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  • This slide lists the faculty who were involved in the production of these slides.
  • This slide lists the disclosure information of the faculty and staff involved in the development of these slides.
  • Adam et al. Proc Am Soc Clin Oncol . 2003;23:296. Abstract 1188.
  • Amgen Corporate Template
  • 5-FU, fluorouracil; CEA, carcinoembryonic antigen; ECOG, Eastern Cooperative Oncology Group; FOLFOX, leucovorin/fluorouracil/oxaliplatin; PS, performance status.
  • CT, computed tomography; PET, positron-emission tomography.
  • CEA, carcinoembryonic antigen; CT, computed tomography; FOLFOX, leucovorin/fluorouracil/oxaliplatin; WT, wild-type.
  • CEA, carcinoembryonic antigen ; CT, computed tomography.
  • 5-FU, fluorouracil; FOLFOX, leucovorin/fluorouracil/oxaliplatin; FOLFOXIRI, leucovorin/fluorouracil/oxaliplatin/irinotecan; FOLFIRI, irinotecan/fluorouracil/leucovorin.
  • FOLFIRI, irinotecan/fluorouracil/leucovorin; mIFL, modified irinotecan/fluorouracil/leucovorin; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival.
  • FOLFIRI, irinotecan/fluorouracil/leucovorin; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; WT, wild-type.
  • 5-FU, fluorouracil; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, irinotecan/fluorouracil/leucovorin; HR, hazard ratio; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; RR, relative risk; WT, wild-type.
  • ATE, arterial thromboembolic events; BP, blood pressure; CV, cardiovascular; GI, gastrointestinal; HTN, hypertension; NSCLC, non-small-cell lung cancer; VTE, venous thromboembolic events .
  • EGFR, epidermal growth factor receptor.
  • CEA, carcinoembryonic antigen ; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, irinotecan/fluorouracil/leucovorin; PS, performance status.
  • 5-FU, fluorouracil; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; FOLFOXIRI, leucovorin/fluorouracil/oxaliplatin/irinotecan.
  • CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer; PFS, progression-free survival; XELOX, capecitabine/oxaliplatin.
  • CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival; XELOX, capecitabine/oxaliplatin.
  • 5-FU, fluorouracil; ASCO, American Society of Clinical Oncology; bev, bevacizumab; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; LV, leucovorin; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PD, progression of disease; PR, partial response; PS, performance status; QOL, quality of life; R, response; SD, stable disease; CAPOX, capecitabine/oxaliplatin.
  • CEA, carcinoembryonic antigen ; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, irinotecan/fluorouracil/leucovorin; PS, performance status.
  • 5-FU, fluorouracil; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; FOLFOXIRI, leucovorin/fluorouracil/oxaliplatin/irinotecan.
  • BBP, bevacizumab beyond first progression; CI, confidence interval; NA, not applicable; OS, overall survival; PD, progression of disease. Grothey et al. J Clin Oncol . 2008;26:5326.
  • AIO, Arbeitsgemeinschaft Internistische Onkologie; ASCO, American Society of Clinical Oncology; CAPIRI, capecitabine/irinotecan; CAPOX, capecitabine/oxaliplatin; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; FUFOX, fluorouracil/oxaliplatin; IRI, irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; XELIRI, capecitabine/irinotecan; XELOX, capecitabine/oxaliplatin.
  • ECOG, Eastern Cooperative Oncology Group; FOLFIRI, fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; Ox, oxaliplatin; Q2W, once every 2 weeks; PFS, progression-free survival; PS, performance status.
  • CI, confidence interval; FOLFIRI, irinotecan/fluorouracil/leucovorin; HR, hazard ratio; mCRC, metastatic colorectal cancer; OS, overall survival.
  • ASCO, American Society of Clinical Oncology; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; mCRC, metastatic colorectal cancer; VEGF, vascular endothelial growth factor; WT, wild-type.
  • CEA, carcinoembryonic antigen; CCY, cholecystectomy; CRC, colorectal cancer; ECOG; Eastern Cooperative Oncology Group; PS, performance status.
  • 5-FU, fluorouracil; CEA, carcinoembryonic antigen; CCY, cholecystectomy; CRC, colorectal cancer; ECOG; Eastern Cooperative Oncology Group; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; PS, performance status.
  • 5-FU, fluorouracil; CEA, carcinoembryonic antigen; CCY, cholecystectomy; CRC, colorectal cancer; ECOG; Eastern Cooperative Oncology Group; FOLFIRI, irinotecan/fluorouracil/leucovorin; FOLFOX, leucovorin/fluorouracil/oxaliplatin; PS, performance status.
  • PCR, polymerase chain reaction.
  • FOLFOX, leucovorin/fluorouracil/oxaliplatin.
  • CI, confidence interval; mCRC, metastatic colorectal cancer; OR, odds ratio; WT, wild-type.
