1. Minimal versus Intense Upfront Systemic Therapy in Metastatic Colorectal Cancer Paulo M. Hoff, MD, FACP Hospital Sirio Libanes Sao Paulo, Brazil Centro de Oncologia

2. Medical Oncology Treatment Objectives in CRC To cure patients: –Adjuvant chemotherapy –Convert inoperable into operable disease To palliate symptoms: –Reduce tumor volume To prolong survival –Control disease growth

3. 5 – Fluorouracil: 1957 NHNH HN O O F 5-FU 50 years later, fluoropyrimidines remain the backbone of colorectal cancer treatment.

4. Treatment Options for Advanced Colorectal Cancer in 2006 Six different classes of drugs available: –Fluoropyrimidines 5-FU, FUDR, Capecitabine, UFT, S-1 –Platins Oxaliplatin –Topoisomerase I inhibitors Irinotecan –Direct TS inhibitors Raltitrexed –Anti-VEGF Bevacizumab –Anti-EGFR Cetuximab, Panitumumab

5. Irinotecan Combination Trials IFL* (n=231) 5-FU/LV (n=226) RANDOMIZE Irinotecan (n=226) Saltz et al. N Engl J Med. 2000;343:905-914 Metastatic Colorectal Cancer

6. Saltz et al. N Engl J Med. 2000;343:905-914. Irinotecan Combination Trials: Efficacy Irinotecan + 5-FU/LV5-FU/LVP Value RR (confirmed, %) 39% 21% <.001* PFS (median, mo) 7.0 4.3.004 OS (median, mo) 14.8 12.6.04

7. Oxaliplatin as Second-Line Treatment for CRC Rothenberg et al. J Clin Oncol. 2003;21:2059-2069. LV5FU2 (n=151) Oxaliplatin (n=156) RANDOMIZERANDOMIZE FOLFOX4 (n=152) Metastatic Colorectal Cancer S/P IFL

8. Oxaliplatin as Second-Line Treatment for CRC LV5FU2FOLFOX4OxaliplatinP Value RR0%9.9%1.3% <.0001 TTP2.7 mo4.6 mo1.6 mo<.0001 Overall Survival 8.7 mo9.8 mo8.1 mo.07 Rothenberg et al. J Clin Oncol. 2003;21:2059-2069.

9. N9741: Modified Schema IFL (n=264) IROX (n=264) FOLFOX4 (n=267) Goldberg et al. J Clin Oncol. 2004;22:23-30. RANDOMIZERANDOMIZE Metastatic Colorectal Cancer

10. N9741: Efficacy Results IFL (N=264) FOLFOX (N=267) IROX (N=264) RR (CR + PR)31%45%34% Median TTP (Months) 6.98.76.5 Median OS (Months)14.819.517 Goldberg et al. J Clin Oncol. 2004;22:23-30.

11. N9741: Second Line Treatment SaltzFOLFOX-4Wasserman CPT-11Oxaliplatin CPT-11 5-FU/LV 5-FU/LV Oxaliplatin N=235N=235N=237 Any59%67%63% CPT-1122%52%28% Oxaliplatin17% 6% 6% 5-FU35%33%45% Other28%20%27%

12. FOLFOX6 (n=111) FOLFIRI With FOLFOX6 Sequencing Trial in CRC Tournigand et al. J Clin Oncol. 2004;22:229-237. FOLFIRI (n=109) RANDOMIZERANDOMIZE FOLFIRI (n=69) FOLFOX6 (n=81) Until progression

13. RR, %561554 4 PFS, mo8.54.2 8.0 2.5 OS, mo21.520.6 FOLFIRI  FOLFOX6 FOLFOX6  FOLFIRI n = 109 n = 81 n = 111 n = 69 Tournigand C et al. J Clin Oncol 2004;22:229-237 FOLFIRI With FOLFOX6 Sequencing Trial in CRC

14. Availability of All Cytotoxic Agents and Survival Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442. Patients With 3 Drugs (%) 0 Median OS (months) 10 20 3040506070 80 13 14 15 16 17 18 19 20 21 22 12

