1. A Report from ECCO 14 Oral Chemotherapy in Colorectal Cancer John L. Marshall, MD Chief, Division of Hematology/Oncology Associate Director of Clinical Research Director, Developmental Therapeutics and GI Oncology Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC

2. Capecitabine in the Treatment of Colorectal Cancer ECCO 2007 trials of capecitabine in colorectal cancer –Oral vs. IV 5-FU Adjuvant: X-ACT Trial First-line metastatic: COFFEE Trial (SICOG) –First-line metastatic CRC First BEAT Trial CAIRO2 (CAPOX-B ± cetuximab) CAIRO (sequential vs. combination chemotherapy) Novel Approaches (XELOXIRI) –Second-line mCRC –Capecitabine dosing

3. Capecitabine vs. IV 5-FU

4. ECCO 14 Abstract 1LB 5-Year Overall Survival Update from the X-ACT Trial of Capecitabine vs. 5-FU/LV as Adjuvant Treatment for Stage III Colon Cancer C. Twelves, W. Scheithauer, J. McKendrick, M. Nowacki, J. Seitz, G. Van Hazel, A. Wong, E. Diaz-Rubio, J. Cassidy

5. X-ACT Trial Design 1° endpoint: disease-free survival (DFS) Chemo-naïve Dukes C, resection ≤ 8 weeks Capecitabine 1250 mg/m 2 twice daily, d 1-14, q21d (N = 1004) Bolus 5-FU/LV 5-FU 425 mg/m 2 plus LV 20 mg/m 2, d 1-5, q28d (N = 983) 24 weeks Twelves C, et al. ECCO 14. Abstract 1LB.

6. Standard Eligibility Criteria Eligible patients –Age 18–75 years –Histologically confirmed Dukes’ C colon cancer –Fully recovered after surgery –ECOG PS: ≤1 –Life expectancy ≥ 5 years Excluded patients –Metastatic disease –Prior cytotoxic chemotherapy or organ allografts –Clinically significant cardiac disease –Severe renal impairment –Central nervous system disorders –Pregnant or lactating women Twelves C, et al. ECCO 14. Abstract 1LB.

7. Previously Presented Primary Efficacy (ITT) and Safety Findings At a median follow-up of 3.8 years DFS in the capecitabine group was at least equivalent to 5-FU/LV – HR = 0.87 (95% CI: 0.75–1.00) OS in the capecitabine group was at least equivalent to 5-FU/LV –HR = 0.84 (95% CI: 0.69–1.01) Capecitabine was associated with significantly fewer adverse events than 5-FU/LV (P < 0.001) Twelves C et al. NEJM 2005;352:2696–704.

8. X-ACT Disease-Free Survival 5-year update – median follow-up 6.8 years (ITT) Estimated Probability 1.0 0.8 0.6 0.4 0.2 0.0 0642487896 Months HR = 0.88 (95% CI: 0.77–1.01) NI margin 1.20 1218243036546066728490 5-year Capecitabine (N = 1 004) 60.8% 5-FU/LV (N = 983) 56.7% Test of non-inferiority P < 0.0001 Test of superiority P = 0.0682 Twelves C, et al. ECCO 14. Abstract 1LB.

9. X-ACT Overall Survival 5-year update – median follow-up 6.8 years (ITT) 5-year Capecitabine (N = 1 004) 71.4% 5-FU/LV (N = 983) 68.4% 1.0 0.8 0.6 0.4 0.2 0.0 06424878961218243036546066728490 Estimated Probability Months HR = 0.86 (95% CI: 0.74–1.01) NI margin 1.14 Test of non-inferiority P = 0.000116 Test of superiority P = 0.06 Twelves C, et al. ECCO 14. Abstract 1LB.