  • mCRC, metastatic colorectal cancer; OS, overall survival; WT, wild-type.
  • mCRC, metastatic colorectal cancer; OR, overall response rate; PFS, progression-free survival; WT, wild-type.
  • PCR, polymerase chain reaction; WT, wild-type.
  • PCR, polymerase chain reaction.
  • FOLFOX, leucovorin/fluorouracil/oxaliplatin.
  • Advances in the Treatment of Colorectal Cancer EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; MoAb, monoclonal antibody; PD, progression of disease; PR, partial response; SD, stable disease; WT, wild-type.
  • Advances in the Treatment of Colorectal Cancer EGFR, epidermal growth factor receptor; MoAb, monoclonal antibody; OS, overall survival; PFS, progression-free survival; WT, wild-type.
  • CRC, colorectal cancer; EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; M, mutated; MoAb, monoclonal antibody; NM, nonmutated; OS, overall survival; PFS, progression-free survival; WT, wild-type.
  • CRC, colorectal cancer; EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; M, mutated; MoAb, monoclonal antibody; NM, nonmutated; OS, overall survival; PFS, progression-free survival; WT, wild-type.
  • CRC, colorectal cancer.
  • CRC, colorectal cancer; EGFR, epidermal growth factor receptor; WT, wild-type.

Transcript

  • 1. Treating the Patient With Newly Diagnosed, Metastatic Colorectal Cancer: Case PresentationsThis program is supported by an educational grant from
  • 2. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com)DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of theCCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providingeducational grants. The materials may discuss uses and dosages for therapeutic products that have notbeen approved by the United States Food and Drug Administration. A qualified healthcare professionalshould be consulted before using any therapeutic product discussed. Readers should verify all informationand data before treating patients or using any therapies described in these materials.
  • 3. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Faculty Edward Chu, MD Peter C. Enzinger, MD Chief Clinical Director, Gastrointestinal Division of Hematology/Oncology Cancer Center University of Pittsburgh School of Dana-Farber Cancer Institute Medicine Assistant Professor of Medicine Deputy Director Harvard Medical School University of Pittsburgh Cancer Institute Boston, Massachusetts Pittsburgh, Pennsylvania John L. Marshall, MD Cathy Eng, MD Chief, Division of Hematology/Oncology Associate Professor Department of Medicine Department of Gastrointestinal Medical Georgetown University Hospital Oncology Washington, DC The University of Texas M. D. Anderson Cancer Center Houston, Texas
  • 4. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Disclosures Edward Chu, MD, has no significant financial relationships to disclose. Cathy Eng, MD, has disclosed that she has received consulting fees from Amgen and Genentech and fees for contracted research from Amgen, Daiichi, and Kerxy. Peter C. Engzinger, MD, has disclosed that he has received consulting fees from Boehringer Ingelheim, Genentech, sanofi- aventis, and Taiho. John L. Marshall, MD, has disclosed that he has received consulting fees and fees for contracted research from Amgen and Genentech.
  • 5. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Overview  Three case-based presentations originally presented as part of a live, CME-certified educational symposium 1. Clinical Management of a Patient Newly Diagnosed With Liver-Limited Metastatic Colorectal Cancer 2. Treatment Conundrums for a Patient With Wild-Type KRAS 3. Impact of KRAS and BRAF Mutations on Treatment Decisions in Patients With Metastatic Colorectal Cancer
  • 6. Clinical Management of a Patient NewlyDiagnosed With Liver-Limited MetastaticColorectal Cancer
  • 7. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Patient Case  68-yr-old male presents with sigmoid colon adenocarcinoma  CT scan: multiple suspicious lesions in both lobes of the liver  History of hypertension, under good control  Abnormal kidney function, secondary to AODM – CrCl: 35 mL/min  No previous history of chemotherapy  No previous history of bleeding or arterio-embolic events
  • 8. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Patient Case  Feels well, c/o RUQ pain  ECOG PS of 1  Serum chemistries and CBC are normal  Serum CEA: 150 ng/mL; ALP: 250 IU/L; LDH: 300 IU/L; serum bilirubin: 2.2 mg/dL  Assessment of colon adenocarcinoma reveals wild-type KRAS
  • 9. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Should one of the liver lesions be biopsied? A. No B. Yes, to confirm the diagnosis of metastatic disease C. Yes, to confirm KRAS mutation status D. Yes, to confirm diagnosis and KRAS status
  • 10. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Liver-Limited mCRC: Scope of Problem 400,000 CRC cases/yr (US/Europe) 30% synchronous metastases Additional ~ 50% will develop metastases 30% to 35% “liver only” metastases 10% to 25% 75% to 90% candidates for not candidates for surgery SURGERY PALLIATIVE THERAPY Aim: R0 resection R0 resection not possible Cure rate: 20% to 30% 70% to 80% relapse5-yr survival: 40% to 60% within 2 yrs
  • 11. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Response to Neoadjuvant Therapy of Liver Metastases Prior to Resection Is Important  131 (of 441) patients with CRC and > 4 liver metastases underwent (mostly) FOLFOX-based neoadjuvant therapy  Survival outcome by response to chemotherapy Response SD PD P Value Patients, n (%) 58 (44) 39 (30) 34 (26) Hepatic relapse, % 55 77 82 1-yr OS, % 95 92 63 5-yr OS, % 37 30 8 < .0001Adam R, et al. Ann Surg. 2004;240:1052-1061.
