mutations Clinical implicationsPredictiveanti-EGFR anti-VEGF Prognostic in metastatic disease

3 Sequencing Sequencing Direct sequencing Pyrosequencing Scanning Scanning Unknown mutations Unknown mutations Known mutations Known mutationsSNap-shot Real-time PCR k-ras Mutations Detection Molecular diagnostic strategies

4 Cod.13 Cod.12 Cod.12 Cod.13 sensoantisenso KRAS KRAS Cod.12 Cod.13 Cod.13 Cod.12 sensoantisenso

5 K-ras testing Costs of genetic analysis Direct Sequencing~ 26 E/sample SNaPshot~ 26 E/sample

6 MCRC I line treatment: activity and efficacy ORR (%) PFS (months) OS (months) Mono Doublet Triplet Poker-Bev Bruera and Ricevuto, Jan10

7 Cetuximab in MCRC according to k-ras genotype Cetuximab + Irinotecan/5-FU/FA: Efficacy (Van Cutsem et al, NEJM 2008) ITTKRAS wtKRAS mt Parameters FOLFIRI N. 599 Cetuximab +FOLFIRI N. 599 FOLFIRI N. 176 Cetuximab +FOLFIRI N. 172 FOLFIRI N. 87 Cetuximab +FOLFIRI N. 105 Overall response (%) CR PR SD ORR (%) (C.I. 95%) 39 (35-43)47 (43-51)43 (36-51)59 (52-67)40 (30-51)36 (27-46) p-value DCR (%) Median PFS, months (C.I. 95%) 8.0 ( ) 8.9 ( ) 8.7 ( ) 9.9 ( ) 8.1 ( ) 7.6 ( ) HR (C.I. 95%) p-value 0.85 ( ) ( ) ( ) 0.75 Median OS, months (C.I. 95%) 18.6 ( ) 19.9 ( ) 21 ( ) 24.9 ( ) 17.7 ( ) 17.5 ( ) HR (C.I. 95%) p-value 0.93 ( ) ( ) ( ) 0.85

8 Cetuximab + Oxaliplatino/5-FU/FA: Efficacy (Bokemeyer et al, JCO 2009) ITTKRAS wtKRAS mt Parameters FOLFOX-4 N. 168 Cetuximab +FOLFOX-4 N. 169 FOLFOX-4 N. 73 Cetuximab +FOLFOx-4 N. 61 FOLFOX-4 N. 47 Cetuximab +FOLFOX-4 N. 52 Overall response (%) CR PR SD ORR (%) p-value DCR (%) Median PFS, months (C.I. 95%) 7.2 ( ) 7.2 ( ) 7.2 ( ) 7.7 (7.1-12) 8.6 ( ) 5.5 (4-7.4) HR (C.I. 95%)0.93 ( )0.57 ( )1.83 ( ) p-value Cetuximab in MCRC according to k-ras genotype

9 Efficacy of Panitumumab in KRAS wt patients (Phase III) PRIME trial (I Line) (Douillard et al, ESMO 2009) (II Line) (Peeters et al, ESMO 2009) FOLFOX-4 N.590 Panitumumab+ FOLFOX-4 N. 593 FOLFIRI N. 595 Panitumumab+ FOLFIRI N. 591 ORR (%) p-value0.003n.v. Median PFS (months) HR0.80 ( )0.73 ( ) p-value Median OS (months) n.v HRn.v.0.85 ( ) p-valuen.v Panitumumab in MCRC according to k-ras genotype

10 Ince et al, PNAS 05 Bevacizumab in MCRC according to kras genotype

11 Efficacy variable Wild-typeMutant IFL+ Placebo (n. 67) IFL+BV (n.85) p-value HR (95% CI) IFL+ Placebo (n. 34) IFL+BV (n. 44) p-value HR (95% CI) Median OS (months) 17,627, ( ) 13,619, ( ) Median PFS (months) 7,413, ( ) 5,59, ( ) ORR n. (%) 25 (37,3) 51 (60) (41,2) 19 (43,2) 0.86 Hurwitz HI, Ince W et al, The Oncologist 2009; 14:22-28 Bevacizumab in MCRC according to k-ras genotype