10. 5-year Overall Survival Subgroup Analysis ITT population Male Female < 40 40–69 years old ≥ 70 pN1 pN2 Baseline CEA < ULN Baseline CEA > ULN 1987 1074 912 76 1513 396 1389 593 1672 155 N Hazard Ratio and 95% CI Favours Capecitabine 0.40.60.81.01.21.41.61.8 Favours 5-FU Twelves C, et al. ECCO 14. Abstract 1LB.

11. Multivariate Analysis of Overall Survival Factor Hazard Ratio95% CIP-value Age (years)1.0101.001–1.0190.0238 Gender (female vs. male)0.7700.654–0.9080.0018 Regional lymph nodes (PN1 vs. PN0, PN2, PNx)0.5770.489–0.682< 0.0001 Baseline CEA (< vs. ≥ ULN)0.4010.320–0.503< 0.0001 Time from surgery to randomisation (days)1.0040.997–1.0120.2418 Treatment effect (capecitabine vs. 5-FU/LV)0.8280.705–0.9710.0203 Twelves C, et al. ECCO 14. Abstract 1LB.

12. Treatment Duration and Intensity Capecitabine (N = 995) Bolus 5-FU/LV (N = 974) Completed full course of treatment 84%88% Needed dose reduction42%44% Needed dose reduction, interruption or delay 57%52% Twelves C, et al. ECCO 14. Abstract 1LB.

13. Safety Profile of Capecitabine vs. Bolus 5-FU/LV (All Grades) *P < 0.001 † Laboratory value Treatment-related AEs Capecitabine (N = 993) Bolus 5-FU/LV (N = 974) * * * * Diarrhea Stomatitis Hand-foot Neutropenia † Nausea /Alopecia syndrome vomiting 100 80 60 40 20 0 * * Patients (%) Scheithauer W et al. Ann Oncol 2003;14:1735–43.

14. Systemic Treatments (  2%) Given at Relapse Treatment Capecitabine (N = 1004) 5-FU/LV (N = 983) 5-FU22%20% Oxaliplatin15% Irinotecan17%19% Capecitabine5%10% Raltitrexed2% Cetuximab2% Twelves C, et al. ECCO 14. Abstract 1LB.

15. Locoregional Procedures (  2%) at Relapse Treatment or procedure Capecitabine (N = 1004) 5-FU/LV (N = 983) Patients with  1 treatment, N 343 (34%)350 (36%) Radiotherapy7%8% Partial hepatectomy3%4% Laparotomy3%2% Malignant tumour excision2%3% Partial colectomy<1%2% Lobectomy (lung)1%2% Twelves C, et al. ECCO 14. Abstract 1LB.

16. X-ACT and MOSAIC Overall Survival in Stage III Patients (ITT) Estimated Probability 012345678 0.4 0.6 0.8 1.0 Years X-ACT Bolus 5-FU/LV (N = 983) Capecitabine (N =1 004) MOSAIC 1 LV5FU2(N = 675) FOLFOX(N = 672) 1 De Gramont A et al. J Clin Oncol 2007;25(18S):4007. Twelves C, et al. ECCO 14. Abstract 1LB.

17. NO16968 Study Update XELOX (N = 938) Capecitabine 1000mg/m 2 bid d1–14 q3w + Oxaliplatin 130mg/m 2 IV d1 q3w 5-FU/LV (N = 926) Mayo Clinic bolus 5-FU/LV Roswell Park bolus 5-FU/LV Stage III Colon Cancer XELOX is feasible and safe –Similar tolerability to bolus 5-FU/LV and FOLFOX4 –Better tolerability than FLOX Efficacy data are due at end of 2008 Schmoll H-J et al. J Clin Oncol 2007;25:102–9.

18. X-ACT 5-year Survival Update Conclusions Capecitabine is known to be an effective and better tolerated alternative to bolus 5-FU/LV in the adjuvant treatment of stage III colon cancer Update shows that capecitabine is at least equivalent to bolus 5-FU/LV with a trend to superiority (P = 0.06) in terms of 5-year overall survival First indication in the adjuvant setting from a cross-trial comparison showing that capecitabine is equivalent to infusional 5-FU Twelves C, et al. ECCO 14. Abstract 1LB.

