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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy

Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy. Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy. Jimmy Hwang, MD Associate Professor, Hematology/Oncology John L. Marshall, MD Associate Professor, Hematology/Oncology Department of Medicine

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Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy

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  1. Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy

  2. Management of Metastatic Colorectal Cancer: Focus on Targeted Therapy Jimmy Hwang, MD Associate Professor, Hematology/Oncology John L. Marshall, MD Associate Professor, Hematology/Oncology Department of Medicine Lombardi Cancer Center Georgetown University Hospital Washington, DC

  3. Colorectal Cancer: Epidemiology • Data from the United States (2006)[1] • 148,610 new cases: third highest cancer incidence • 55,170 deaths: second leading cause of cancer-related death in men, third leading cause in women • Worldwide (2002)[2] • 1,023,256 new cases: third highest incidence after lung, breast cancer • 529,020 deaths: fourth overall cause of cancer-related death after lung, gastric, liver cancer 1. Jemal A, et al. CA: Cancer J Clin. 2006;56:106-130.2. Kamangar F, et al. J Clin Oncol. 2006; 24:2137-2150.

  4. Pathophysiology of Colorectal Cancer • Normal colonic epithelial cells transformed by histopathologic, molecular events • Adenomatous polyps • Intermediate stage in carcinogenic process • Polyps occur in 33% of general population by age 50 • 50% incidence by age 70 • Genetic basis for adenoma transformation to colorectal cancer • Mutations in APC, K-ras, at earlier, nonmalignant stages • p53 mutation appears to trigger malignancy Janne PA, et al. N Engl J Med. 2000;342:1960-1968.Vogelstein B, et al. N Engl J Med. 1988;319:525-532.

  5. The Adenoma-Carcinoma Process • Mutations leading to formation of colorectal tumor Normal colonic epithelium Mutation in APC Dysplastic aberrant crypt foci Initial adenoma develops Mutation in K-ras Intermediate adenoma Mutation in DCC Late adenoma Mutation in p53 Carcinoma Other alteration? Metastasis Kinzler KW, et al. New York, The genetic basis of human cancer. NY: McGraw-Hill, 1998:565-87. Vogelstein B, et al. N Engl J Med. 1988;319:525-532. Fearon ER, et al. Cell. 1990;61:759-767.

  6. Screening and Cancer Prevention • Screening with colonoscopy may detect precancerous polyps and other early-stage disease[1] • Recommended beginning at age 50, every 10 years • May begin at 40 years for patients at increased risk • Aspirin, cyclooxygenase-2 (COX-2) inhibitors associated with reduction in incidence of colorectal adenomas[2,3] • Despite these techniques, ~ 25% of patients present with metastatic disease[4] • Nearly one half of patients with colorectal cancer require systemic therapy 1. Regula J, et al. N Engl J Med. 2006;355:1863-1872. 2. Baron JA, et al. N Engl J Med. 2003;348:891-899. 3. Bertagnolli MM, et al. N Engl J Med. 2006;355:873-874.

  7. Chemotherapy for Metastatic Colorectal Cancer • Thymidylate synthase inhibitors • Fluoropyrimidines: 5-FU (intravenous), capecitabine (oral) • Raltitrexed • Topoisomerase I inhibitors • Irinotecan • Alkylating agents • Oxaliplatin • Traditional 5-FU–based chemotherapy associated with modestly improved survival • Newer agents (ie, irinotecan, oxaliplatin) lengthen survival outcomes

  8. Fluoropyrimidines in Metastatic Disease • No increase in survival benefit regardless of schedule • Median survival: ~ 12 months Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

  9. Multiple Active Agents Associated With Increased Survival • Combinations of multiple active agents associated with better outcome • 5-FU, irinotecan, oxaliplatin • Compared with 5-FU/LV, use of all 3 active therapies associated with improved survival • Median survival with triple-drug regimens: ~ 20 months • First-line doublet chemotherapy • Associated with increased exposure to all 3 active agents during therapeutic course Grothey A, et al J Clin Oncol. 2005;23:9441-9442.