  • 12. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology OS Based on Initial Response to Chemotherapy 100 95 PR (n = 34) 92 Stabilization (n = 39) 80 Progression (n = 58) Patients (%) 63 60 55 40 44 37 30 20 12 8 0 0 1 2 3 4 5 YrsAdam R, et al. Ann Surg. 2004;240:1052-1061.
  • 13. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Survival After Primary or Secondary Resection of Liver Metastases 100 Resectable (n = 425) Initially nonresectable (n = 95) Patients Surviving (%) 80 60 54 50 34 40 27 20 34 29 19 0 0 1 2 3 4 5 6 7 8 9 10 Survival Time (Yrs)Adam R. Ann Oncol. 2003;14(suppl 2):ii13-ii16.
  • 14. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Response Correlates With Resection in Initially Unresectable mCRC 0.6 Studies including selected patients 0.5 (liver metastases only, no extrahepatic disease) r = 0.96; P = .002 Resection Rate 0.4 0.3 Studies including all patients (solid line) r = 0.74; P = .001 0.2 Phase III studies 0.1 (dashed line) r = 0.67; P = .024 0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response RateFolprecht G, et al. Ann Oncol. 2005;16:1311-1319.
  • 15. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Which cytotoxic chemotherapy regimen would you recommend for this patient? A. 5-FU/LV B. Capecitabine C. FOLFIRI D. FOLFOX E. CAPIRI F. CAPOX G. FOLFOXIRI
  • 16. Is There an “Optimal” Cytotoxic Regimen?
  • 17. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Clinical Efficacy of Cytotoxic Regimens Regimen, % Response Rate Resection Rate FOLFOX 40-50 25-35 FOLFIRI 40-50 25-30 FOLFOXIRI 50-60 30-50Alberts SR, et al. J Clin Oncol. 2005;23:9243-9249. Barone C, et al. Br J Cancer. 2007;97:1035-1039.De La Cámara R, et al. ASCO 2004. Abstract 3593. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.Abad A, et al. ASCO 2005. Abstract 3618. Ho WM, et al. Med Oncol. 2005;22:303-312.
  • 18. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III Trial of FOLFOXIRI vs FOLFIRI as First-line Therapy of Advanced CRC FOLFIRI FOLFOXIRI P Value (n = 122) (n = 122) RR, % 34 60 < .0001 CR + PR + SD, % 68 81 R0 resection (all patients), % 6 15 .033 R0 resection (liver limited), % 12 36 .017 PFS, mos 6.9 9.8 .0006 OS, mos 16.7 22.6 .032Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.
  • 19. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Which biologic agent would you recommend? A. Bevacizumab B. Cetuximab C. Panitumumab D. None
  • 20. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Which biologic agent would you recommend if a KRAS mutation were detected? A. Bevacizumab B. Cetuximab C. Panitumumab D. None
  • 21. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology CRYSTAL Trial: Liver Resection Increased With Addition of Cetuximab FOLFIRI alone Cetuximab + FOLFIRI ITT Population Liver Metastases Only Population 10 OR: 3.0 10 9.8 9 (95% CI: 1.4-6.5; 8 9 P = .0034) 8 Patients (%) 7 6.0 Patients (%) 6 7 5 4.3 6 4 5 4.5 3 2.5 4 2 1.5 3 1 2 0 1 n= 134 122 Surgery With No Residual 0 Curative Intent Tumor After No Residual Tumor in Patients Resection With Liver Metastases n = 599 / Group n = 599 / GroupVan Cutsem E, et al. ASCO 2007. Abstract 4000
  • 22. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology PRIME: R0 Resection in Pts With WT KRAS Tumors and Liver-Limited Disease Final Analysis Pmab + FOLFOX4 FOLFOX4 (n = 325) (n = 331) Patients with liver-only metastases 61 (19) 57 (17) at baseline, n (%) ORR, % 57 48 Patients with complete liver 17 (28%) 10 (18%) resection, n (%)Douillard JY, et al, ASCO 2011. Abstract 3510.
  • 23. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology OS After R0 Surgical Resection for Pts With Liver-Limited Disease and WT KRAS 1.0 0.9 Kaplan-Meier Estimate 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 Mos Events, n (%) Median Mos (Range) Liver complete resection 3/27 (11) Not reached (NA) No liver complete 54/91 (59) 23.6 (19.4-30.9) resectionDouillard JY, et al. ASCO 2011. Abstract 3510.