12 FIr-B/FOx in MCRC: Treatment Schedule 5-Fluorouracil (5-FU), time flat infusion of 12h, Irinotecan (CPT-11) / Bevacizumab (BEV), Oxaliplatin (l-OHP), as first line treatment of metastatic colorectal cancer: fase II study. Bev 5 mg/kg Bruera G et al, 2010 Submitted

13 FIr-B/Fox in MCRC: Activity and efficacy Intent-to-treat Analysis As-treated Analysis No% % Enrolled patients Evaluable patients Objective Response Partial Response Complete Response (CI±11) (CI±11) 75 9 Stable Disease2425 Progressive Disease Median Progressio-free survival, months Range Progression events Median Overall Survival, months Range Deaths Liver metastasectomies No/Overall patients (50) No/Patients with liver metastases (33) No/Patients with liver-only metastases (21) Bruera G et al, 2010 Submitted

14 Kaplan-Meier survival estimate: Progression-free survival Median Follow-up 21 months Median PFS 12 months (3-46+) Bruera G et al, 2010 Submitted

15 Median Follow-up 21 months Median OS 28 months (3-47) Kaplan-Meier survival estimate: Overall survival Bruera G et al, 2010 Submitted

16 FIr-B/Fox in MCRC: Cumulative toxicity PatientsCycles Number50247 NCI-CTC Grade Nausea (%)23 (46)15 (30)3 (6)-81 (33)23 (9)4 (2)- Vomiting (%)10 (20)6 (12)2 (4)-19 (8)9 (4)2 (1)- Diarrhea (%)20 (40)12(24)14 (28)-76 (30)28 (11)15 (6)- Hypoalbuminemia (%)2 (4)1 (2)--2 (1)1 (0.5)-- Constipation (%)17 (34)1 (2)--22 (9)1 (0.5)-- Stomatitis/mucositis (%)16 (32)2 (4)3 (6)-29 (12)3 (1) - Erythema (%)1 (2)- -3 (1)-1 (0.5)- Asthenia (%)13 (26)20 (40)3 (6)-48 (19)38 (15)3 (1)- Neurotoxicity (%)36(72)5 (10)--126(51)6 (2)-- Hypertension (%)15 (30)4 (8)1 (2)-27 (11)4 (2)1 (0.5)- Hypotension (%)1 (2)---1 (0.5)--- Hematuria (%)2 (4)1 (2)--3 (1)1 (0.5)-- Gengival recession/gengivitis (%)7 (14)---10 (4)--- Rhinitis (%)38 (76)---110(44.5)--- Epistaxis (%)31 (62)2 (4)--68 (27.5)2 (1)-- HFS (%)2 (4)---2 (1)--- Headache (%)6 (12)---9 (4)--- Hypokalemia (%)3 (6)-1 (2)-3 (1)-1 (0.5)- Hypertransaminasemy (%)3 (6)2 (4)1 (2) 9 (4)6 (2)1 (0.5) Hyperpigmentation (%)6 (12)2 (4)--14 (6)5 (2)-- Fever without infection (%)10 (20)---10 (4)--- Alopecia (%)5 (10)9 (18)3 (6)-11 (4)17 (7)7 (3)- Bruera G et al, 2010 Submitted

17 Intent-to-treat Analysis As-treated Analysis No% % Enrolled patients Evaluable patients Objective Response Partial Response Complete Response (CI±14) (CI±14) Stable Disease2829 Progressive Disease1414 Median Progression-free survival, months Range Progression events Median Overall Survival, months Range Deaths Liver metastasectomies No/Overall patients (25) No/Patients with liver metastases (16) No/Patients with liver-only metastases (11) Medical Oncology, LAquila, 2010, preliminary unpublished data FIr-B/Fox in MCRC: k-ras wld-type patients