  10. Chemotherapy Efficacy Plateau • Median survival with addition of newer agents appears to plateau at 20 months Meta-analysis Group in Cancer. J Clin Oncol. 1998;16:301-308. Saltz LB, et al. N Engl J Med 2000;343:905-914. de Gramont A, et al. J Clin Oncol. 2000;18:2938-2947. Goldberg RM, et al. J Clin Oncol. 2002;20:4591-4596. Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

  11. Molecular Targets in Metastatic Colorectal Cancer • Epidermal growth factor receptor (EGFR) • Vascular endothelial growth factor receptor (VEGFR) • COX-2 • Other targets • Carcinoembryonic antigen • Protein kinase C • Matrix metalloproteinases • Ras • Cyclin dependent kinase

  12. EGFR Inhibitors in Colorectal Cancer • EGFR overexpression found in up to 90% of metastatic tumors • Activation of EGFR ultimately results in inhibition of apoptosis, malignant cell proliferation, migration, and angiogenesis • EGFR-expressing tumors more aggressive with worse prognosis • Monoclonal antibodies targeting EGFR • Cetuximab, panitumumab • Tyrosine kinase inhibitors (TKIs) of EGFR • Gefitinib, erlotinib Venook A. Oncologist. 2005;10:250-261 Mayer A, et al. Cancer. 1993;71:2454-2560.

  13. EGFR Inhibitors in Colorectal Cancer (cont’d) • To date, few promising results with EGFR-targeted TKIs in colorectal cancer setting • Phase II gefitinib study in 110 patients with refractory disease[1] • 2 doses studied, only 1 response noted in higher-dose (500 mg) group • No objective responses noted in study of erlotinib in second-line setting[2] • To date, monoclonal antibodies have exhibited better activity in metastatic disease 1. Rothenberg ML, et al. J Clin Oncol. 2005;23:9265-9274.2. Townsely CA, et al. Br J Cancer. 2006;94:1136-1143.

  14. Cetuximab ± Irinotecan: The BOND Study Irinotecan dose and schedule used during progression Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week(n = 218) Patients with progressive colorectal cancer on or within 3 months of irinotecan-based chemotherapy (N = 329) Irinotecan dose and schedule used during progression Cetuximab 400 mg/m21st infusion, then 250 mg/m2/week Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week (n = 111) PD PD, progressive disease. Primary endpoint: response. Cunningham D, et al. N Engl J Med. 2004;351:337-345.

  15. The BOND Study: Efficacy • Improved response, disease control, median TTP with irinotecan + cetuximab *Disease control = complete and partial responses + stable disease. Cunningham D, et al. N Engl J Med. 2004;351:337-345.

  16. The BOND-2 Study Bevacizumab/Cetuximab + Irinotecan* Cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly Bevacizumab 5 mg/kg every other week Irinotecan at same dose and schedule given just before study entry (n = 41) Metastatic colorectal cancer patients refractory to irinotecan (N = 81) Bevacizumab/Cetuximab* Cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly Bevacizumab 5 mg/kg every other week (n = 40) *Patients received cetuximab on Day 1 (plus irinotecan, if randomized to that arm) and bevacizumab on Day 2. Saltz L, et al. ASCO 2005. Abstract 3508.

  17. BOND-2 Efficacy Results • Significant response for bevacizumab + cetuximab • Addition of irinotecan improved responses • Bevacizumab extends time to tumor progression vs historical controls • Median TTP 100 CET/IRI/BEV CET/IRI/BEV CET/BEV CET/BEV CET* CET/IRI* CET* CET/IRI* 80 P = .03 60 5.6 P < .01 Partial Response (%) 1.5 P = .05 37 40 7.9 23 P < .01 23 4.0 20 11 0 2 4 6 8 10 12 0 *Historical controls. Time to Tumor Progression (Mos) Saltz L, et al. ASCO 2005. Abstract 3508.

  18. BOND and BOND-2: Safety • BOND: overall incidence of adverse events higher in cetuximab-irinotecan arm; 65% vs 44%; P < .001 • Diarrhea, neutropenia more common with combination therapy • Acne-like rash in 80% of patients in each treatment arm • Rash appeared within first 3 weeks of cetuximab treatment in majority of cases (89%) • BOND-2: no synergistic toxicity noted for combined therapies • No antibody-related grade 3 allergic reactions; 17% to 20% incidence of antibody-related grade 3 rash • Most common irinotecan-related toxicity; grade 3/4 diarrhea (24%), neutropenia (22%) Cunningham D, et al. N Engl J Med. 2004;351:337-345.Saltz L, et al. ASCO 2005. Abstract 3508.

