1 / 44

BOPA 2009

BOPA 2009. Clinical Update: Colorectal Cancer Dr Nick Maisey. Treatment Intent. Adjuvant. Palliative. ADJUVANT CHEMOTHERAPY. Moertel et al, 1990 / 1995. Irinotecan in Adjuvant Therapy. CALGB 89803. Saltz et al ASCO 2004. CALGB 89803: Saltz et al, ASCO 2004.

kemp
Download Presentation

BOPA 2009

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BOPA 2009 Clinical Update: Colorectal Cancer Dr Nick Maisey

  2. Treatment Intent Adjuvant Palliative

  3. ADJUVANT CHEMOTHERAPY

  4. Moertel et al, 1990 / 1995

  5. Irinotecan in Adjuvant Therapy CALGB 89803. Saltz et al ASCO 2004 CALGB 89803: Saltz et al, ASCO 2004 ACCORD-2 Trial, Ychou et al ASCO 2005 PETACC-3, Van Cutsem, ASCO 2005 PETACC 3: Van Cutsem et al, ASCO 2005 ACCORD-2: Ychou et al, ASCO 2005

  6. Oxaliplatin: MOSAIC Trial FU/LV FOLFOX 5Y DFS (III) 58.9% 66.4% 7.5% p=0.005 5Y DFS (II) 79.9% 83.7% 3.8% p=NS 5Y DFS (HRII) 74.6% 82.3% 7.7% p=NS 6Y OS (III) 76% 78.5% 2.5% p=0.045 6Y OS (II) 86.8% 86.9% 0.1% p=NS Overall survival (A) by treatment arm and (B) by treatment arm and by stage Andre, T. et al. J Clin Oncol; 27:3109-3116 2009

  7. Adjuvant Biologics Bevacizumab Cetuximab NSABP C-08 AVANT QUASAR-2 PETACC-8 Intergroup 0147

  8. R NSABP C-08 FOLFOX 6/12 Stage II / III CRC (n=2714) FOLFOX 6/12 AVASTIN 12/12 Wolmark et al, JCO 2009

  9. 3Y DFS 1.0 1.5 2.0 2.5 3.0 FOLFOX 75.5% (n=1338) 0.6 0.74 0.81 0.85 0.87 0.0004 0.004 0.02 0.05 0.08 FOLFOX-B 77.4% (n=1334) NSABP-C08

  10. Adjuvant Summary • Most patients benefit from a FP • Irinotecan does not work • Oxaliplatin has small but significant OS effect • Data supports use of oral FP • No data to support Biologics

  11. PALLIATIVE CHEMOTHERAPY

  12. Patient outcomes have improved with the evolution of mCRC treatment options Median OS 30 25 20 15 10 5 0 Months 1980s 1990s 2000s 2009 BSC 5-FU Irinotecan1 Capecitabine2 Oxaliplatin3 Bevacizumab4 Cetuximab5 1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 20043. Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004 5. Karapetis, et al. NEJM 2008 BSC = best supportive care

  13. What order to give the drugs? Tournigand et al, JCO 2004

  14. Survival and Access to 3 Drugs Grothey et al, JCO 2004

  15. EARLY BENEFIT CONTINUED BENEFIT Regression of existing microvasculature Inhibition of vessel regrowth and neovascularisation Normalisation of surviving microvasculature Avastin: mechanism of action

  16. IFL + placebo1 (n=411) IFL + Avastin1 (n=402) 5-FU/FA + Avastin2 (n=110) Overall response rate (%) 35 45 39 Duration of response (months) 7.1 10.4 8.5 15.6 20.3 18.3 Median overall survival (months)* Median progression-free survival (months)* 6.2 10.6 8.8 First-Line Avastin and Irinotecan * p<0.001 Avastin + IFL vs IFL alone Adapted from 1. Hurwitz H et al. N Engl J Med 2004;350(23):2335-42. 2. Hurwitz H et al. J Clin Oncol 2005;23(15):3502-8.