  • 24. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology First BEAT and N016966 BEV Trials: Patients Undergoing Resections Study/Patient Surgery With R0 Hepatic Resections R0 Hepatic Population, % Curative Intent Resections With Curative Intent Resections First BEAT (BEV + CT)  All evaluable pts 11.8 9.0 7.6 6.0 (n = 1914)  BEV + oxaliplatin 16.1 12.2 10.4 8.0 CT (n = 949)  BEV + irinotecan 9.7 7.4 6.5 5.1 CT (n = 662) N016966  BEV + CAPOX or 8.4 6.3 N/A N/A FOLFOX4  CAPOX or 6.1 4.9 N/A N/A FOLFOX4Okines A, et al. Br J Cancer. 2009;101:1033-1038.
  • 25. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Clinical Practice*: 2-Yr OS by Hepatic Metastasectomy and R0 Resection 1.00 89 Hepatic metastasectomy 86 and R0 resection 0.75 (n = 114)OS Estimate Hepatic 0.50 metastasectomy total (n = 145) 47 No curative hepatic 0.25 metastasectomy (n = 1769) 0 0 5 10 15 20 25 30 Mos *BEAT (nonrandomized study): first bevacizumab expanded access trial.Okines A, et al. Br J Cancer. 2009;101:1033-1038.
  • 26. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Role of Bevacizumab in Conversion Therapy  Nonrandomized phase II trial: CAPOX + BEV – 56 patients with potentially resectable liver metastases Assessment Surgery B B B B B B B B B B B CAPOX 5 wks 5 wks No treatment B = bevacizumab – Objective response rate: 73.2% – pCR: 8.9% – No long-term follow-up reportedGruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
  • 27. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Bevacizumab in Potentially Resectable mCRC: OS in Resected Patients 1.0 100% 94.4% 0.8 OS Estimate 0.6 63.6% 0.4 Response CR PR 0.2 SD 0 0 20 40 MosGruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
  • 28. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Bevacizumab in Potentially Resectable Metastatic CRC: Surgical Complications Patients, n (%) Event All Patients Synchronous Patients (n = 52) (n = 11) No increased bleeding; only 3 patients No complications required blood 42 (79) transfusions (6%) 8 (73) Complications 11 (21) 3 (27) Sepsis 3 (6) 1 (9) Hyperbilirubinemia Postoperative liver function and 2 (4) – Biliary leak regeneration normal in 98% of patients 1 (2) – Postoperative bowel(assessed perioperatively and 3 mos perforation 1 (2) – after surgery followed (2) chemotherapy) 1 (9) Anastomotic leakage 1 by Wound infection 1 (2) 1 (9) Hematoma 1 (2) –Gruenberger B, et al. J Clin Oncol. 2008;26:1830-1835.
  • 29. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Postoperative Complications Following Neoadjuvant Bevacizumab  Retrospective analysis of neoadjuvant BEV to evaluate potential association with postoperative complications – Patients with colorectal cancer who underwent hepatic surgery for liver metastases  Findings – No significant increase in hepatobiliary, wound, or other postoperative complications with BEV + CT vs CT alone Day From Last BEV Dose to Surgery Complication ≤ 60 Days, % (n = 40) > 60 Days, % (n = 35) P Value Median: 49 days Median: 74 days Any 55 46 .43 Wound 33 29 .70 Hepatobiliary 8 3 .39Kesmodel SB, et al. J Clin Oncol. 2008;26:5254-5260.