19. ECCO 14 Abstract P#3044 Capecitabine or Folinic acid/Fluorouracil IV Bolus Plus Eloxatin Evaluation (COFFE trial) in Metastatic Colorectal Carcinoma (MCRC): Final Results of the Southern Italy Cooperative Oncology Group (SICOG) Phase III Trial 0401 P. Comella, B. Massidda, G. Filippelli, A. Farris, D. Natale, L. Maiorino, G. Condemi, S. Palmeri, S. Leo, A. Gambardella

20. COFFEE Trial Study Design Primary Endpoint: Response rate (WHO criteria) Secondary Endpoints: PFS, QoL OXXEL Oxaliplatin 100 mg/m 2 d1 + Capecitabine 1,000 mg/m 2 twice daily, d 1-11 q 2-weeks (N = 150) OXAFAFU Oxaliplatin 85 mg/m2 d1 + Bolus 5-FU/FA 5-FU 850 mg/m 2 + FA 250 mg/m 2, d 2, q 2-weeks (N = 156) mCRC Prior adjuvant therapy (N = 306) to disease progression Comella P, et al. ECCO 14. Abstract P#3044.

21. COFFEE Trial Baseline Characteristics OXAFAFU (N = 164) OXXEL (N = 158) Characteristic N%N% Male/Female89/7554/46104/5466/34 Median age, years (range)65 (37-79)64 (39-84) Age ≥ 70 years64395132 ECOG PS: 099609661 1-265406239 Primary tumor site: Colon1157611472 Rectal49244428 Number of sites: 174457950 255334529 3+35213421 Previous surgery1257611472 Previous adjuvant chemotherapy41253925 Comella P, et al. ECCO 14. Abstract P#3044.

22. COFFEE Trial Treatment Disposition OXAFAFU (N = 164) OXXEL (N = 158) Characteristic N%N% Total number of cycles1,2721,243 Median cycles/patient (range)8 (1-12) Patients treated with: ≥ 4 cycles1458814089 ≥ 8 cycles95589661 ≥ 12 cycles46284428 Patients still on therapy7474 Patients off treatment for: Protocol (CR, PD during treatment, or planned cycles) 1106710063 Refusal1381610 Toxicity1062214 Disease complication14853 Physician’s decision10685 Comella P, et al. ECCO 14. Abstract P#3044.

23. COFFEE Trial Hematologic Toxicity % of Patients 27% 10% 13% 6% 3% 4% 1% 3% Neutropenia Febrile Neutropenia Thrombocytopenia Anemia P < 0.001 P < 0.043 Comella P, et al. ECCO 14. Abstract P#3044.

24. COFFEE Trial Non-Hematologic AEs % of Patients VomitingDiarrheaStomatitisFatigue Neurological HFS Hepatic Comella P, et al. ECCO 14. Abstract P#3044.

25. COFFEE Trial Efficacy OXAFAFU (N = 164) OXXEL (N = 158) CharacteristicN%N% Complete response64117 Partial response48294227 Stable disease57355736 Progression37222918 Not assessed16101911 Overall response rate, % (95% CI) 33 (25-41)34 (26-42) Comella P, et al. ECCO 14. Abstract P#3044.

26. COFFEE Trial Progression-Free Survival Comella P, et al. ECCO 14. Abstract P#3044.

27. COFFEE Trial Conclusions OXXEL regimen produced a similar RR and PFS compared to OXAFAFU –RR: 34% vs. 33% –PFS: 6.2 mos. vs. 6.3 mos. Occurrence of severe adverse events was significantly lower with OXXEL regimen (32% vs. 43%) –Although more patients went off therapy for toxicity in the OXXEL vs. OXAFAFU arm (14% vs. 6%) OXXEL regimen resulted in significantly lower incidence of severe neutropenia (10% vs. 27%) and febrile neutropenia (6% vs. 13%), but GI symptoms were significantly more pronounced These data provide additional support for capecitabine as an effective alternative to IV 5-FU/LV in the treatment of colorectal cancer Comella P, et al. ECCO 14. Abstract P#3044.

