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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.
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BOPA 2009 Clinical Update: Colorectal Cancer Dr Nick Maisey
Treatment Intent Adjuvant Palliative
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
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
Adjuvant Biologics Bevacizumab Cetuximab NSABP C-08 AVANT QUASAR-2 PETACC-8 Intergroup 0147
R NSABP C-08 FOLFOX 6/12 Stage II / III CRC (n=2714) FOLFOX 6/12 AVASTIN 12/12 Wolmark et al, JCO 2009
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
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
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
What order to give the drugs? Tournigand et al, JCO 2004
Survival and Access to 3 Drugs Grothey et al, JCO 2004
EARLY BENEFIT CONTINUED BENEFIT Regression of existing microvasculature Inhibition of vessel regrowth and neovascularisation Normalisation of surviving microvasculature Avastin: mechanism of action
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.
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
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
Duration of Treatment? Bev No Bev Hurwitz 40.4 wks 27.6 wks Saltz 27.1 wks* 25.1 wks *discontinuations for chemo tox
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
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
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)
KRAS mutation on PFS with panitumumab v BSC: a predictive marker Mutant ras Wild type ras Amado et al, JCO 2008
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
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
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
Rationale • ‘In-Vivo’ test of sensitivity • Kill off microscopic disease • Down-size to allow operability
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
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
Survival after ‘down-sizing’ in initially unresectable disease Bismuth et al, Ann Surg 1996
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)
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
Response rates * 106 pts evaluable for efficacy These are confirmed response rates Folprecht et al. ASCO GI 2009 Abstract no. 296
Resection rates * 106 pts evaluable for efficacy Folprecht et al. ASCO GI 2009 Abstract no. 296
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
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
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