18 Intent-to-treat Analysis As-treated Analysis No% % Enrolled patients Evaluable patients Objective Response Partial Response Complete Response (CI±19) (CI±19) 86 7 Stable Disease---- Progressive Disease31817 Median Progression-free survival, months Range Progression events Median Overall Survival, months Range Deaths Liver metastasectomies No/Overall patients (17) No/Patients with liver metastases (10) No/Patients with liver-only metastases (8) Medical Oncology, LAquila, 2010, preliminary unpublished data FIr-B/Fox in MCRC: k-ras mutant patients

19 _____ KRAS wt _____ KRAS mt P = Medical Oncology, LAquila, 2010, preliminary unpublished data FIr-B/Fox in MCRC OS in k-ras wild-type and mutant patients

20 MCRC Treatment Costs Mono (E/cycle) Doublet (E/cycle) Triplet (E/cycle) Poker (E/cycle) CT F FIri FOx FIr/FOx 76, , , ,78 CT+Bev F-Bev FIri-Bev FOx-Bev FIr-B/FOx 4118, , , ,30 CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C 7740, , , ,18

21 MCRC Treatment Costs Mono (E/cycle) Doublet (E/cycle) Triplet (E/cycle) Poker (E/cycle) CT F FIri FOx FIr/FOx CT+Bev F-Bev FIri-Bev FOx-Bev FIr-B/FOx CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C

22 MCRC k-ras wt : I line treatment options Mono (E/cycle) Doublet (E/cycle) Triplet (E/cycle) Poker (E/cycle) CT F FIri FOx FIr/FOx CT+Bev F-Bev FIri-Bev FOx-Bev FIr-B/FOx CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C

23 Mono (E/cycle) Doublet (E/cycle) Triplet (E/cycle) Poker (E/cycle) CT F FIri FOx FIr/FOx CT+Bev F-Bev FIri-Bev FOx-Bev FIr-B/FOx CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C MCRC k-ras wt : II line treatment options

24 I lineCostII lineCostTotal (E) CT FIri FOx 1CT+Cet Iri-Cet FIri-Cet FOx-Cet (9383) CT+Bev FIri-Bev FOx-Bev 3.56CT+Cet Iri-Cet FIri-Cet FOx-Cet (13420) CT+Cet Iri-Cet FIri-Cet FOx-Cet 4.95 CT+Bev FIri-Bev FOx-Bev (13420) MCRC k-ras wt : I-II line treatment options

25 I lineCostII lineCostTotal (E) CT FIri FOx 1CT+Cet Iri-Cet FIri-Cet FOx-Cet (6103) CT+Bev FIri-Bev FOx-Bev 3.56CT+Cet Iri-Cet FIri-Cet FOx-Cet (10140) CT+Cet Iri-Cet FIri-Cet FOx-Cet 4.95 CT+Bev FIri-Bev FOx-Bev (11054) MCRC k-ras wt : I-II line treatment options (58%)

26 I lineCostII lineCostTotal (E) CT FIr/FOx 1,85CT+Cet Iri-Cet FIri-Cet FOx-Cet 2,874,72 (7443) CT+Bev FIri-Bev FOx-Bev 3.56CT+Cet Iri-Cet FIri-Cet FOx-Cet 2,876,43 (10140) CT+Cet Iri-Cet FIri-Cet FOx-Cet 4,95 CT+Bev FIri-Bev FOx-Bev 2,067,01 (11054) MCRC k-ras wt : I-II line treatment options (58%)

27 I lineCostII lineCostTotal (E) CT FIr/FOx 1,85CT+Cet Iri-Cet FIri-Cet FOx-Cet 2,874,72 (7443) CT+Bev FIr-B/FOx 4,40CT+Cet Iri-Cet FIri-Cet FOx-Cet 2,877,27 (11464) CT+Cet Iri-Cet FIri-Cet FOx-Cet 4,95 CT+Bev FIri-Bev FOx-Bev 2,067,01 (11054) MCRC k-ras wt : I-II line treatment options (58%)