28. Capecitabine in First-Line Metastatic CRC

29. ECCO 14 Abstract P#3020 Preliminary Efficacy of Bevacizumab with First-Line FOLFOX, XELOX, FOLFIRI and Fluoropyrimidines for mCRC: First BEAT Trial S. Berry, D. Cunningham, M. Michael, A. Kretzschmar, F. Rivera, M. DiBartolomeo, M. Mazier, B. Lutiger, E. Van Cutsem

30. First BEAT Trial Study Design 1,965 mCRC patients from 41 countries –Accrued from June 2004 – February 2006 First-line chemotherapy with bevacizumab until disease progression (physicians choice) –Bevacizumab at 5 mg/kg q2w for 5-FU-based CT –Bevacizumab at 7.5 mg/kg q3w with capecitabine-based CT Regimens –FOLFOX (28%) –FOLFIRI (26%) –XELOX (18%) –5-FU/capecitabine (15%) Berry S, et al. ECCO 14. Abstract P#3020.

31. First BEAT Trial Results RegimenMedian Progression-Free Survival (mos.) Overall (1,110 events)10.7 FOLFOX + Bev10.6 XELOX + Bev10.7 FOLFIRI + Bev11.3 5-FU/Capecitabine + Bev9.1 Berry S, et al. ECCO 14. Abstract P#3020. Median TTP 11.1 mos. (1,026 events) OS data immature; 614 patients died

32. ECCO 14 Abstract O#3000 Randomised Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) with or without Cetuximab in Advanced Colorectal Cancer (ACC), the CAIRO2 Study of the Dutch Colorectal Cancer Group (DCCG). An Interim Safety Analysis J. Tol, M. Koopman, C.J. Rodenburg, A. Cats, G.J. Creemers, C.A.M. de Swart, F.L.G. Erdkamp, L. Mol, N.F. Antonini, C.J.A. Punt

33. CAIRO2 Study Design Target Accrual: 755 patients Efficacy results pending maturation of data CAPOX-B + Cetuximab (N = 186) Advanced CRC No prior therapy (N = 381) CAPOX-B (N = 195) Tol J, et al. ECCO 14. Abstract P#3000.

34. CAIRO2 Study Interim Safety Analysis Grade 3/4 Toxicity CAPOX-B (N = 195) CAPOX-B + Cetuximab (N = 186) Overall incidence66%76% Hand-foot syndrome12%13% Diarrhea16%23% Vomiting7%6% Febrile neutropenia1%0% Hypertension4%2% Cardiovascular events4%3% Thrombembolic events5%7% Allergic reactions3%6% GI perforations2%1% None of these differences were statistically significant Tol J, et al. ECCO 14. Abstract P#3000.

35. CAIRO2 Study Interim Safety Analysis Cetuximab associated toxicities (occurring only in the CAPOX-B + Cetuximab arm) –Acneiform skin reaction: Grade 3: 80% Grade 4: 20% –Nail Changes Grade 3: 27% Grade 4: 4% Tol J, et al. ECCO 14. Abstract P#3000.

36. CAIRO2 Study Interim Safety Analysis Conclusions: –Toxicity was acceptable in both arms –Except for skin toxicity, no difference in the incidence of other grade 3/4 toxicities were observed between the two treatment arms –Study is ongoing Tol J, et al. ECCO 14. Abstract P#3000.