15. 5-FU/IRI vs FOLFOXIRI: Falcone et al N = 244 FOLFOXIRI 5-FU/IriDouillard Falcone ASCO 2007 RANDOMIZERANDOMIZE Metastatic Colorectal Cancer

16. Efficacy 5-FU/IRI N=122 FOLFOXIRI N=122 P-value Response rate (%) 41%66%? PFS (mos)6.9 (BICC = 8.3) 9.90.0009 OS (mos)16.7 (BICC = 23) 23.60.042 Falcone ASCO 2007

17. Availability of All Cytotoxic Agents and Survival Courtesy of Dr. Goldberg, adapted from Grothey A and Sargent D. J Clin Oncol. 2005;23:9441-9442. Patients With 3 Drugs (%) 0 Median OS (months) 10 20 3040506070 80 13 14 15 16 17 18 19 20 21 22 12 * FOLFOXIRI

18. FU/IRI (42 pts) FOLFOXIRI (39 pts) R0 12%* (5 pts) 36%* (14 pts) * p=0.017 Post-ChemoRx Resections (patients with liver mts only) Falcone ASCO 2007

19. Phase III Trial With Bevacizumab Therapy in First-Line MCRC Bolus IFL + BV (n = 403) 5-FU/LV + BV (n = 110) Bolus IFL + placebo (n = 412) RANDOMIZE Untreated MCRC Hurwitz H, et al. N Engl J Med 2004;350:2235–42

20. Phase III Trial of Bevacizumab in First-Line MCRC IFL + Placebo (n=411) IFL + Bevacizumab (n=402)P Value ORR (%) CR PR 35 2.2 32.5 45 3.7 41.2 0.0036 Hurwitz H, et al. N Engl J Med 2004;350:2235–42

21. Median PFS (months) IFL + placebo: 6.2 (95% CI: 5.6–7.7) IFL + Bevacizumab: 10.6 (95% CI: 9.0–1.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001 Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 0102030 PFS (months) 6.2 10.6 IFL + Bevacizumab IFL + placebo Phase III trial : PFS Hurwitz H, et al. N Engl J Med 2004;350:2335–42

22. Median survival (months) IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs IFL + Bevacizumab: 20.3 (95% CI: 18.5–24.2) HR=0.66 (95% CI: 0.54–0.81) p<0.001 Probability of survival 1.0 0.8 0.6 0.4 0.2 0 010203040 Survival (months) IFL + Bevacizumab IFL + placebo 15.6 20.3 Hurwitz H, et al. N Engl J Med 2004;350:2335–42 Phase III trial : Survival

23. FOLFIRI (n=144) R mIFL (n=141) XELIRI (n=145) Feb 2003 – April 2004 Initial design n=430 FOLFIRI+Bev. mIFL+Bev. (n=60) (n=57) May 2004 – Dec 2004 n=117 Primary endpoint: PFS Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design Protocol amended due to approval of bevacizumab Amended design R * Celecoxib data not shown Fuchs et al, ASCO 2007

24. BICC Efficacy in 430 Patients mIFLCapeIRIFOLFIRIP-value Response rate (%) 43.338.647.2N.S. PFS (mos)6.05.78.20.01 OS (mos)17.618.923.1N.S. Fuchs et al, ASCO 2007

25. Adverse Event Grade 3-4 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Nausea8.87.318.4 Vomiting8.87.315.6 Diarrhea13.91947.5 Dehydration5.87.319.1 Neutropenia43.140.931.9 Febrile neutropenia3.612.47.1 Hand-foot syndrome009.9 60-day mortality3.65.13.5 Period 1: Grade 3-4 AEs Fuchs et al, ASCO 2007

26. Period 2: Efficacy mIFL + Bev N=60 FOLFIRI + Bev N=57 P-value Response rate (%) ??? PFS (mos)8.311.20.28 OS (mos)19.2Not reached0.01 Fuchs et al, ASCO 2007