28 I lineCostII lineCostTotal (E) CT FIr/FOx 1.85CT+Cet Iri-Cet FIri-Cet FOx-Cet (7443) CT+Bev FIr-B/FOx 4.40CT+Cet Iri-Cet FIri-Cet FOx-Cet FIr-C/FOx-C (11464) 7.76 (12237) CT+Cet FIr-C/FOx-C 5.80CT+Bev FIri-Bev FOx-Bev (12395) MCRC k-ras wt : I-II line treatment options (58%)

29 I lineCostII lineCostTotal (E) CT FIri FOx FIr/FOx 1 0,9 1,85 CT Ox Iri CT+Bev FIri-Bev FOx-Bev 0,52 0,58 2,06 1,52 1,48 (2365) 3,91 (6166) CT+Bev FIri-Bev FOx-Bev 3.56CT FOx FIri 0,52 0,584,14 (6528) MCRC k-ras mut : I-II line treatment options (58%)

30 I lineCostII lineCostTotal (E) CT FIri FOx FIr/FOx 1 0,9 1,85 CT Ox Iri CT+Bev FIri-Bev FOx-Bev 0,52 0,58 2,06 1,52 1,48 (2365) 3,91 (6166) CT+Bev FIr-B/FOx 4,40CT ? 4,40 (6938) MCRC k-ras wt : I-II line treatment options (58%)

31 K-ras testing: conclusions (1) Low cost of genetic analysis Useful for differentiation between selection of treatment options High-cost in k-ras wild-type Moderate-cost in k-ras mutated Urgent need to consider randomized studies comparing triplet CT versus doublet/triplet CT associating anti-targets (anti-EGFR, anti-VEGF) according to kras genotype

32 K-ras testing: Perspectives Consideration of 4-drugs combinations also due to their relative increase in costs (<10%) Further lines of treatment in k-ras mutated patients Binomial testing in primary tumors and metastatic sites Evaluation of tumoral cells heterogeneity

33

34 Ringrazio Department of Pathology, Rouen University Hospital, Northwest Canceropole (FR) Dr. JC Sabourin Dr.ssa A. Lamy Dr.ssa F. Blanchard INSERM U614, Faculty of Medicine, Rouen(FR) Prof. Mario Tosi Prof. Tierry Frebourg Dr.ssa G. Bougeard Dr.ssa J. Tinat Dpt. Medicina Sperimentale, Università di LAquila Prof. Enrico Ricevuto Università G. DAnnunzio Chieti-Pescara Prof. S. Iacobelli

35 MCRC I line: ORR MCRC I line ORR ReferencesTrialMonoDoubletsTripletsPoker ORR (%) Kabbinavar JCO 2003 Bev+5FU/LV 5FU/LV17 40 Hurwitz NEJM 2004 Bev+IFL IFL+Placebo Kabbinavar JCO 2005 Bev+5FU/LV 5FU/LV (unfit for CPT) Hurwitz JCO 2005 Bev+5FU/LV IFL Falcone JCO 2007 FOLFOXIRI FOLFIRI41 66 Souglakos BJC 2006 FOLFOXIRI FOLFIRI Morelli Oncol Rep 2010 FIr/FOx66.7 Hochster JCO 2008 mFOLFOX6+Bev bFOL+Bev CapeOx+Bev mFOLFOX6 bFOL CapeOX Gruenberger JCO 2008 XelOx+Bev Liver mets resectable (High risk early recurrence) 73.2 Saltz JCO 2008 XelOx+Bev FOLFOX4+Bev XelOx FOLFOX Masi ESMO 2009 Bev+FOLFOXIRI77 Van Cutsem NEJM 2009 Cet+FOLFIRI FOLFIRI (EGFR+) Bokemeyer JCO 2009 Cet+FOLFOX4 FOLFOX4 (EGFR+) Folprecht Lancet Onc 2009 Cet+FOLFOX6 Cet+FOLFIRI (Liver mets unresectable) Tabernero JCO 2007 Cet+FOLFOX479 Garufi ESMO 2009 POCHER79 Douillard ESMO 2009 Panitumumab+FOLFOX4 FOLFOX4 (KRAS wt) Bruera 2010 submittedFIr-B/FOx84

