1. Chemotherapy for Metastatic Colon Cancer Scott Berry Sunnybrook Health Sciences Centre

2. Where Were We Until 2000?

3. NHNH HN O O F 5-FU

4. FOLFOX FOLFIRI IFL irinotecan NN C O O N NO O O C 2 H O C 2 H C 3 H H C 3 H oxaliplatin NH 2 Pt O OC O C bevacizumab cetuximab PTK 787 Capecitabine Panitumumab

5. OS for 1 st line Combinations 5-FU/LV (Saltz) 5-FU/LV (Douillard) 5-FU/LV (de Gramont) IFL (Goldberg) IFL (Saltz) FOLFIRI (Douillard) FOLFOX (de Gramont) FOLFOX (Goldberg) IFL+ Bevacizumab 05 10 15 20 25 Median OS (months)

6. Overview/Objectives Review key evidence from randomized trials evaluating the chemotherapies and chemotherapy strategies that have emerged for metastatic colorectal cancer looking at both: Review key evidence from randomized trials evaluating the chemotherapies and chemotherapy strategies that have emerged for metastatic colorectal cancer looking at both: Efficacy Efficacy Safety Safety Key Strategies and Questions: Key Strategies and Questions: Which doublet should be used? Which doublet should be used? ? Should we be using triplet therapy ? Should we be using triplet therapy Can capecitabine replace infusional 5FU in doublets? Can capecitabine replace infusional 5FU in doublets? Can sequential monotherapy replace initial doublet therapy? Can sequential monotherapy replace initial doublet therapy? Can toxicity be reduced and efficacy maintained with “on/off” chemotherpay strategies? Can toxicity be reduced and efficacy maintained with “on/off” chemotherpay strategies?

7. Chemotherapy

8. Case 50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases –ECOG 1 – some RUQ pain and cough What is the optimal chemotherapy choice for her?

9. CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI

10. Efficacy of Chemotherapy in First- Line CRC: Phase III Trial Results Saltz et al. N Engl J Med. 2000;343:905; Douillard et al. Lancet. 2000;355:1041; de Gramont et al. J Clin Oncol. 2000;18:2938 RegimenRR (%) Median OS (mo) 5-FU/LV IFL (Saltz trial) 21 39 (P<0.001) 12.6 14.8 (P=0.04) 5-FU/LV FOLFIRI (Douillard trial) 22 35 (P<0.005) 14.1 17.4 (P=0.031) 5-FU/LV FOLFOX4 (de Gramont trial) 22 51 (P=0.0001) 14.7 16.2 (P=0.12)

11. CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI

12. Phase III Intergroup N9741 Study (Goldberg JCO, 2004) RANDOMIZATION Irinotecan + Oxaliplatin IFL FOLFOX 4

13. Phase II Sequential, Randomized CrossoverStudy Tournigand et al JCO 2004 FOLFIRI FOLFOX 6

14. N9741/Tournigand Trial: Results N9741Tournigand IFLFOL FOX P- value FOL FIRI FOL FOX P- value RR % 3145.035654.26 TTP mos 6.98.7.0098.58.0.26 OS mos 1519.5.000221.520.6.99

15. Tournigand Trial: Results Curative Surgery Rate: 22% FOLFOX, 9% FOLFIRI

16. FOLFIRI FOLFOX 0 10 20 30 F. neutropenia Nausea Vomiting Diarrhea Paresthesia % 7% 13% 0% 3% 14% 11% 10% 3%3% 34% 40 Tournigand Toxicity grade >3 >0.05 for P>0.05 for Comparisons marked by arrows Alopecia Any grade 60% vs 28% 60-day Mortality: 4% vs 3%

17. Combination Chemotherapy - Summary Combination chemotherapy with FOLFIRI or FOLFOX are both acceptable first line chemotherapy regimens for people with metastatic colorectal cancer Follow by alternate combination (or single agent Irinotecan after FOLFOX) Considerations: –Toxicity profile –? Considering surgery : FOLFOX based on “circumstantial” evidence