  19. Cetuximab 400 mg/m2 loading dose, then 250 mg/m2 once weekly(n = 55) Placebo(n = 58) Cetuximab 400 mg/m2 loading dose, then 250 mg/m2 once weekly(n = 55) Placebo(n = 58) CALGB 80203: Study Design FOLFOXOxaliplatin 85 mg/m2 Days 1, 8LV 20 mg/m2 over 2 hours Days 1, 85-FU 500 mg/m2 bolus, Days 1, 8every 3 weeks Patients with untreated metastatic colorectal cancer (N = 238)* FOLFIRIIrinotecan 180 mg/m2 Day 1LV 400 mg/m2 over 2 hours Day 15-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion Days 1-2 every 3 weeks Primary endpoint: OS.Secondary endpoints: PFS, RR. *Original accrual goal of 2200 patients; after bevacizumab received FDA approval, study closed and redesigned in January 2005 as phase II randomized trial. Venook A, et al. ASCO 2006. Abstract 3509.

  20. CALGB 80203: Preliminary Data • PFS, OS: more follow-up needed • Addition of cetuximab appears to increase response Venook A, et al. ASCO 2006. Abstract 3509.

  21. CALGB/SWOG 80405: Study Design Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weekly Patients with untreated metastatic colorectal cancer (N = 2289)* Patient/physician choice: mFOLFOX6orFOLFIRI Bevacizumab 5 mg/kg IV every 2 weeks Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once weeklyBevacizumab 5 mg/kg IV every 2 weeks Primary endpoint: OS.Secondary endpoints: PFS, RR. *~300 patients enrolled as of November 2006. Study open through CTSU.org

  22. Panitumumab in Colorectal Cancer • Activity in phase II studies • Panitumumab 2.5 mg/kg weekly in 148 previously treated patients • PR: 9%; SD: 29% • PFS: 3.1 mos; OS: 9.4 mos • Panitumumab combined with first-line IFL (n = 19), FOLFIRI (n = 24) • Well tolerated in combination with FOLFIRI • PR: 33%; SD: 46% • Based on these results, phase III study conducted Malik I, et al. ASCO 2005 Abstract 3520. Hecht J. ASCO GI 2006. Abstract 237.

  23. Panitumumab vs BSC in Metastatic Colorectal Cancer Panitumumab 6 mg/kg every 2 weeks + BSC (n = 231) Patients with metastatic colorectal cancer who failed prior standard chemotherapy (N = 463) BSC* (n = 232) Stratification by ECOG score (0-1 vs 2) and geographic locale BSC, best supportive care. *Patients who experienced progressive disease eligible for crossover to panitumumab in optional, separate trial. Peeters M, et al. AACR 2006. Abstract CP-1.

  24. Panitumumab vs BSC: Main Findings • PFS significantly better for panitumumab-treated patients* • HR: 0.54 (95% CI: 0.44-0.66; P < .000000001) 50 Panitumumab + BSC 40 BSC 30 Progression Free (%) 20 10 *Median follow-up: 19 weeks. 1 1 1 4 49 30 35 4 14 26 9 18 10 5 0 Wk 8 Wk 12 Wk 16 Wk 24 Wk 32 Wk 40 Wk 48 Peeters M, et al. AACR 2006. Abstract CP-1.

  25. Panitumumab vs BSC: Main Findings (cont’d) • Panitumumab efficacy consistent across all subgroups • 42% of 174 BSC patients who switched over to separate panitumumab study achieved disease control Peeters M, et al. AACR 2006. Abstract CP-1.

  26. Panitumumab vs BSC: Other Outcomes • Panitumumab generally well tolerated • No patients experienced grade 3/4 infusion reactions Peeters M, et al. AACR 2006. Abstract CP-1.