  • 30. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Treatment-Associated Liver Toxicity  5-FU: steatosis  Irinotecan: steatohepatitis  Oxaliplatin: sinusoidal/vascular injury  Bevacizumab – Potential wound healing complications – Need to wait 6-8 wks before surgical resection  Cetuximab: no acute or chronic effects to date  Incidence of postoperative complications increases with prolonged use
  • 31. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Summary: Take-Home Messages  Conversion chemotherapy appears to enhance long-term outcomes  Multiagent chemotherapy regimens provide similar clinical benefit with resection rates in the 30+% range  pCR appears to be 5% with current regimens  Active area of clinical investigation  Multidisciplinary team approach required
  • 32. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Conversion Therapy: Practical Issues  Role of FOLFOX better established than FOLFIRI – Better toxicity profile, more clinical data  FOLFOXIRI attractive but at expense of increased toxicity  Limit duration of preoperative therapy to 3-4 mos – Treat to resectability and not to best response – Minimizes hepatotoxicity  Role of biologics is evolving – Data with cetuximab appears to be most mature in wild-type KRAS CRC – Bevacizumab is an appropriate option in setting of mutant KRAS – If bevacizumab is used, discontinue 6-8 wks before planned surgery
  • 33. Treatment Conundrums for aKRAS-WT Metastatic ColorectalCarcinoma Patient
  • 34. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study  K.L. is a woman aged 65 yrs with a history of: – 2008: stage III colon cancer, treated with adjuvant 5-FU – 2009: single left liver metastasis resected, followed by 6 mo of adjuvant FOLFOX – November 2011: new right hepatic lesion, segment V, 16 × 15 mm – Biopsy: moderately differentiated adenocarcinoma consistent with colon cancer – CEA: 1.3 ng/mL – ECOG PS: 0
  • 35. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology What would you do next? A. Consider PET/CT B. Neoadjuvant chemotherapy C. Liver resection D. Radiofrequency ablation of the liver
  • 36. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study  Patient is to go on to surgical resection for the single liver lesion  Preoperative studies include: – CEA: rose to 6.5 ng/mL – CT chest: within normal limits – CT abdomen/pelvis: 10 new hepatic lesions (mostly < 1 cm, but bilobar)  Systemic chemotherapy is discussed  Biomarker analysis: KRAS WT, BRAF WT
  • 37. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study: CT Images 11/3/11, CEA: 1.3 ng/mL Preoperative CT
  • 38. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Which of the following regimens would you choose? A. FOLFOX/bevacizumab B. FOLFIRI/bevacizumab C. 5-FU/bevacizumab D. FOLFOXIRI E. FOLFOX/cetuximab or panitumumab F. FOLFIRI/cetuximab or panitumumab G. 5-FU/cetuximab or panitumumab
  • 39. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III BICC-C Trial of FOLFIRI + Bevacizumab in mCRC: Survival PFS OSFOLFIRI vs mIFL P = .004 100 1.0 FOLFIRI + bevacizumab Proportion of Patients Progression Free (%)FOLFIRI vs capelri P = .015 mIFL + bevacizumab 0.8 Who SurvivedmIFL vs75 capelri P = .46 0.6 50 FOLFIRI mIFL 0.4 25 Capelri 0.2 P = .037 0 0 10 20 30 0 10 20 30 30 Mos MosFuchs CS, et al. J Clin Oncol. 2007;25:4779-4786. Fuchs CS, et al. J Clin Oncol. 2008;26:689-690.
  • 40. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III CRYSTAL Study of Cetuximab + FOLFIRI in mCRC: KRAS Update and OS Median KRAS KRAS WT P Survival, Mutant HR (n = 172) Value Mos (n = 105) PFSProportion Alive Without Progression 1.0 PFS 9.9 8.4 0.70 .0012 0.9 OS 23.5 20.0 0.80 .0093 0.8 0.7 KRAS WT OS: 20% reduction 0.6 0.5 KRAS mutant in risk of death 0.4 with WT vs mutant 0.3 KRAS 0.2 0.1 HR: 0.63 (P = .007) 0 0 2 4 6 8 10 12 14 16 MosVan Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019.
  • 41. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III Study of Second-line FOLFIRI ± Panitumumab in mCRC Panitumumab 6.0 mg/kg + FOLFIRI* q2w Patients with mCRC (55% (n = 591) KRAS WT), 1 prior regimen, ECOG PS ≤ 2 (N = 1186) FOLFIRI* q2w (n = 595) Primary endpoints *180 mg/m2 irinotecan, 400 mg/m2  PFS leucovorin, 500 mg/m2 5-FU  OS Outcome in FOLFIRI + FOLFIRI P Value KRAS WT Panitumumab (n = 221) Secondary endpoints Patients (n = 325)  ORR RR, % 35 10 < .001 PFS, mos 5.9 3.9 .004  DOR (HR: 0.73)  Safety OS, mos 14.5 12.5 .12Peeters M, et al. J Clin Oncol. 2010;28:4706-4713.
  • 42. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Bevacizumab Associated Toxicity Adverse Event Incidence With Bev Comments Across Indications,[1] % Grade ≥ 3 ATE 2.6  Risk of ATE increased in pts 65 yrs of age or older or with ATE history Grade 3/4 HTN 5-18*  Patients should receive otherwise standard CV prophylaxis and have BP monitored and managed GI perforations 0.3-2.4 Grade ≥ 3 1.2-4.6†  Bevacizumab not recommended for pts with serious hemorrhagic hemorrhage or recent hemoptysis event  Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors Wound 15‡  Discontinue 4-8 wks before surgery, resume 6-8 wks complications postsurgery *Predominantly grade 3. † May apply more to NSCLC. ‡ When surgery conducted during bevacizumab therapy.  Potential for increased VTE risk controversial, increased risk noted in 1 study, but not in others [2,3]1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA. 2008;300;2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.
  • 43. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Acneiform Eruption Associated With EGFR Inhibitors  Preventive measures include the use of antibiotics (monocycline, doxycycline) and moisturizers/sunscreensLacouture ME, et al. Support Care Cancer. 2011;19:1079-1095. Segaert S, et al. Ann Oncol. 2005;16:1425-1433.