  17. NO16966: XELOX ± Avastin vsFOLFOX ± Avastin in first-line mCRC RecruitmentJune 2003 – May 2004 RecruitmentFebruary 2004 – February 2005 XELOX n=317 XELOX +placebo n=350 XELOX + Avastin n=350 FOLFOX4 n=317 FOLFOX4 +placebo n=351 FOLFOX4 + Avastin n=349 Initial two-arm open-label study(n=1 000) Protocol amended to 2x2 placebo-controlled design after Avastin Phase III data became available (n=1 400) Cassidy, et al. J Clin Oncol 2008Cassidy, et al. ASCO GI 2008

  18. Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008

  19. Second-line2 Median OS10.8 vs 12.9 months(HR=0.75; p=0.0011) 1.0 0.8 0.6 0.4 0.2 0 FOLFOX4 + bevacizumab FOLFOX4 R Estimated probability 10.8 12.9 0 10 20 30 40 OS (months) Second Line FOLFOX-B 829pts pretreated with 5FU + Irinotecan FOLFOX (RR=8.6%) FOLFOX-B (RR=22.7%) B (RR=3.3%) Giantonio et al, JCO 2007

  20. Duration of Treatment? Bev No Bev Hurwitz 40.4 wks 27.6 wks Saltz 27.1 wks* 25.1 wks *discontinuations for chemo tox

  21. Post-progression therapy 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531) No treatment (n=253) Estimated probability Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57) p<0.001 12.6 19.9 31.8 0 5 10 15 20 25 30 35 OS (months) BRiTE:* continuation of bevacizumab post-first progression significantly increases OS‡ *Non-randomised, observational trial‡Time from initiation of first-line treatment to death Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008

  22. The EGFr Antibodies

  23. Cetuximab In Irinotecan Refractory mCRC Saltz 2001 Cunningham 2003 Saltz 2004 22.5% 22.9% 10.8% 8.8% CETUXIMAB + IRINOTECAN CETUXIMAB ALONE • Saltz et al, ASCO 2001 • Cunningham et al, NEJM 2004 • Saltz et al, JCO 2004

  24. The role of KRAS

  25. KRAS wild-type and EGFR inhibitor efficacy in chemorefractory CRC: Response Reference Treatment No. of patients (wild-type: mutant) Objective responsen (%) Wild-type Mutant Lièvre A, et al. J Clin Oncol 2008 CETUXIMAB ± CT 114 (78:36) 34 (44) 0 (0) Benvenuti S, et al. Cancer Res 2007 Panitumumab or CETUXIMAB orCETUXIMAB + CT 48 (32:16) 10 (31) 1 (6) DeRoock W, et al. Ann Oncol 2008 CETUXIMAB or CETUXIMAB + irinotecan 113 (67:46) 27 (41) 0 (0) Capuzzo F, et al. Br J Cancer 2008 CETUXIMAB ± CT 81 (49:32) 13 (26) 2 (6) Di Fiore F, et al. Br J Cancer 2007 CETUXIMAB + CT 59 (43:16) 12 (28) 0 (0) Khambata-Ford S, et al. J Clin Oncol 2007 CETUXIMAB 80 (50:30) 5 (10) 0 (0) Amado RG, et al. J Clin Oncol 2008 Panitumumab 208 (124:84) 21 (17) (0) Karapetis CS, et al. NEJM 2008 CETUXIMAB + BSC or BSC 287 (117:81) 15 (12.8) 1 (1.2)

  26. KRAS mutation on PFS with panitumumab v BSC: a predictive marker Mutant ras Wild type ras Amado et al, JCO 2008

  27. NCIC CTG C0.17: Overall survival in K-ras Wild-Type patients 1 0.8 0.6 Proportion Alive 0.4 0.2 Cetuximab BSC 0 0 2 4 6 8 10 12 14 16 18 Time from Randomisation (Months) Cetuximab 117 108 95 81 52 34 20 9 6 2 113 92 69 36 24 17 12 5 3 BSC 3 HR 0.5595% CI (0.41,0.74) Log rank p-value:<0.0001 Log rank p<0.001 Karapetis CS, et al. NEJM 2008; 359:17, 1757 -1765

