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Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

A Report from ASCO-GI 2008 and ASCO 2007 Up-to-Date Review of the Treatment of Adjuvant Colorectal Cancer. Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN. History of Adjuvant Therapy of Colon Cancer. 5-FU/LV superior to 5-FU/lev

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Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

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  1. A Report from ASCO-GI 2008and ASCO 2007 Up-to-Date Review of the Treatment of Adjuvant Colorectal Cancer Axel Grothey, MD Professor of Oncology Mayo Clinic College of Medicine Rochester, MN

  2. History of Adjuvant Therapy of Colon Cancer • 5-FU/LV superior to 5-FU/lev • 6- and 12-month treatment cycles equivalent • Lev unnecessary • High-dose and low-dose LV equivalent • Monthly and weekly treatment equivalent • 5-FU/lev superior to surgery alone • LV5FU2 and monthly bolus equivalent • 5-FU/LV superior to surgery alone 1990 1994 1998 2002 Moertel et al. Ann Intern Med. 1995;122:321. Francini et al. Gastroenterol. 1994;106:899. Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract O’Connell et al. J Clin Oncol. 1998;16:295. Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982. Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.

  3. May 05, 2004: ODAC recommends3-yr DFS as new regulatory endpointfor FULL approval in adjuvant colon cancer 5-yr OS = 0.0002 + 0.998* 3-yr DFS 3 Year DFS vs 5 Year OS Sargent, et al. J Clin Oncol 2005;23:8664–8670.

  4. 5-FU: Historical Standardin the Adjuvant Setting Observation1 5-FU/high-dose LV (Mayo)2 6 months 5-FU/LV (Mayo)1 5-FU/low-dose LV (Mayo)3 LV5FU24 55 60 65 70 75 3-year disease-free survival (%) Stage II and III colon cancer patients 1IMPACT Investigators, Lancet 1995;345:939–44. 2Wolmark N, et al. J Clin Oncol 1993;11:1879–87. 3QUASAR Group. Lancet 2000;355:1588–96. 4André T, et al. J Clin Oncol 2003;21:2896–903.

  5. Beyond 5-FU in the Adjuvant Setting Completed studies: • Oxaliplatin (MOSAIC, NSABP C-07) • Irinotecan (CALGB 89803, ACCORD-2, PETACC-3) • Capecitabine (X-ACT) Ongoing studies: • CAPOX (XELOXA) • Bevacizumab (NSABP C-08, AVANT, E5202) • Cetuximab (N0147, PETACC-8)

  6. Primary end-point: disease-free survival Secondary end-points: safety, overall survival MOSAIC: Study Design • N = 2,246 • Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries) • Completely resected colon cancer • Stage II, 40%; Stage III, 60% • Age 18–75 years • KPS ≥60 • No prior chemotherapy (N =1,123) FOLFOX4 (LV5FU2 + oxaliplatin 85 mg/m²) R LV5FU2 (N =1,123) LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

  7. 1.0 0.9 0.8 5.9% 0.7 0.6 0.5 Probability Events FOLFOX4 304/1,123 (27.1%) LV5FU2 360/1,123 (32.1%) HR [95% CI]: 0.80 [0.68–0.93] 0.4 FOLFOX4 LV5FU2 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 Disease-free survival (months) Disease-free Survival: ITT 5.3% P = 0.003 Data cut-off: June 2006 De Gramont A, et al. ASCO 2007. Abstract #4007.

  8. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] P - value Stage II 0.84 [0.62–1.14] 0.258 Stage III 0.78 [0.65–0.93] 0.005 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Months Disease-free Survival:Stage II and Stage III Patients P = 0.258 3.8% P = 0.005 7.5% Data cut-off: June 2006 De Gramont A, et al. ASCO 2007. Abstract #4007.

  9. MOSAIC: Disease-free Survival –Final Update Data cut-off: June 2006 De Gramont A, et al. ASCO 2007. Abstract #4007.

  10. “High-risk” Stage II Colon Cancer • Clinico-pathological parameters (MOSAIC) - T4 tumors - Obstruction/perforation - Lymphatic or vascular invasion - Undifferentiated histology - Less than 10 (12) Ln examined • Molecular parameters - LOH 18q - MSS - Other? De Gramont A, et al. ASCO 2007. Abstract #4007.

  11. Long-term Safety Second cancer Peripheral Sensory Neuropathy Data cut-off: January 2007 De Gramont A, et al. ASCO 2007. Abstract #4007.