37. Combination vs. Sequential Chemotherapy

38. ECCO 14 Abstract O#3015 Sequential Compared to Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer: A Dutch Colorectal Caner Group (DCCG) Phase III Study M. Koopman, N. F. Antonini, J. Douma, J. Wals, A. H. Honkoop, F. L. G. Erdkamp, R. S. de Jong, C. J. Rodenburg, L. Mol, C. J. A. Punt

39. CAIRO Study Design Primary Endpoint: Survival Secondary Endpoints: PFS, RR, Safety, QoL Sample Size: 1,298 patients in 221 centers CAPIRI (N = 378) Capecitabine (N = 397) mCRC No prior therapy (N = 820) CAPOX (N = 213) Irinotecan (N = 251) CAPOX (N = 143) Koopman M, et al. ECCO 14. Abstract O#3015.

40. CAIRO Study Clinical Efficacy CombinationSequenceP-value OS (mos.)17.416.3n.s. 1-yr Survival67%64%n.s. PFS (mos.)7.85.80.0002 RR (%)41%20%< 0.0001 Koopman M, et al. ECCO 14. Abstract O#3015.

41. CAIRO Study Conclusions Median OS is equivalent between sequential and combination strategies Highlights the role of effective salvage treatments in mCRC Sequential therapy is a reasonable treatment option for patients with mCRC –Consider in good risk patients –Role of biologics in improving clinical efficacy and maintaining safety profile Koopman M, et al. ECCO 14. Abstract O#3015.

42. Novel Chemotherapy Regimens

43. ECCO 14 Abstract P#3063 Capecitabine (C), in Combination with Irinotecan (I) and Oxaliplatin (O) (XELOXIRI) as First-Line Treatment of Metastatic Colorectal Cancer (MCRC): Results of a Pilot Study by the Gruppo Oncologico Nord-Ovest (G.O.N.O.) S. Bursi, G. Masi, F. Loupakis, A. Antonuzzo, S. Chiara, E. Pfanner, I. Petrini, M. T. Barletta, G.G. Baldi, A. Falcone

44. XELOXIRI Study Design Phase I –Dose of C in combination with I and O (q 2wk regimen) Irinotecan: 165mg/m 2 d1 Oxaliplatin 85 mg/m 2 d1 Capecitabine 2,500 mg/m 2 /die d1-7; then, increase to 3,000 mg/m 2 /die or decrease to 2,000 mg/m 2 /die based on DLT –Recommended dose of C was 2,000 mg/m 2 DLT: diarrhea Phase II –36 patients –Endpoints: RR and toxicities Bursi S, et al. ECCO 14. Abstract P#3063.

45. XELOXIRI Study Patient Characteristics Bursi S, et al. ECCO 14. Abstract P#3063. PatientsN = 36100% Age, median (range)65 (42-73) Sex (M/F)28/878%/22% ECOG PS 0/1-232/489%/11% Primary colon/rectum26/1072%/28% Previous adjuvant CT925% Multiple sites of disease1850% Liver involvement = 25%1644%

46. XELOXIRI Study Toxicity per Patient Adverse EventGrade 1-2Grade 3-4 Nausea72%3% Diarrhea53%30% Neutropenia39%28%* Thrombocytopenia31%8% Neurotoxicity56%6% * Febrile neutropenia: 8% 3 patients were hospitalized for febrile neutropenia and diarrhea and 1 died from sepsis Bursi S, et al. ECCO 14. Abstract P#3063.

47. XELOXIRI Study Toxicity per Cycle Adverse EventGrade 1-2Grade 3-4 Nausea29%-- Diarrhea28%5% Neutropenia26%4%* Thrombocytopenia11%1% Neurotoxicity32%1% * Febrile neutropenia: 1% Dose reduction (% of cycles): capecitabine 30%; oxaliplatin 14%; irinotecan 37% Bursi S, et al. ECCO 14. Abstract P#3063.