18. 2nd Line FOLFOX FOLFOX 4 OXALI n=463 2nd line mCRC post IFL DE GRAMONT FOLFOXFULVOXALI RR9.9%01.3% SD554036 TTP4.6 mos2.7 mos1.6 mos Tumour Related Symptoms 33%12% Rothenberg JCO 2003

19. CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI

20. Overall survival Integrated CRC Capecitabine (n=603) 5-FU/LV (n=604) 13.1 051015202530 Time (months) Estimated probability 1.0 0.8 0.6 0.4 0.2 0

21. What About Capecitabine As a Partner? Capecitabine + Irinotecan

22. BICC-C study FOLFIRI +/- celecoxib CAPIRI (Cape 1000mg/m 2 d1-14) +/- celecoxib n=430 1 st line mCRC mIFL +/- celecoxib FOLFIRImIFLCAPIRI Median OS (mos)23.117.6 (p=0.1)18.9 (p=0.42) Median PFS (mos)8.26.0 (p=0.01)5.7 (p=0.01) g3/4 nausea6.6 18.4 g3/4 vomiting5.86.615.6 g3/4 diarrhea13.916.847.5 g3/4 dehydration5.86.619.1 G3/4 HFS009.9 Febrile neutropenia3.612.47.1 Slide Courtesy D Jonker from data presented at ASCO 2007

23. EORTC 40015 study FOLFIRI +/- celecoxib CAPIRI (Cape 1000mg/m 2 bid x14d)+/- celecoxib n=85 1 st line CRC FOLFIRICAPIRI Req dose adjustment (%)33%53% g3/4 diarrhea13%37% Median number cycles5 (10w)3 (9w) Dose intensity irinotecan85%83% Median OS (mos)19.914.8 Median PFS (mos)9.65.9 Celecoxib vs Placebo : No Survival difference Slide Courtesy D Jonker

24. What About Capecitabine As a Partner? Capecitabine + Oxaliplatin

25. Capecitabine + Oxaliplatin Randomized Trials : Efficacy RegimenRR (%) Median OS (mo) Capecitabine (1000 bid) + Ox (130 q 3wks) FOLFOX 6 (oxali 100 q 2wks) (Ducreux ASCO 2007 N=306) 42 46 Non-Inferior 19.9 20.5 (p=NS) Capecitabine + Ox FOLFOX 4 (Cassidy ASCO 2007 N=2034) NR 19.6 19.8 (p=NS) Capecitabine+ Ox FOLFOX 4 (Rothenberg ASCO 2007 N= 627) 15 12 13.2 12.8 (p=NS) SecondLine FirstLine

26. Capecitabine + Oxaliplatin Randomized Trials : Toxicity RegimenToxicity Capecitabine (1000 bid) + Ox (130 q 3wks) FOLFOX 6 (oxali 100 q 2wks) (Ducreux ASCO 2007 N=306) FOLFOX arm had significantly more Gr 3/4: Neuropathy (25 v 11%), Feb Neut (6 v 0%) Capecitabine + Ox FOLFOX 4 (Cassidy ASCO 2007 N=2034) FOLFOX arm had more Gr 3/4: Feb Neut (5 v <2%) CapeOx arm had more Gr 3/4: Diarrhea (20 v 12%) and HFS (6 v 1%) Capecitabine + Ox FOLFOX 4 (Rothenberg ASCO 2007 N= 627) FOLFOX arm had more Gr 3/4: Feb Neut CapeOx arm had more Gr 3/4: Diarrhea (20 v 7) and HFS (4 v <2%) SecondLine FirstLine

27. Can Capecitabine Replace Infusional 5FU in mCRC? Capecitabine and Irinotecan –At doses studied CapeIri is more toxic and less effective than FOLFIRI Capecitabine and Oxaliplatin –CapeOx has same efficacy as FOLFOX –Differential toxicity profile between CapeOx and FOLFOX