  12. Overall Survival: ITT 1.0 P = 0.057 0.9 0.8 2.6% 0.7 0.6 6 yrs: 78.6% vs. 76.0% 0.5 Probability 0.4 Events FOLFOX4 243/1,123 (21.6%) LV5FU2 279/1,123 (24.8%) HR [95% CI]: 0.85 [0.72–1.01] FOLFOX4 LV5FU2 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) Data cut-off: January 2007 De Gramont A, et al. ASCO 2007. Abstract #4007.

  13. 1.0 P = 0.996 0.1% 0.9 P = 0.029 0.8 4.4% 0.7 0.6 0.5 Probability 0.4 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98] 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Data cut-off: January 2007 Overall survival (months) Overall Survival: Stage II and Stage III De Gramont A, et al. ASCO 2007. Abstract #4007.

  14. Take-Home Messages MOSAIC • DFS benefit for FOLFOX is maintained over 5 years • Significant OS benefit for stage III, but NOT for unselected stage II patients • “High-risk” stage II with trend toward better DFS with FOLFOX, but clinical consequence unclear • No increased rate of secondary cancers, but more deaths of cancer in FOLFOX group (21 vs. 11) • Even 4 years after FOLFOX, 3.5% of patients still have grade 2/3 neurotoxicity (+12% grade 1)  FOLFOX is standard adjuvant therapy for stage III and can be considered for high-risk stage II CC

  15. NSABP C-07 FU Rest 500 N = 2,407 RP LV 500 x3 R FU 500 Rest LV 500 FLOX OHP 85 2hr Endpoint 3yr DFS Week 1 2 3 4 5 6 7 8 Accrual 02/00 - 11/02 Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

  16. C-07: DFS Ev # 3yr DFS FLOX 272 76.5% FULV 332 71.6% P < 0.004 HR: 0.79 [0.67 – 0.93] 21 % risk reduction Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

  17. C-07 and MOSAIC - Oxaliplatin benefit De Gramont A, et al. ASCO 2007. Abstract #4007. Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

  18. Cross-Study ComparisonToxicity: MOSAIC / C-07 De Gramont A, et al. ASCO 2007. Abstract #4007. Kuebler JP, et al. J Clin Oncol 2007;25:2198–2204.

  19. Abstract 347 Diabetes Mellitus and the Incidence and Time to Onset of Oxaliplatin-Induced Peripheral Sensory Neuropathy (PSN) in Patients with Colorectal Cancer: A Pooled Analysis of Three Randomized Studies • Ramanathan RK, André T, Rothenberg ML, de Gramont A, • Tournigand C, Goldberg RM, Gupta S

  20. Pooled Analysis • Data from 3 randomized clinical trials including FOLFOX4 • EFC3313 (MOSAIC): 5-FU and LV (LV5–FU2) + oxaliplatin as adjuvant therapy in CRC • EFC4584: Three-arm study of LV5–FU2, LV5–FU2 with oxaliplatin, or oxaliplatin alone as second-line therapy of metastatic CRC • EFC2962: Phase II/III study of LV5FU2 + oxaliplatin first-line • PSN data from the overall study population with or without diabetes were analyzed for: • Incidence and time to onset of PSN • Trends indicating clinically relevant differences in the incidence and severity of PSN Ramanathan 2008 ASCO GI abstract # 347

  21. Incidence and Severity of PSN Ramanathan 2008 ASCO GI abstract # 347

  22. Probability of PSN by Cumulative Dose EFC3313: any grade EFC3313: grade ≥ 3 EFC4584: any grade EFC4584: grade ≥ 3 Ramanathan 2008 ASCO GI abstract # 347

  23. Conclusions FOLFOX in Diabetics • In CRC trials with FOLFOX4 no difference in: - the probability of developing PSN nor - the severity of grade between all treated patients and the subset with diabetes mellitus was observed • This data suggests patients with diabetes mellitus have no increased risk of developing cumulative neurotoxicity Ramanathan 2008 ASCO GI abstract # 347

  24. CALGB 89803: DFS and OS Not Improvedwith IFL in Stage III Colon Cancer 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Proportion surviving Proportion disease-free FU/LV IFL FU/LV IFL 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years N Events FU/LV 629 227IFL 635 248 P (stratified) = 0.85 (1-sided) N Events FU/LV 629 171IFL 635 181 P (stratified) = 0.74 (1-sided) OS = overall survival; IFL = irinotecan, 5-FU plus leucovorin Saltz L, et al. J Clin Oncol 2007;25:3456–61