48. XELOXIRI Study Efficacy Bursi S, et al. ECCO 14. Abstract P#3063. N (35)% Complete response26% Partial response2365% Stable disease823% Progression26% PFS: 13.9 mos. (12 events) OS: Not reached (10 events) 71%

49. XELOXIRI Study Conclusions XELOXIRI is feasible with grade 3/4 being the DLT Recommended dose (q 2-weeks): –Capecitabine 2,000 mg/m 2 /die d1-7 –Irinotecan: 165mg/m 2 d1 –Oxaliplatin 85 mg/m 2 d1 At this dose, XELOXIRI is feasible with manageable toxicities but requires administration of a reduced dose intensity of capecitabine compared to XELOX or XELIRI Preliminary response rate is promising (RR: 71%) This study is ongoing to better determine activity and safety profile of the combination at the recommended dose Bursi S, et al. ECCO 14. Abstract P#3063.

50. Capecitabine in Second-Line Metastatic CRC

51. ECCO 14 Abstract O#3012 Capecitabine + Oxaliplatin (XELOX) vs. 5-FU/LV + Oxaliplatin (FOLFOX4) as Second-Line Treatment for Patients with Metastatic Colorectal Cancer (MCRC): Phase III Trial Results D. Cunningham, M. Rothenberg, M. Navarro, C. Butts, Y. Bang, J. Cox, R. Goel, S. Gollins, L. Siu

52. XELOX vs. FOLFOX4 Study Design Primary Endpoint: TTP, PFS, OS XELOX Capecitabine 1,000 mg/m 2 twice daily, d 1-14 + Oxaliplatin 130 mg/m 2 d1 q 3-weeks FOLFOX4 Oxaliplatin 85 mg/m 2 d1 + LV 200 mg/m 2 followed by 5-FU 400 mg/m 2 bolus and 600 mg/m 2 22-h infusion d 1-2 q 2-weeks mCRC (N = 627) Cunningham D, et al. ECCO 14. Abstract O#3012.

53. XELOX vs. FOLFOX4 Results XELOXFOLFOX4HR [95% CI] PFS (PPP), mos.5.15.51.03 [0.87-1.24] PFS (ITT), mos.4.74.80.97 [0.83-1.14] OS (PPP), mos.12.713.21.07 [0.88-1.31] OS (ITT), mos.11.912.61.03 [0.87-1.23] Response rate23%20% Response rate (independent review) 18%14% Grade 3/4 toxicity60%72% Cunningham D, et al. ECCO 14. Abstract O#3012.

54. XELOX vs. FOLFOX4 Conclusions Second-line treatment of mCRC with XELOX is non- inferior to FOLFOX4 in terms of PFS, OS, and RR Safety profile is similar between the two regimens with no unexpected toxicities –Grade 3/4 toxicities: 60% XELOX vs. 72% FOLFOX4 –Consistent with previous studies Cunningham D, et al. ECCO 14. Abstract O#3012.

55. Capecitabine-Based Regimens Issues to Consider What is the optimal dose of capecitabine when used in combination with oxaliplatin? –1,000 mg/m 2 bid 2 weeks on / 1 week off –Lower doses, 750-850 mg/m 2 bid –Fixed dose What is the optimal schedule for capecitabine-based regimens? –2 weeks on / 1 week off (every 3 weeks) –1 week on / 1 week off (every 2 weeks)

56. Capecitabine Dosing U.S. vs Europe European trials –Capecitabine 1,000-1,250 mg/m 2 bid (d1-14, q3w) United States trials –Capecitabine 1,250 mg/m 2 bid dose too toxic (d1-14, q3w) –1,000 mg/m 2 bid more tolerable, but still toxic –Lower doses more tolerable in U.S. (850 mg/m 2 bid) Reasons for discrepancy? –United States diet fortified with folic acid –Vitamin/nutritional supplements Folic acid exacerbates capecitabine toxicity –Pharmacogenetic differences in folate metabolism, DPD? –Other?

57. Capecitabine in the Treatment of Colorectal Cancer Closing Comments John L. Marshall, MD