  • 44. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study: Status After 8 Cycles of FOLFIRI/Bevacizumab Results: CEA: 1.4 ng/mL ECOG PS: 0 Despite her response, her surgeon has deferred any future resection
  • 45. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology How would you proceed following her response? A. FOLFOX/bevacizumab B. FOLFIRI/bevacizumab C. 5-FU/bevacizumab D. FOLFOXIRI E. FOLFOX/cetuximab or panitumumab F. FOLFIRI/cetuximab or panitumumab G. 5-FU/cetuximab or panitumumab H. Single-agent bevacizumab I. Radiofrequency ablation J. Stop all therapy and observe
  • 46. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III MACRO Trial of Bevacizumab ± CAPOX as Maintenance in mCRC: PFS 1.00 Median PFS, Mos (95% CI) CAPOX + bevacizumab: 10.41 (9.36-11.88) Bevacizumab: 9.66 (8.30-10.58) HR: 1.098 (P = .381) 0.75 Survival Probability Censored CAPOX + bevacizumab (n = 239) Bevacizumab (n = 241) 0.50 0.25 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 MosDíaz-Rubio E, et al. Oncologist. 2012;17:15-25.
  • 47. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III MACRO Trial of Bevacizumab ± CAPOX as Maintenance in mCRC: OS 1.00 Median OS, Mos (95% CI) CAPOX + bevacizumab: 23.20 (19.79-26.01) Bevacizumab : 19.99 (17.08-23.25) HR: 1.098 (P = .381) 0.75 Survival Probability Censored CAPOX + bevacizumab (n = 239) Bevacizumab (n = 241) 0.50 0.25 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 MosDíaz-Rubio E, et al. Oncologist. 2012;17:15-25.
  • 48. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III DREAM Study: First-line Bev + Chemo ± Erlotinib in Unresectable mCRC FOLFOX + Patients with Bev 5-FU/LV or untreated, Bev PD Capecitabine unresectable + Bev CR mCRC, CAPOX +ECOG PS ≤ 2 Bev PR R (planned N = 640) Bev + SD PD FOLFIRI Erlotinib + Bev  Primary endpoint: PFS  Secondary endpoints: duration of disease control, OS, ORR, chemotherapy-free interval, salvage surgery rates, safety, QOL, pharmacogenetics, pharmacoeconomics  Patients stratified by ECOG PS, number of metastatic sites (1 vs >1), age, previous adjuvant chemotherapy, and baseline alkaline phosphatase Recruitment  Status: to be presented at ASCO 2012 January 2007 - June 2010ClinicalTrials.gov. NCT00265824.
  • 49. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study: Status After 8 Cycles of Maintenance 5-FU/bevacizumab  Patient K.L. develops PD in the liver  She resumes FOLFIRI/bevacizumab, but after 2 months of therapy she develops lung metastases  ECOG PS = 0
  • 50. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Now what would you recommend? A. FOLFOX/bevacizumab B. FOLFOX/cetuximab C. FOLFOX/panitumumab D. FOLFIRI/cetuximab E. FOLFIRI/panitumumab F. Irinotecan G. Cetuximab H. Panitumumab
  • 51. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology BRiTE Observational Cohort Registry Study: Post-PD Therapy Survival Outcomes All Patients No Post-PD No BBP BBP (N = 1953) Treatment (n = 531) (n = 642) (n = 253) Deaths, n (%) 932 (48) 168 (66) 306 (58) 260 (40) Median OS, mos 25.1 12.6 19.9 31.8 (95% CI) (23.4-27.5) (10.6-15.7) (18.0-22.0) (27.9-NA) 1-yr survival rate, % 74.7 52.5 77.3 87.7 (95% CI) (72.7-76.7) (46.2-58.8) (73.7-80.9) (85.2-90.3) Median survival 12.0 3.6 9.5 19.2 beyond first PD, (11.1-13.3) (2.7-4.3) (8.4-11.2) (16.8-20.7) mos (95% CI)  In a multivariate analysis, BBP was independently associated with increased survival beyond first progression (P < .001)Grothey A, et al. J Clin Oncol. 2008;26:5326-5334.
  • 52. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III ML18147 Study: Bevacizumab + Crossover Fluoropyrimidine Chemo in mCRC Bevacizumab* + Patients with standard second-line chemotherapy† progressive mCRC (n = 591) after first-line bevacizumab/ chemotherapy Standard second-line chemotherapy‡ (planned N = 822) (n = 595) *5 mg/kg on Days 1, 14 of 4-wk cycle or 7.5 mg/kg on Days 1, 22 of 6-wk cycle. † AIO-IRI, FOLFIRI, CAPIRI, or XELIRI. ‡ FUFOX, FOLFOX, or CAPOX.  Primary endpoint: PFS  Secondary endpoints: OS, ORR, safety  Status: completed; to be presented at ASCO 2012ClinicalTrials.gov. NCT00700102.