  28. Cetuximab used First-Line in KRAS w/t mCRC CRYSTAL1 OPUS2 N=1217 / 540 N=337 / 233 FOLFOX FOLFIRI FOLFIRI-C FOLFOX-C med PFS 8.7 9.9 7.2 7.7 ORR 43% 59% 37% 61% med OS 21.0 24.9 - - • Van Cutsem et al, NEJM 2009 • Bokemeyer et al, JCO 2009

  29. Palliative Chemotherapy: Summary • Survival continues to improve • Avastin appears to improve overall survival if used ‘optimally’ • Patients with mutated KRAS do not benefit from cetuximab • Cetuximab confers survival advantage in chemo-resistant disease • First line cetuximab improves PFS and RR

  30. Neoadjuvant Chemotherapy

  31. Rationale • ‘In-Vivo’ test of sensitivity • Kill off microscopic disease • Down-size to allow operability

  32. Curing Metastatic Disease

  33. Who is considered for curative liver resection? Untreatable primary Insufficient remant liver Unresectable extra-hepatic disease Progression through chemo No Bilobar Disease No more than 3 mets No extra-hepatic disease Marathon runner fitness

  34. Resection rate of metastases and tumour response Studies including selected patients(liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) 0.6 0.5 0.4 Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001) Resection rate 0.3 0.2 0.1 Phase III studies including nonselected patientswith mCRC (dashed line) (r=0.67; p=0.024) 0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response rate Folprecht G, et al. Ann Oncol 2005;16:1311–1319

  35. Survival after ‘down-sizing’ in initially unresectable disease Bismuth et al, Ann Surg 1996

  36. Effect of Cetuximab in KRAS w/t tumours CETUXIMAB + chemotherapy Chemotherapy alone CRYSTAL OPUS 70 60 61 59 50 40 43 Response rate (%) 37 30 20 10 0 n=176 n=172 n=73 n=61 RO resection FOLFIRI vs FOLFIRI-C 1.7% vs 4.8% Odds ratio 3.02 (p=0.002) 1. Van Cutsem E, et al.: NEJM 360(14): 1408-17 (2009); 2. Bokemeyer C, et al.: J Clin Oncol 27(5): 663-671 (2009)

  37. EMR 604-CELIM study Patients with technically unresectable/≥5 liver metastases without extrahepatic disease RESECTION Adjuvant therapy for 6 cycles (same schedule as pre-operatively) ERBITUX + FOLFOX (n=56) Technically resectable R ERBITUX + FOLFIRI (n=55) Technically unresectable 4 further treatment cycles Primary endpoint: Response rate 8 cycles (~4 months) Folprecht et al. ASCO GI 2009 Abstract no. 296

  38. Response rates * 106 pts evaluable for efficacy These are confirmed response rates Folprecht et al. ASCO GI 2009 Abstract no. 296

  39. Resection rates * 106 pts evaluable for efficacy Folprecht et al. ASCO GI 2009 Abstract no. 296

  40. Bevacizumab: significant pathological response when combined with FOLFOX1,2 Pathological response predicts for survival2 Major response Complete response 100 80 60 40 20 0 p=0.011 p=0.007 Pathological response (%) 1–8 cycles ≥9 cycles 1–8 cycles ≥9 cycles FOLFOX FOLFOX + bevacizumab Complete response: no residual cells Major response: 1–49% residual cells Minor response: ≥50% residual cells 1. Zorzi, et al. ASCO GI 2009; 2. Blazer, et al. JCO 2008

  41. NO16966: surgery with curative intent XELOX/FOLFOX4 + placebo XELOX/FOLFOX4 + Avastin ITT population Patients with liver metastases only 10 5 0 20 15 10 5 0 19.2 8.4 12.9 6.1 Patients (%) Patients (%) Placebo Avastin Placebo Avastin (n=701) (n=699) (n=178) (n=177) Saltz, et al. WCGC 2007

  42. Neoadjuvant Therapy: Summary • Metastatic disease can be cured • Higher response rates lead to higher resection rates • Cure depends on successful resection • Cetuximab increases reponse rate and R0 resections • Bevacizumab may augment neoadjuvant chemo

More Related