  25. 400 patients with resected high risk stage III colon cancer (N2 or N1 with occlusion/perforation) Accrual completed in Spring 2002 Stratified: - Center - N stage - Delay to chemotherapy - Age ACCORD-02Irinotecan in High-risk Stage III Colon Cancer R A N D O M I Z E • FOLFIRI: • LV5FU2 • CPT-11 180 mg/m2 • on day 1 LV5FU2 12 cycles planned Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

  26. 3-year DFS (%) LV5FU2 60 FOLFIRI 51 1.0 0.8 0.6 0.4 0.2 0 HR = 1.19 (95% CI: 0.90–1.59)P = 0.22 Estimated probability 0 1 2 3 4 5 6 Years ACCORD-02: DFS Not Improved with FOLFIRI in High-risk Colon Cancer Ychou M, et al. J Clin Oncol 2005;(Suppl. 16):246s (Abstract 3502)

  27. PETACC-3: Study Design LV5FU2 R A N D O M I Z AT I ON FA 200 mg/m2 F 5-FU bolus 400 mg/m2 5-FU CI 600 mg/m2 • Stratification: • Stage II vs. III • Center Day 1 Day 2 Irinotecan 180 mg/m2 LV5FU2 as above IF Repeat q 2 weeks for 12 Cycles Day 1 Day 2 210 pts treated with AIO regimen ± irinotecan within given centers will be presented later. Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8)

  28. PETACC-3: Results Stage III Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8)

  29. PETACC-3: DFS not significantly improved with FOLFIRI in stage III N 3-year DFS (%) 1.0 0.9 0.8 0.7 0.6 0.5 0 FOLFIRI 1,044 63.3 5-FU/LV 1,050 60.3 Estimated probability HR=0.89 (95% CI: 0.77–1.11)P = 0.091 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Months DFS = disease free survivalHR = hazard ratio; CI = confidence interval Van Cutsem E, et al. J Clin Oncol 2005; 23:(Suppl. 16):3s (Abstract LBA8)

  30. X-ACT Trial - Design Capecitabine 1 250mg/m2 twice daily, d1–14, q21d N = 1,004 Recruitment 1998–2001 • Endpoints • - DFS • - RFS • - overall survival (OS) • - tolerability (NCIC CTG) • - pharmacoeconomics • - quality of life (QoL) Chemo-naïve stage III colon cancer, resection 8 weeks 24 weeks Bolus 5-FU / LV 5-FU 425mg/m2 plus LV 20mg/m2, d1–5, q28d N = 983 Twelves et al., N Engl J Med 2005

  31. X-ACT: 5-year DFS (median follow-up 6.8 years) 5-year DFS (%) Capecitabine 1,004 60.8 5-FU/LV 983 56.7 1.0 0.8 0.6 0.4 0.2 0 N Estimated probability HR = 0.88 (95% CI: 0.77–1.01) NI margin 1.20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months ITT population Test of non-inferiority P < 0.0001 Test of superiority P = 0.0682 ITT (intent-to-treat) population; NI = non-inferiority Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

  32. X-ACT: 5-year OS (median follow-up 6.8 years) 5-year OS (%) Capecitabine 1,004 71.4 5-FU/LV 983 68.4 N 1.0 0.8 0.6 0.4 0.2 0 Estimated probability HR = 0.86 (95% CI: 0.74–1.01) NI margin 1.14 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority P = 0.000116 Test of superiority P = 0.06 ITT population Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

  33. X-ACT: Improved Safety with Capecitabine Grade 3/4 adverse events 50 40 30 20 10 0 Capecitabine (N = 993) 5-FU/LV (N = 974) Patients (%) * * * * HFS Nausea/vomiting Diarrhea Stomatitis Febrileneutropenia Neutropenia *P < 0.001HFS = hand foot syndrome Scheithauer W, et al. Ann Oncol 2003;14:1735–43

  34. XELOXA: Phase III Trial of CAPOX in the Adjuvant Setting • Primary endpoint: disease-free survival RANDO MIS ATION CAPOX Capecitabine 1,000mg/m2 b.i.d. days 1–15 Oxaliplatin 130mg/m2 day 1 q3w N = 944 Chemo/radiotherapy-naïve stage III colon cancer Duration of therapy: 24 weeks Bolus 5-FU/LVMayo Clinic or Roswell Park N = 942 Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