  • 53. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III VELOUR Study: FOLFIRI ± Aflibercept as Second-line Therapy in mCRC Stratified by previous bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2) Arm A: FOLFIRI + Aflibercept 4 mg/kg q2w Patients with mCRC (n = 600) progressing on first-line Ox-based chemotherapy* Arm B: FOLFIRI + Placebo q2w (planned N = 1226) (n = 600)*30% had priorbevacizumab.  Primary endpoint: OS  Secondary endpoints: PFS, ORR, safety, immunogenicity  No correlativesClinicalTrials.gov. NCT00561470.
  • 54. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Phase III VELOUR Study of FOLFIRI ± Aflibercept in mCRC: OS 1.0 0.9 Placebo/FOLFIRI Median: 12.06 mos Proportion of Surviving Patients 0.8 Aflibercept/FOLFIRI Median: 13.50 mos 0.7 Stratified HR: 0.817 (95.34% CI: 0.713-0.937; Log-rank P = .0032) 0.6 0.5 0.4 0.3 0.2 0.1 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 MosTabernero J, et al. ECCO-ESMO 2011. Abstract LBA6. Courtesy of Van Cutsem E.
  • 55. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Conclusions  Treatment for all patients with mCRC should be individualized – Multidisciplinary management must occur early  Anti-VEGF and anti-EGFR therapy options for a patient with KRAS WT may vary – First line – Second line – Third line  ASCO 2012 will highlight the TML and DREAM trials, which may change second line and maintenance therapies as well as the role of EGFR tyrosine kinase inhibitors  If approved by the FDA, aflibercept will be another option
  • 56. Impact of KRAS and BRAF Mutations onTreatment Decisions in Patients WithMetastatic Colorectal Cancer
  • 57. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study  A.S. is an artist aged 56 yrs and a mother of 2 who recently developed fatigue, weight loss, and abdominal discomfort  Her history is remarkable for – Hypertension – CCY – Type 2 diabetes – Remote smoking history: 22 pack-yrs – Paternal uncle with CRC at age 76  Workup reveals – Transverse colon cancer – Diffuse liver metastases – Lung nodules  Examination is notable for an enlarged, moderately tender liver  CEA: 243 ng/mL  ECOG PS: 1
  • 58. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study: First-line Treatment  Treatment with first-line FOLFOX + bevacizumab produces an initial partial response  She then develops severe peripheral neuropathy and is switched to 5-FU/LV + bevacizumab
  • 59. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study  She eventually has POD in lungs & liver, still has severe neuropathy with an ECOG PS of 1  She is switched to FOLFIRI + bevacizumab, but quickly develops POD  CEA is now 473 ng/mL
  • 60. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study: KRAS Testing  Specimen type: Unstained colon biopsy  Test information – Genomic DNA was extracted from paraffin-embedded tumor tissue and KRAS sequence analysis was performed on a PCR product using primers spanning exon 2. Sequence was analyzed by pyrosequencing using a Biotage Pyromark MD instrument  Result – Amino acid substitution at position 13 in KRAS, from a glycine (G) to an aspartic acid (D)  Interpretation – Mutation of codon 13: KRAS c.38G > A (G13D)
  • 61. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology What therapy would you recommend for this patient? A. FOLFOX + bevacizumab B. Cetuximab ± irinotecan-based therapy C. Panitumumab D. BSC and wait for regorafinib approval E. BSC and wait for FOLFIRI + aflibercept approval F. Consider hospice G. Consider clinical trial
  • 62. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology KRAS p.G13D Mutation and Response to Cetuximab in Refractory mCRC KRAS Mutation Objective Response KRAS p.G13D Other KRAS Mutation KRAS WT Mutation (n = 45) (n = 265) (n = 464) Any cetuximab-based treatment, n 32 188 345  Response rate, % (95% CI) 6.3 (0-14.6) 1.6 (0-3.3) 26.4 (21.7-31.0)  Univariate OR (95% CI)* 1 [Reference] 4.28 (0.69-26.70) 0.19 (0.05-0.82)  Fisher exact test P value .15 .02  Multivariate OR (95% CI)* 1 [Reference] 3.64 (0.53-25.13) 0.16 (0.04-0.72)  Logistic regression P value .19 .02 Cetuximab monotherapy, n 10 89 146  Response rate, % (95% CI) 0 2.3 (0-5.3) 15.8 (9.8-21.7)  Univariate OR (95% CI)* 1 [Reference] NC NC  Fisher exact test P value .94 .36  Multivariate OR (95% CI)* 1 [Reference] NC NC  Logistic regression P value .97 .97 Cetuximab + chemotherapy, n 22 99 199  Response rate, % (95% CI) 9.1 (0-21.1) 1.0 (0-3.0) 34.2 (27.6-40.80)  Univariate OR (95% CI)* 1 [Reference] 10.42 (0.90-120.8) 0.20 (0.05-0.90)  Fisher exact test P value .08 .03  Multivariate OR (95% CI)* 1 [Reference] 8.63 (0.71-105.6) 0.22 (0.05-0.97)  Logistic regression P value .09 .046 *ORs are expressed for comparison of KRAS p.G13D mutation vs other status.De Roock W, et al. JAMA. 2010;304:1812-1820.