  27. VEGF-Targeted Therapy • VEGF pathway implicated in angiogenesis • Inhibition of VEGF curbs angiogenesis, slows production of new blood vessels necessary for tumor growth • Monoclonal antibody against VEGF • Bevacizumab • Anti-VEGFR TKIs • Sunitinib • Sorafenib

  28. Bevacizumab-Irinotecan in Metastatic Colorectal Cancer IFLPlacebo (n = 411) PD Patients with untreated metastatic colorectal cancer (N = 923) IFLBevacizumab 5 mg/kg; every 2 weeks (n = 402) PD* 5-FU/LVBevacizumab 5 mg/kg; every 2 weeks (n = 110) PD* Primary endpoint: survival. *Patients receiving bevacizumab could continue therapy past disease progression in combination with second-line therapy. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

  29. Bevacizumab-Irinotecan in Metastatic Colorectal Cancer (cont’d) *By stratified log-rank test. †By chi2 test. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

  30. The BICC-C Study: Original Design FOLFIRI Irinotecan 180 mg/m2 Day 1LV 100 mg/m2 over 2 hours Day 15-FU 400 mg/m2 bolus, then 2400 mg/m246-hour infusion Days 1, 2 every 2 weeks(n = 144) Second randomization (all subjects) Celecoxib 400 mg twice daily Patients with previously untreated metastatic colorectal cancer (N = 430) mIFLIrinotecan 125 mg/m2 Days 1, 8LV 20 mg/m2 over 2 hours Days 1, 85-FU 500 mg/m2 bolus Days 1, 8every 3 weeks(n = 141) Placebo CapIRIIrinotecan 250 mg/m2 Day 1Capecitabine 1000 mg/m2 twice daily Days 1-14 every 3 weeks(n = 145) Primary endpoint: PFS for FOLFIRI vs mIFL. Fuchs C, et al. ASCO 2006. Abstract 3506.

  31. The BICC-C Study: Modified Design Second randomization (all subjects) FOLFIRI Bevacizumab 5.0 mg/kg;every 2 weeks (n = 57) Celecoxib 400 mg twice daily Patients with previously untreatedmetastatic colorectal cancer After May 2004, patients randomized to FOLFIRI or mIFL plus bevacizumab (N = 117) mIFLBevacizumab 7.5 mg/kg; every 3 weeks (n = 60) Placebo CapIRIevery 3 weeks Fuchs C, et al. ASCO 2006. Abstract 3506.

  32. The BICC-C Study: Results • Longer median PFS with FOLFIRI vs mIFL or CapIRI (prior to addition of bevacizumab) • FOLFIRI vs mIFL: 8 mos vs 6.2 mos; P = .01 • FOLFIRI vs CapIRI: 8 mos vs 5.7 mos; P = .01 • Significant improvement in OS with FOLFIRI + bevacizumab compared with mIFL + bevacizumab • HR: 2.5 (95% CI: 1.3-5.0; P = .01) • Median OS not reached for FOLFIRI + bevacizumab vs 18.8 mos for mIFL + bevacizumab • No effect with celecoxib Fuchs C, et al. ASCO 2006. Abstract 3506.

  33. BICC-C: Safety and Tolerability • More discontinuations in CapIRI group due to toxicity vs FOLFIRI or mIFL groups • 17% vs 7% and 12%, respectively • Selected grade 3/4 events (prior to addition of bevacizumab) Fuchs C, et al. ASCO 2006. Abstract 3506.

  34. TREE 1 Study Design mFOLFOX Oxaliplatin 85 mg/m2 Day 1 LV 350 mg/m2 Day 1 5-FU 400 mg/m2 bolus, then 2400 mg/m2 46-hour infusion Days 1, 2 every 2 weeks(n = 50) Patients with inoperable, metastatic colorectal cancer No prior chemotherapy for metastatic disease (N = 223) bFOL Oxaliplatin 85 mg/m2 Days 1, 15 LV 20 mg/m2 over 2 hours Days 1, 8, 15 5-FU 500 mg/m2 bolus Days 1, 8, 15 every 4 weeks(n = 50) CapeOx Oxaliplatin 130 mg/m2 Day 1 Capecitabine 1000 mg/m2 twice daily Days 1-15 every 3 weeks (n = 50) Primary endpoint: grade 3/4 toxicity.Secondary endpoints: RR, TTP, TTF. Hochster HS, et al. ASCO 2006. Abstract 3510.

  35. TREE 2 Study Design* mFOLFOX Bevacizumab 5.0 mg/kgevery 2 weeks(n = 75) bFOL Bevacizumab 5.0 mg/kgevery 4 weeks(n = 74) Patients with inoperable, metastatic colorectal cancer (N = 223) CapeOx†Bevacizumab 7.5 mg/kgevery 3 weeks(n = 74) *TREE 1 study modified to include bevacizumab. †Reduced dose of capecitabine used in TREE 2: 850 mg/m2 Days 1-15. Hochster HS, et al. ASCO 2006. Abstract 3510.