  35. Adjuvant CAPOX: Toxicity Compared with FOLFOX and FLOX 50 40 30 20 10 0 Grade 3/4 Adverse Events CAPOX1 (N = 938) FOLFOX42 (N = 1,108) FLOX3 (N = 1,200) Patients (%) * * * HFS Vomiting Nausea Febrileneutropenia Stomatitis Diarrhea Neutropenia Neurosensory Cross-trial comparison *Not reported 1Schmiegel WH, et al. J Clin Oncol 2007;25(Suppl. 18):172s (Abstract 4034)2André T, et al. N Engl J Med 2004;350:2343–51 3Wolmark N, et al. J Clin Oncol 2005;23(Suppl. 16 Pt I):246s (Abstract LBA 3500)

  36. Ongoing US Cooperative Group Trials Adjuvant Therapy of Colon Cancer Intergroup N0147 mFOLFOX6 6m Stage III colon cancer (N = 2,300) mFOLFOX6 6m +Cetuximab 6m NSABP C-08 mFOLFOX6 6m Stage II/III colon cancer (N = 2,400) Accrual completed mFOLFOX6 6m +Bevacizumab 12m

  37. Should Patients with Stage II Colon Cancer Receive Adjuvant Therapy? • Direct evidence of randomized trials • Meta-analyses • Identification of “high-risk” patients

  38. Approximate Number of Patients Needed to Detect a Realistic Treatment Benefit* • Dukes’ B Dukes’ C • No. of No. of • Survival ARR Patients Survival ARR Patients • At 3-years 85% 2.5% 8,000 65% 5.2% 3,400 • At 4-years 80% 3.3% 5,800 58% 6.0% 2,800 • At 5-years 75% 4.0% 4,700 50% 6.6% 2,400 • Abbreviation: ARR = absolute risk reduction • For 90% power of detecting the treatment benefit using two-tailed significance tests at the 5% level, • assuming the true relative risk reduction is 18% for both Dukes’ B and Dukes’ C. Buyse, Piedbois, 2001

  39. QUASAR: Study Design 2 x 2 randomization to 5-FU with low- or high-dose LV and Lev or placebo Clear indication for chemotherapy (N = 4,320) • Colon or rectal cancer • Stage I-III • Complete resection with no evidence of residual disease R A N D O M I Z E Observation (N = 1,617) No clear indicationfor chemotherapy (mainly stage II) (N = 3,239) Chemotherapy (N = 1,622)* * Prior to 10/1997 chemotherapy patients were randomized as in clear indication arm; after 10/1997 patients received 5-FU/low-dose LV. QUASAR Group, Lancet 2007

  40. QUASAR: Overall Survival in Patients with“no clear indication for chemo” 100 Observation (N = 1,622) Chemotherapy (N = 1,617) 80 60 5-yr OS difference: 2.9% % of Patients 40 P = .02 5-year OS, Observation = 77.4% vs Chemotherapy = 80.3% Relative risk = 0.83 (95% CI, 0.71-0.97) 20 0 0 1 2 3 4 5 6 7 8 9 10 Years QUSAR group, Lancet 2007

  41. ASCO Guidelines 2004 • Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. • Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. • The ultimate clinical decision should be based on discussions withthe patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. • Patients with stage II disease should be encouraged to participate in randomized trials. Benson et al. J Clin Oncol. 2004

  42. “High-risk” Stage II Colon Cancer • Clinico-pathological parameters • T4 tumors • Obstruction/perforation • Lymphatic or vascular invasion • Undifferentiated histology • Less than 10 (12) Ln examined • Molecular parameters • LOH 18q • MSS • Other?

  43. Analysis of Molecular Markers in Patients with Stage III Colon Cancer Watanbe T, et al. N Engl J Med 344(16);1196-1206, 2001

  44. Colon Stage II – AdjuvantE5202: High Risk Stage II Expect 2 weeks for tissue review mFOLFOX6 • High Risk • MSS + 18q LOH • MSI-L + 18q LOH Register R mFOLFOX6 + bevacizumab Tumor block assessment for 18q/MSI • Low Risk • MSS, no 18q LOH • MSI-L, no 18q LOH • MSI-H +/- 18q LOH Observation N = 3,610

  45. What is the Standard Adjuvant Therapy in Colon Cancer ? • FOLFOX is the standard adjuvant therapy in stage III and high-risk stage II colon cancer • Capecitabine (UFT,S1?) for patients who are not considered candidates for oxaliplatin • Irinotecan-based combinations are NOT options in the adjuvant setting • XELOX data eagerly awaited • Bevacizumab and Cetuximab are under investigation

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