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Best of ASCO Colorectal & Pancreatic Cancers

Best of ASCO Colorectal & Pancreatic Cancers. Ali Shamseddine, MD Professor of Medicine Head of Hematology/Oncology Division American University of Beirut Medical Center. Adjuvant Chemotherapy in Colorectal Cancer. Survival Results of NSABP C-07. FULV 5-FU 500 m 2 IV bolus weekly x 6 +

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Best of ASCO Colorectal & Pancreatic Cancers

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  1. Best of ASCOColorectal & Pancreatic Cancers Ali Shamseddine, MDProfessor of MedicineHead of Hematology/Oncology DivisionAmerican University of Beirut Medical Center

  2. Adjuvant Chemotherapy in Colorectal Cancer

  3. Survival Results of NSABP C-07 FULV 5-FU 500 m2 IV bolus weekly x 6 + LV 500 mg/m2 IV weekly x 6 of each 8-week cycle x 3 (n = 1209) Patients with stage II or III carcinoma of the colon stratified by number of positive lymph nodes (N = 2409) FLOX FULV + Oxaliplatin 85 mg/m2 IV on Weeks 1, 3, and 5 of each 8-week cycle x 3 (n = 1200) • Primary endpoint: DFS Wolmark N, et al. ASCO 2008. Abstract LBA4005.

  4. C-07: Disease-Free Survival Wolmark N, et al. ASCO 2008. Abstract LBA4005.

  5. C-07: Overall Survival Wolmark N, et al. ASCO 2008. Abstract LBA4005.

  6. Initial Safety Report of NSABP C-08 Arm AmFOLFOX6 every 2 wks x 12 doses (n = 1356) Patients with stage II or III colon adenocarcinoma with ECOG performance score of 0/11 (N = 2710) Arm B: mFOLFOX6 + Bevacizumab 5 mg/kg every 2 wks x 26 doses (n = 1354) • Patients were stratified by the number of positive lymph nodes and were randomized between Days 29 and 50 postoperatively • mFOLFOX6 regimen: leucovorin 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46 hrs; oxaliplatin 85 mg/m2 IV • Primary endpoint: DFS Allegra CJ, et al. ASCO 2008. Abstract 4006.

  7. C-08: Grade 3/4 Toxicities Significantly Increased With Bevacizumab *5 patients had grade 4 hypertension. †All grade 3. • Median time on study: 22.4 months • No significant increases in GI perforation, hemorrhage, arterial, or venous thrombotic events, or deaths have been observed with the addition of bevacizumab Allegra CJ, et al. ASCO 2008. Abstract 4006.

  8. Metastatic Colorectal Cancer

  9. Continuous Oxaliplatin* mFOLFOX7 + Bevacizumab + Placebo (n = 34) Continuous Oxaliplatin* mFOLFOX7 + Bevacizumab + Ca2+/Mg2+ (n = 35) Patients with metastatic colorectal cancer (N = 140) Intermittent Oxaliplatin† mFOLFOX7 + Bevacizumab + Placebo (n = 36) Intermittent Oxaliplatin† mFOLFOX7 + Bevacizumab + Ca2+/Mg2+ (n = 35) CONcePT Trial Design *Treat to failure. †8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin. Grothey A, et al. ASCO 2008. Abstract 4010.

  10. CONcePT: Treat-to-Failure • Treat-to-failure • Continuous oxaliplatin (CO): 4.2 months (95% CI: 3.7-5.5) • Intermittent oxaliplatin (IO): 5.6 months (95% CI: 4.7-7.0) • Unstratified (IO relative to CO): P = .002* • Stratified by CaMg (IO relative to CO): P = .003* *Log-rank test. Grothey A, et al. ASCO 2008. Abstract 4010.

  11. CONcePT: Progression-Free Survival • Treat-to-failure • Continuous oxaliplatin (CO): 7.3 months (95% CI: 6.9-NE) • Intermittent oxaliplatin (IO): 12.0 months (95% CI: 8.2-NE) • Unstratified (IO relative to CO): P = .044* • Stratified by CaMg (IO relative to CO): P = .030* *Log-rank test. Grothey A, et al. ASCO 2008. Abstract 4010.

  12. Clinical practice*: Hepatic metastasectomy in patients with liver disease only Hepatic metastasectomy 25 20 15 10 5 0 Hepatic metastasectomy with no residual disease (R0) 20.3 15.5 15.2 14.3 12.1 11.7 Patients (%) n=107 n=85 n=71 n=54 n=33 n=27 Avastin + CTx All (n=704) Avastin + CTxIncluding oxaliplatin(n=349) Avastin + CTxIncluding irinotecan(n=230) *BEAT: largest prospective trial with a predefined analysis for resectability (non-randomised study) Cassidy, et al. ASCO 2008 (poster)

  13. Clinical practice*: Significant improvement in 2-year OS for patients who underwent hepatic metastasectomy with R0 resection 1.00 0.75 0.50 0.25 0 89% Hepatic metastasectomy and R0 resection (n=114) Hepatic metastasectomy total (n=145) No hepatic metastasectomy (n=1,791) 86% OS estimate 47% p<0.001 0 5 10 15 20 25 30 Months *BEAT (non-randomised study)OS = overall survival Cassidy, et al. ASCO 2008 (poster)

  14. FDG-PET Improves Selection of Patients With CRC Liver Metastases CT imaging only (n = 75) Laparotomy Findings at laparotomy and F/U Patients with colorectal cancer liver metastases selected for surgical treatment by imaging with CT scan (N = 150) Laparotomy Findings at laparotomy and F/U CT imaging + FDG-PET (n = 75) Excluded by PET • Patients were followed for at least 3 yrs for OS and DFS • No standard chemotherapy was given postoperatively Wiering B, et al. ASCO 2008. Abstract 4004.