27. Progression Free Survival Proportion of Subjects Who Did Not Progress RegimenPFS (Mos) P Value FOLFIRI + BEV 11.2-- mIFL + BEV 8.30.28 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0102030 Time to Progression (months) FOLFIRI + Bevacizumab mIFL + Bevacizumab Fuchs et al, ASCO 2007

28. Overall Survival Survival Time (months) Regimen Median OS (Months)1 Year P Value FOLFIRI+ BEVNot Reached87%-- mIFL + BEV19.261%0.01 Proportion of Subjects Who Survived FOLFIRI + Bevacizumab mIFL + Bevacizumab 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 010204030 Fuchs et al, ASCO 2007

29. E3200: Phase III Trial of Bevacizumab in Second-Line Metastatic CRC FOLFOX4 BV monotherapy FOLFOX4 + BV Previously IFL Treated Metastatic CRC (n=880) Giantonio, ASCO 2005

30. E3200: Efficacy 4.8 P < 0.0001 vs. BV 3.0%9.2%21.8% P < 0.0001 vs. FOLFOX RR 2.77.2 P < 0.0001 vs. FOLFOX PFS (months) 10.2 230 Bevacizumab 10.8 12.9 P = 0.0018 vs. FOLFOX OS (months) 271 FOLFOX4FOLFOX4 + bevacizumab Giantonio BJ et al. ASCO 2005

31. Phase III Trial of Bevacizumab With Oxaliplatin-Based Therapy in CRC Primary end point: PFS Previously untreated MCRC (N=1600) XELOX FOLFOX4 + Placebo + Bevacizumab (7.5 mg/kg, q3w) + Bevacizumab (5 mg/kg, q2w) Saltz L, et al. ASCO 2007

32. Efficacy XELOX/FOLFOX N=701 XELOX/FOLFOX + bev N=699 P-value Response rate (%) 49%47%0.99 PFS (mos) 8.09.40.0023 OS (mos) 19.921.30.076 Saltz L, et al. GI ASCO 2007

33. Overall survival HR=0.89 (97.5% CI 0.76–1.03) p=0.0769 XELOX / FOLFOX-4 + bevacizumabn=699 (420 events) XELOX / FOLFOX-4 + placebon=701 (455 events) 1.0 0.8 0.6 0.4 0.2 0 Months Survival estimate 0 61218243036 19.921.3 Saltz L, et al. ASCO 2007

34. Cetuximab in Colorectal Cancer “Bond Trial” Irinotecan pre-treated EGF-R positive Metastatic CRC Cetuximab and Irinotecan 218 patients Cetuximab 111 patients * 577 patients screened 329 patients included in a 2:1 randomization PD Cunningham et al. NEJM 2004;351:337-345

35. Cetuximab Combination Therapy “BOND” Trial IRI/Cx Cx Assessment(n=218)(n=111)P-value Response Rate 22.9%10.8%0.007 TTP 4.1 mo. 1.5 mo.<0.001 (Median) Survival (Median) 8.6 mo. 6.9 mo.0.48 Cunningham et al. NEJM 2004;351:337-345 Cetuximab may circumvent irinotecan resistance

36. Correlation Between Response Rate and Prior Treatment Subgroups Combination n/N (%) Monotherapy n/N (%) Prior regimens 17/41 (17.1)5/27 (18.5) 220/79 (25.3)5/41 (12.2) ≥323/98 (23.5)2/43 (4.7) Prior oxaliplatin yes30/135 (22.2)6/71 (8.5) no20/83 (24.1)6/40 (15.0)

37. The BOND II Trial RANDOMIZERANDOMIZE Bevacizumab + Cetuximab Bevacizumab + Cetuximab + Irinotecan CRC patients who progressed on irinotecan (any line) Saltz et al, ASCO 2005

38. The BOND II Trial Best response on study –CBI (n= 41)PR = 37% –CB (n=40)PR = 20% Median time to tumor progression: –Cetux/Bev/IRI 7.9 months –Cetux/Bev5.6 months Saltz et al, ASCO 2005