28. CAPECITABINE FOLFOX FOLFIRI CAPE IRI CAPE OX FOLFOXIRI

29. Triplet Therapy

30. 5-FU/IRI vs FOLFOXIRI: Falcone et al N = 244 FOLFOXIRI 5-FU/Iri Douillard Randomization Slide Courtesy of R Goldberg

31. FOLFOXIRI Schedule 5FU flat continuous infusion 3200mg/m 2 L-LV 200 mg/m 2 Oxaliplatin 85 mg/m 2 2 hours Repeated every 14 days CPT-11 165 mg/m 2 48 hours Day 1 Day 2 Day 3 1 hour Slide Courtesy of R Goldberg

32. Efficacy 5-FU/IRIN=122FOLFOXIRI N=122 N=122P-value Response rate (%) 41%66%? PFS (mos) 6.9 (BICC = 8.3) 9.90.0009 OS (mos) 16.723.60.042 Slide Courtesy of R Goldberg

33. FU/IRI (42 pts) FOLFOXIRI (39 pts) R0 R0 12%* 12%* (5 pts) 36%* 36%* (14 pts) * p=0.017 Post-ChemoRx Resections (patients with liver mts only) Post-ChemoRx Resections (patients with liver mts only) Slide Courtesy of R Goldberg

34. Grade 3-4 Toxicity (N=122) p =0.0006 Slide Courtesy of R Goldberg

35. Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442. Survival improves with availability of three active drugs * FOLFOXIRI P=0.0001

36. Is FOLFOXIRI more active than 5-FU/IRI? Yes, including better resection rates Yes, including better resection rates But is comparator arm inferior? But is comparator arm inferior? More toxic More toxic

37. Monotherapy

38. Overall survival Integrated CRC Capecitabine (n=603) 5-FU/LV (n=604) 13.1 051015202530 Time (months) Estimated probability 1.0 0.8 0.6 0.4 0.2 0

39. Monotherapy versus doublets

40. ? Have 3 active chemo agents in mCRC Lead with combination ? Can we use agents sequentially and maintain efficacy and reduce toxicity FOCUS and CAIRO –Do both have fatal flaws?

41. FOCUS Lancet, 2008

42. 2,135 Untreated Stage IV patients A: 5 FU/LV (de Gramont) C: FOLFOX vs FOLFIRI B: 5 FU/LV (de Gramont) RANDOMISATIONRANDOMISATION FOCUS UK MRC CR08 IRI FOLFOX or FOLFIRI FOLFOX or FOLFIRI

43. FOCUS UK MRC CR08 Breaks allowed –Not before 3 mos –Only 4 weeks in 2 nd 3 mos –After that – allowed with re-start of previous regimen as long as progression hadn’t occurred within 12 weeks of stopping

44. FOCUS UK MRC CR08 Up to Dec 02, recommended salvage in all groups Infusional 5FU and Mit-C Since Dec 02, "balanced salvage" with CapOx or CapIri Primary Endpoint: Survival

45. Survival OS (mos) 5FU TO IRI 13.9 5FU TO FOLFOX 15.2 5FU TO FOLFIRI 15.0 FOLFOX 15.4 FOLFIRI 16.7 (p=0.01)

46. Table 4

47. FOCUS

48. QOL Mean overall QOL : varied little between arms and regimens In particular, no differences seen at 3 and 6 mos

49. FOCUS Conclude that sequential strategy is a valid option Median Survivals of all arms inferior to FOLFOX arm of N9741 and both arms of Tournigand trial ? Seeing an effect of restricting access to all 3 drugs

50. Percentage of Patients Receiving All 3 Active Drugs OS (mos) A5FU TO IRI 16% B 5FU TO FOLFOX 19% 5FU TO FOLFIRI C FOLFOX 33% FOLFIRI