  15. FDG-PET Improves Selection of Patients With CRC Liver Metastases • Primary endpoint: futile laparotomies, defined as a laparotomy that • Did not result in complete tumor treatment • Revealed benign disease • Did not result in DFS longer than 6 months • Secondary endpoint: OS and DFS Wiering B, et al. ASCO 2008. Abstract 4004.

  16. FDG-PET in CRC Liver Metastases: Conclusions • Number of futile laparotomies was reduced from 45% to 28% • Addition of FDG-PET to the workup for surgical resection of colorectal liver metastases prevents unnecessary surgery in 1 out of 6 patients • No significant differences in OS or DFS were noted in the first 3 yrs of follow-up Wiering B, et al. ASCO 2008. Abstract 4004.

  17. KRAS Status and Efficacy in Metastatic Colorectal Cancer

  18. KRAS Status and Efficacy of First-Line FOLFOX ± Cetuximab: OPUS • Genomic DNA was isolated from archived tumor material • KRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay • Population with tissue available for KRAS analysis (n = 233) was representative of overall ITT population (n = 337) in terms of demographics and efficacy parameters • KRAS mutations detected in 42% (99/233) of evaluable samples Bokemeyer C, et al. ASCO 2008. Abstract 4000.

  19. OPUS: Results PFS and Response Rates by KRAS Mutation Status • The benefit from addition of cetuximab to standard treatment is higher forthe population with WT KRAS • No benefit could be shown of adding cetuximab to FOLFOX for patients with KRAS mutations Bokemeyer C, et al. ASCO 2008. Abstract 4000.

  20. OPUS: PFS according to K-Ras status PFS – K-Ras mutant PFS – K-Ras wild-type 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Cetuximab + FOLFOX FOLFOX Cetuximab + FOLFOX FOLFOX Kaplan-Meier estimate Kaplan-Meier estimate K-Ras mutant: HR=1.83; p=0.0192 Cetuximab + FOLFOX: 5.5 monthsFOLFOX: 8.6 months K-Ras wild-type: HR=0.57; p=0.016 Cetuximab + FOLFOX: 7.7 monthsFOLFOX: 7.2 months 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Progression-free time (months) Progression-free time (months) Bokemeyer, et al. ASCO 2008

  21. KRAS and Efficacyof Irinotecan and Cetuximab in mCRC: EVEREST Control Standard Cetuximab regimen (250 mg/m2/wk) (n = 23) SCREENING Cetuximab 400 mg/m2 initial dose then 250 mg/m2/wk + Irinotecan180 mg/m2 Q2W Patients with irinotecan-refractory metastatic cancer Day 22 Randomized:skin toxicity grade 0/1 Dose Escalation Cetuximab dose increases of 50 mg/m2 Q2W up to maximum 500 mg/m2/wk (n = 31) Not eligible for randomization: skin toxicity grade 2/3 • All patients continued to receive irinotecan • Treatment until progression, unacceptable toxicity or withdrawal of consent • Skin and tumor biopsy at baseline, Week 3, and at maximum cetuximab dose in dose-escalation arm Nonrandomized Standard Cetuximab regimen (250 mg/m2/wk) Tejpar S, et al. ASCO 2008. Abstract 4001.

  22. EVEREST: PFS (ITT Population) KRAS mutation present KRAS mutant 1.0 WT KRAS 0.8 0.6 83 days (95% CI: 75.9-90.2) PFS Estimate 173 days (95% CI: 141.3-204.7) 0.4 P < .0001 0.2 0 0 200 400 600 800 Days Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.

  23. EVEREST: PFS by Treatment Group and KRAS Status Control Dose Escalation Nonrandomized KRAS mutation present KRAS mutation present KRAS mutation present 1.0 1.0 1.0 KRAS mutant KRAS mutant KRAS mutant WT KRAS WT KRAS WT KRAS 0.8 0.8 0.8 PFS Estimate PFS Estimate PFS Estimate 0.6 0.6 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0.0 0.0 0.0 600 600 0 0 600 0 200 400 800 200 400 800 200 400 800 Days Days Days P = .014 P < .001 P = .020 Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.

  24. Pancreatic Cancer

  25. Treatment of Advanced Pancreatic Cancer Targeted Therapy beyond ErlotinibTreatment of Gemcitabine-Refractory Disease

  26. Primary endpoint = overall survival Stratified according to country, KPS (<80 vs ≥80), albumin level (<2.9g/dL vs ≥2.9g/dL) AVITA: study design Tarceva (100mg) + gemcitabine + Avastin (5mg/kg every 2 weeks) PD Previously untreated metastatic pancreatic cancer (n=600) Tarceva (100mg) + gemcitabine + placebo PD KPS = Karnofsky performance statusPD = progressive disease

  27. Gemcitabine + Tarceva + Avastin (n=221 with events) Gemcitabine + Tarceva(n=233 with events) Overall survival probability HR=0.89, p=0.2087 (95% CI: 0.74–1.07) 6.0 7.1 0 3 6 9 12 15 18 21 24 Time (months) Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I):214s (Abs. 4507) AVITA: overall survival 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

  28. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Gemcitabine + Tarceva + Avastin (n=257 with events) Gemcitabine + Tarceva(n=278 with events) HR=0.73, p=0.0002(95% CI: 0.61–0.86) PFS probability 3.6 4.6 0 3 6 9 12 15 18 21 24 Time (months) PFS = progression-free survival Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I):214s (Abs. 4507) AVITA: PFS

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