  36. CapeOx bFOL mFOLFOX 60 30 25 50 40 20 15 30 20 10 10 5 0 0 TREE Study: Efficacy Data Overall Response Rate Median TTP Median OS 53 27 26 48 43 41 20 19 17 17 35 Patients (%) Months 22 10 9 8 8 6 5 TREE 1 TREE 2* TREE 1 TREE 2* TREE 1 TREE 2* *With bevacizumab. Hochster HS, et al. ASCO 2006. Abstract 3510.

  37. TREE: Summary of Safety and Tolerability • Fewer treatment-related events in bFOL arm vs CapeOx or FOLFOX during first 12 weeks of treatment • Increased hypertension with addition of bevacizumab • Tolerability of CapeOx improved with capecitabine dose reduction in TREE 2 Hochster HS, et al. ASCO 2006. Abstract 3510.

  38. ECOG E3200: Bevacizumab for Previously Treated Metastatic Disease FOLFOX4 Oxaliplatin 85 mg/m2 Day 1Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus, then 600 mg/m2over 22-hr continuous infusion Days 1-2 every 2 weeks(n = 290) Previously treated, bevacizumab-naive patients with metastatic CRC (N = 822) Terminated in March 2003 due to inferiority vs other arms Bevacizumab 10 mg/kg every 2 weeks (n = 243) FOLFOX4 + BevacizumabOxaliplatin 85 mg/m2 Day 1Leucovorin 200 mg/m2 IV over 2 hrs5-FU 400 mg/m2 bolus, then 600 mg/m2over 22-hr continuous infusion Days 1-2 every 2 weeksBevacizumab 10 mg/kg every 2 weeks (n = 289) Giantonio BJ, et al. ASCO 2005. Abstract 2.

  39. ECOG E3200: Outcome With Addition of Bevacizumab • Progression-free and overall survival increased with bevacizumab + FOLFOX4 • Increased toxicity with bevacizumab +FOLFOX4 • 3 bowel perforations reported in this group Giantonio BJ, et al. ASCO 2005. Abstract 2.

  40. Valatinib in Untreated Patients With Metastatic Colorectal Cancer FOLFOX4/Valatinib Oxaliplatin 85 mg/m2 Day 1 Leucovorin 200 mg/m2 IV over 2 hrs +5-FU 400 mg/m2 bolus, followed by 5-FU 600 mg/m2 continuous infusion over 22 hrs on Days 1-2 every 2 weeks Valatinib 1250 mg orally once daily (n = 585) Patients with previously untreated metastatic CRC (N = 1168) FOLFOX4 Leucovorin 200 mg/m2 IV over 2 hrs +5-FU 400 mg/m2 bolus 5-FU 600 mg/m2 continuous infusion over 22 hrs on Days 1-2 every 2 weeks Placebo orally once daily (n = 583) Stratification by PS (0/1 vs 2) and low vs high LDH (≤ 1.5 vs > 1.5 x ULN) Hecht J, et al. ASCO 2005. Abstract LBA3.

  41. Valatinib in Untreated Patients With Metastatic Colorectal Cancer (cont’d) • Adding valatinib to FOLFOX4 did not improve response • CR + PR = 42% vs 46% with FOLFOX4 alone • Slight improvement in PFS in secondary investigator analysis • Patients with high LDH levels treated with FOLFOX4/valatinib showed improved PFS • HR: 0.67; P = .010 by independent assessment • HR: 0.61; P = .002 by investigator analysis • More patients on valatinib + FOLFOX4 discontinued treatment due to adverse events • Most common grade 3/4 adverse events included hypertension, neutropenia, and diarrhea Hecht J, et al. ASCO 2005. Abstract LBA3.

  42. Conclusions • EGFR-, VEGF-targeting agents plus chemotherapy • Associated with improved activity, survival in metastatic disease • Nontraditional adverse events (eg, hypertension, delayed wound-healing, rash) with targeted therapy • Ongoing studies investigating • Maintenance therapy with targeted agents between chemotherapy-free intervals • Combinations of several targeted agents

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