51. FOCUS Grothey, JCO, 2004

52. CAIRO

53. Randomized study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer a study of the Dutch Colorectal Cancer Group (DCCG) CJA Punt, M Koopman, J Douma, J Wals, AH Honkoop FLG Erdkamp, RS de Jong, CJ Rodenburg, L Mol, NF Antonini ASCO 2007

54. CAIRO study CKTO 2002-07 Arm A Arm B Randomize capecitabine capecitabine + oxaliplatin irinotecan capecitabine + oxaliplatin capecitabine + irinotecan 1 st line 2 nd line 3 rd line

55. Dose/schedule of drugs all cycles given 3 weekly Capecitabine monotherapy: 1250 mg/m 2 b.i.d. day 1-14 Irinotecan monotherapy: 350 mg/m 2 day 1 CAPIRI 1 : capecitabine 1000 mg/m 2 b.i.d. day 1-14 + irinotecan 250 mg/m 2 day 1 CAPOX 2 : capecitabine 1000 mg/m 2 b.i.d. day 1-14 + oxaliplatin 130 mg/m 2 day 1 1 Rea et al. Ann Oncol 2005 2 Borner et al. J Clin Oncol 2002

56. Trial profile Arm A Arm B Randomize capecitabine N=397 capecitabine + oxaliplatin N=143 (36%) irinotecan N=251 (62%) capecitabine + oxaliplatin N=213 (53%) capecitabine + irinotecan N=398 1 st line 2 nd line 3 rd line

57. Median overall survival Combination treatment 17.4 months (15.2-19.2) ----------- Sequential treatment 16.3 months (14.3-18.2) p = 0.33

58. Efficacy results Sequential N=401 Combination N=402 p value Median overall survival (months)16.317.40.33 Hazard ratio for death1.08 One-year survival rate (%)6467 Median PFS (months) 1 st line5.87.80.0002 Overall response rate (CR + PR)* 1 st line 2 nd line 3 rd line 77 (20%) 23 (10%) 5 (4%) 139 (41%) 24 (12%) - Disease control rate (CR + PR + SD)* 1 st line 2 nd line 3 rd line 280 (74%) 162 (71%) 72 (57%) 297 (87%) 121 (63%) * Percentages are based on patients evaluable for response

59. Grade 3-4 toxicities in first line Toxicity Arm A capecitabine N = 397 Arm B capiri N = 398 p value Hand-foot syndrome12%6%0.002 Diarrhea11%26%<0.001 Nausea4%10%0.004 Vomiting3%9%0.0002 Stomatitis<1%2%0.16 Thrombosis/embolism *7%10%0.20 Febrile neutropenia<1%7%<0.001 * All grades

60. Quality of life Participation to this part of the study was proposed to the first 620 patients entered in the study (QLQ-C30 questionnaire of the EORTC) 403 patients were evaluable for quality of life Quality of life scores were comparable between the two arms, except for diarrhoea which was reported more frequently in combination treatment

61. Conclusions Combination treatment is not superior in terms of efficacy to sequential treatment in patients with advanced colorectal cancer Our results on median overall survival for sequential treatment are the highest reported when a fluoropyrimidine is administered as monotherapy in 1 st line Sequential treatment is a useful alternative for combination treatment Our results may be useful for strategies in which chemotherapy is combined with targeted agents

62. What about use of CapeIri? 62

63. Back to CAIRO PFS Capeiri in CAIRO similar to FOLFIRI in BICC-C –But OS of 17 mos is less than we’ve come to expect in sequential doublets –Cross trial comparisons –CapeIri in CAIRO better tolerated than CapeIri in BICC-C or EORTC trial except for high rates of diarrhea (~ double that seen with FOLFIRI in Tournigand or BICC-C) Would Combination arm in CAIRO have done better if FOLFIRI used? –No one knows. 63

64. ? Reasons for Results ? Geographic differences in capecitabine metabolism –Similar results in Europe ? Celecoxib –Results not published for BICC-C ? Different dose of cape do better –Maybe but not used in this trial 64

65. Summary Both CAIRO and FOCUS validate a sequential approach within the context of their study parameters ? Would they have done so if FOCUS had allowed better access to all 3 chemo drugs and CAIRO had used FOLFIRI? 65

66. Is Less Chemo More?

67. Case 50 yo woman with no history of medical problems presents with bilobar liver and bilateral lung metastases –ECOG 1 – some RUQ pain and cough She agrees to chemotherapy but asks if there is anyway she can take a break during chemo without reducing the benefits of chemo?