36 MCRC I line: PFS MCRC I line PFS ReferencesTrialMonoDoubletsTripletsPoker PFS (months) Kabbinavar JCO 2003 Bev+5FU/LV 5FU/LV5.2 9 Hurwitz NEJM 2004 Bev+IFL IFL+Placebo Kabbinavar JCO 2005 Bev+5FU/LV 5FU/LV (unfit for CPT) Hurwitz JCO 2005 Bev+5FU/LV IFL Falcone JCO 2007 FOLFOXIRI FOLFIRI Souglakos BJC 2006 FOLFOXIRI FOLFIRI Morelli Oncol Rep 2010 FIr/FOx12 Hochster JCO 2008 mFOLFOX6+Bev bFOL+Bev CapeOx+Bev mFOLFOX6 bFOL CapeOX Gruenberger JCO 2008 XelOx+Bev Liver mets resectable (High risk early recurrence) Saltz JCO 2008 XelOx+Bev FOLFOX4+Bev XelOx FOLFOX Masi ESMO 2009 Bev+FOLFOXIRI13.4 Van Cutsem NEJM 2009 Cet+FOLFIRI FOLFIRI (EGFR+) Bokemeyer JCO 2009 Cet+FOLFOX4 FOLFOX4 (EGFR+) 7.2 Folprecht Lancet Onc 2009 Cet+FOLFOX6 Cet+FOLFIRI (Liver mets unresectable) Tabernero JCO 2007 Cet+FOLFOX412.3 Garufi ESMO 2009 POCHER13 Douillard ESMO 2009 Panitumumab+FOLFOX4 FOLFOX4 (KRAS wt) 3.9 Bruera 2010 submittedFIr-B/FOx12

37 MCRC I line: OS MCRC I line OS ReferencesTrialMonoDoubletsTripletsPoker OS (months) Kabbinavar JCO 2003 Bev+5FU/LV 5FU/LV Hurwitz NEJM 2004 Bev+IFL IFL+Placebo Kabbinavar JCO 2005 Bev+5FU/LV 5FU/LV (unfit for CPT) Hurwitz JCO 2005 Bev+5FU/LV IFL Falcone JCO 2007 FOLFOXIRI FOLFIRI Souglakos BJC 2006 FOLFOXIRI FOLFIRI Morelli Oncol Rep 2010 FIr/FOx20 Hochster JCO 2008 mFOLFOX6+Bev bFOL+Bev CapeOx+Bev mFOLFOX6 bFOL CapeOX Gruenberger JCO 2008 XelOx+Bev Liver mets resectable (High risk early recurrence) Saltz JCO 2008 XelOx+Bev FOLFOX4+Bev XelOx FOLFOX Masi ESMO 2009 Bev+FOLFOXIRI Van Cutsem NEJM 2009 Cet+FOLFIRI FOLFIRI (EGFR+) Bokemeyer JCO 2009 Cet+FOLFOX4 FOLFOX4 (EGFR+) Folprecht Lancet Onc 2009 Cet+FOLFOX6 Cet+FOLFIRI (Liver mets unresectable) Tabernero JCO 2007 Cet+FOLFOX430 Garufi ESMO 2009 POCHER Douillard ESMO 2009 Panitumumab+FOLFOX4 FOLFOX4 (KRAS wt) Bruera 2010 submittedFIr-B/FOx28

38 Cumulative toxicity Results Toxicity PatientsCycles Number50247 NCI-CTC Grade Anemia (%)7 (14)4 (8)--16 (6)4 (2)-- Leucopenia (%)13 (26)17 (34)--49 (20)26(10.5)-- Neutropenia (%)9 (18)14 (28)5 (10)-35 (14)32 (13)8 (3)- Trhombocitopeny (%)7 (14)1 (2)--16 (6)1 (0.5)--