39. CALGB 80405 Intergroup Trial mFOLFOX6 or FOLFIRI Bevacizumab Cetuximab Bevacizumab + Cetuximab RANDOMIZERANDOMIZE

40. Panitumumab Phase III Trial in First Line Metastatic CRC: PACCE RANDOMIZE FOLFOX or FOLFIRI + Bevacizumab + Panitumumab FOLFOX or FOLFIRI + Bevacizumab Previously untreated CRC patients N=1000 PACCE: Panitumumab Advanced Colorectal Cancer Evaluation Press release reported lack of benefit in experimental arm

41. First Line Trials: Caveats for Survival as Endpoint Randomization Drug A Drug A + B Crossover to B not encouraged Classic Randomization Drug A Drug A + B Crossover to B mandatory Practical

42. The FOCUS Trail Drug A until it fails… …then B until it fails “staged single agents” A Drug A until it fails… …then add drug B until both fail “staged combination” B Drugs A + B together until both fail “1 st -line combination” C

43. A: FU until it fails, then change to Ir “3 rd drug” salvage OxCap IrCap OxCap IrCap B (ir) : FU until it fails, then add Ir B (ox) : FU until it fails, then add Ox C (ir) : FU+Ir from the start, until it fails C (ox) : FU+Ox from the start, until it fails 700 350 2100 patients Focus Design Seymour et al ASCO 2005

44. Overall survival PlanFirst 2 drugs scheduleMedian OS AFU then Ir13.9 B(ir) B(ox) FU then FU/Ir FU then FU/Ox 14.8 15.2 C(ir) C(ox) 1 st -line FU/Ir 1 st -line FU/Ox 16.3 15.2 Seymour et al ASCO 2005

45. FOCUS Summary Use of sequential chemotherapy, with deferred use of combinations, appears as effective as using the combination upfront; HOWEVER… Sequential single agents appears to be inferior than single agent followed by an appropriate combination Questions remain regarding exposure to all agents Not all agents should be used alone

46. CAIRO: 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 Courtesy of Punt et al, ASCO 2007

47. Median Overall Survival Combination treatment 17.4 months (15.2-19.2) ----------- Sequential treatment 16.3 months (14.3-18.2) p = 0.33 Courtesy of Punt et al, ASCO 2007

48. Who, What, How Definitions Intense therapy: –Implies early use of more complex combinations –Is not the same as piling all active drugs together Minimal therapy: –Seeks to minimize toxicity and perhaps cost –It is not the same as sequential monotherapy –It is not minimalist therapy

49. Who, What, How Who should get upfront intense therapy? –Depends on what you call intense therapy! –Patients who may become resectable with a good response –Patients whose quality of life may improve with a tumor response –Patients who are unlikely to get second and third line treatment regimens (e.g., aggressive tumors)

50. Who, What, How Who should get upfront minimal therapy? –Reserved for patients with little hope for a curative surgery –Patients who have relatively indolent disease, and who can expect to receive additional lines of therapy –Patients with good quality of life who are not interested in trading it for improvements in the therapy’s efficacy

51. Chemotherapy for CRC Summary Doublets are more active than single agents, and triplets may be even better Use of combinations of agents, in some sequence, results in better response rates, resection rates, time to progression, and overall survival However, the agents do not all need to be used upfront Judicious use of combination therapy, in an appropriate sequence, is indicated for most patients

52. How Should We Use the Available Drugs Good activity by itself –5-FU/LV –Capecitabine –UFT –Irinotecan –Raltitrexed Better used in combination –Oxaliplatin FOLFOX / XELOX IROX –Bevacizumab 5-FU Oxaliplatin Irinotecan Cetuximab –Cetuximab Irinotecan FOLFOX / XELOX –Panitumumab?

53. The Building Block Strategy 5-FU + LV 5-FU + Oxaliplatin Irinotecan + Cetuximab Capecitabine Irinotecan 5-FU + Bevacizumab Capecitabine + Oxaliplatin Panitumumab

54. Conclusion Treatment objectives are often different Patients are different Tumor biology and behavior is variable 1 Why should the treatment be the same ? We desperately need studies to learn how to match the correct treatment with the appropriate patient 1 O’Connell et al Abst. 4009, ASCO 2007