68. Which of the following strategies has been shown to reduce toxicity without impacting on efficacy? Induction of FOLFOX for 3 mos followed by infusional 5FU maintanence then reintroduce FOLFOX Induction of FOLFOX for 3 mos followed by no maintanence (complete chemo break) then reintroduce FOLFOX FOLFIRI on for 2 mos, off for 2 mos

69. Stop and Go concept - OPTIMOX1 Tournigand et al, JCO 2006 6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7 FOLFOX4 620 pts R Cum. Oxali7801560 (%)FOLFOX4FOLFOX7 RR58.558.3 PFS9.08.7 DDC 9.010.6 OS19.321.2 G3/4 NTox 17.913.3 Primary endpoint

70. F. Maindrault-Gœbel, G. LLedo, B. Chibaudel, L. Mineur, T. André, M. Bennamoun, M. Mabro, P.Artru, C. Louvet, A. de Gramont OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study.

71. OPTIMOX Studies OPTIMOX-1 FOLFOX 4 until TF FOLFOX 7 sLV5FU2 OPTIMOX-2 mFOLFOX 7 sLV5FU2 mFOLFOX 7 CFI

72. Baseline Progression t T size FOLFOX ProgressionBaseline progression Progression at reintroduction Chemotherapy-free Interval

73. Duration of Disease Control t T size FOLFOX PFS 1 ProgressionBaseline progression PFS 2 Progression at reintroduction DDC = PFS 1 + PFS 2 (if no PD) ASCO 2001, 146a

74. Neuropathy Grade 1 8 % 2 21.2 % 3 2 % Grade 1 29.4 % 2 35.3 % 3 5.9 % Grade 1 6.8 % 2 15.5 % 3 3.9 % Grade 1 36.8 % 2 19.2 % 3 7 % Optimox 1Optimox 2 After the first reintroduction 2 months after FOLFOX Grade 1 70.7 % 2 18.1 % 3 0 % Grade 1 70.8 % 2 16.5 % 3 0 % During C1-C6

75. Chemotherapy-free Interval

76. Duration of Disease Control

77. Overall Survival

78. Alternating vs continuous FOLFIRI in advanced colorectal cancer (ACC): a randomized GISCAD trial Roberto Labianca Ospedali Riuniti – Bergamo, Italy Floriani I, Cortesi E, Isa L, Zaniboni A, Marangolo M, Frontini L, Barni S, Beretta GD, Sobrero A

79. GISCAD-Trial: Design Primary endpoint: OS R FOLFIRIFOLFIRI Evaluation 4 mos N=336

80. PFS Median f-up: 30 m Median time to PD: Arm A 6.2 m Arm B 6.5 m Cox analysis (after adjustment for gender, age and site): HR: 1.01 (0.78-1.27)

81. OS Median f-up: 30 m Median survival time: Arm A 16.9 m Arm B 17.6 m Cox analysis (after adjustment for gender, age and site): HR: 1.03 (0.78-1.35)

82. Toxicity Grade 3/4 toxicities similar in both arms –This paradigm of toxicity measurement is not appropriate for this type of trial No QOL analysis

83. Summary GISCAD –Equivalent DFS, OS, toxicity –? Rationale clinical strategy OPTIMOX2 ? Longer induction needed ? Shorter break before re-introduction ? Different maintenance strategy

84. From OPTIMOX to DREAM OPTIMOX-1 OPTIMOX-2 Efficacy = Toxicity  Efficacy decresed Toxicity = DREAM Bevacizumab Erlotinib Bevacizumab