  • 63. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer clinicaloptions.com/oncology KRAS p.G13D Mutation and OS With Cetuximab in mCRC p.G13D Mutation Other KRAS Mutation KRAS WT 100 Any cetuximab therapyPercentage Alive No cetuximab therapy* Log-rank P = .49 Log-rank P < .001 80 Log-rank P < .001 60 40 20 0 0 5 10 15 20 25 0 5 10 15 20 25 0 5 10 15 20 25 Months Since Randomization Months Since Randomization Months Since Randomization or Start of Cetuximab or Start of Cetuximab or Start of Cetuximab 100Percentage Alive 80 Log-rank P < .001 60 Log-rank P > .99 40 Log-rank P = .02 20 Cetuximab monotherapy No cetuximab therapy 0 0 2 4 6 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Months Since Randomization Months Since Randomization Months Since Randomization or Start of Cetuximab or Start of Cetuximab or Start of Cetuximab *The no-cetuximab group for all patients from the pooled data set is the best supportive care group from the CO.17 trial. Horizontal axis in blue indicates range of time since randomization from 0 though 6 mos. De Roock W, et al. JAMA. 2010;304:1812-1820.
  • 64. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Pooled Data From CRYSTAL and OPUS: KRAS p.G13D Mutations Response, % PFS, mo OS, mo N CT CT + cet CT CT + cet CT CT + cet KRAS wt 845 38.5 57.3 7.6 9.6 19.5 23.5 OR/HR [95%, CI] 2.17 [1.64-2.86] 0.66 [0.55-0.80] 0.81 [0.69-0.94] P < .0001 P < .0001 P = .0063 KRAS G13D 83 22.0 40.5 6.0 7.4 14.7 15.4 OR/HR [95%, CI] 2.41 [0.90-6.45] 0.60 [0.32-1.12] 0.80 [0.49-1.3] P = .0748 P = .1037 P = .37 Other KRAS mt 450 43.8 30.5 8.5 6.4 17.7 15.5 OR/HR [95%, CI] 0.56 [0.38-0.83] 1.42 [1.10-1.83] 1.14 [0.93-1.40] P = .0037 P = .0069 P = .1964Tejpar S, et al. ASCO 2011. Abstract 3511.
  • 65. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Mutant KRAS Codon 12 and 13 alleles in mCRC: Response to Panitumumab  The MT KRAS codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected in tumor biopsies from pts enrolled in 3 phase III clinical trials (combined N = 2606) investigating panitumumab – Phase III studies (20050203, 20050181, and 20020408): Pts randomized to receive FOLFOX4, FOLFIRI, or BSC +/- panitumumab 6.0 mg/kg Q2W  MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096, study 20050203), 45% (486/1083, study 20050181), and 43% (184/427, study 20050181)  No MT KRAS allele consistently prognostic for PFS or OS in the control or panitumumab arms  Investigator conclusion: “The lack of consistent results across three lines of therapy indicates pts with MT KRAS codon 12 or 13 alleles are unlikely to respond to panitumumab therapy”Peeters M, et al. ASCO 2012. Abstract 383.
  • 66. Please now assume the patient inthe case study has the following KRAS and BRAF pattern
  • 67. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study, Part B: KRAS Testing  Specimen type: unstained colon biopsy  Test information – Genomic DNA was extracted from paraffin-embedded tumor tissue and KRAS sequence analysis was performed on a PCR product using primers spanning exon 2. Sequence was analyzed by pyrosequencing using a Biotage Pyromark MD instrument  Result – Only WT sequences were detected  Interpretation – No mutation was detected at codons 12 and 13 of KRAS
  • 68. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Case Study, Part B: BRAF Testing  Specimen type: unstained colon biopsy  Test information – Genomic DNA was extracted from formalin-fixed, paraffin-embedded colon tissue (60% tumor)  BRAF mutational status was assessed by PCR-based amplification of exon 15, followed by pyrosequencing of PCR products using a commercial assay (Qiagen)  Result – BRAF V600E  Interpretation – BRAF V600E mutation is detected
  • 69. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Now what therapy would you recommend? A. FOLFOX + bevacizumab B. Cetuximab ± irinotecan-based therapy C. Panitumumab D. BSC and wait for regorafinib approval E. BSC and wait for FOLFIRI + aflibercept approval F. Consider hospice G. Consider clinical trial
  • 70. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology KRAS and BRAF Mutations and Response to Anti-EGFR MoAbs mCRC patients treated with  KRAS and BRAF mutations correlate panitumumab or cetuximab (N = 113) with lack of response to treatment with monoclonal antibodies targeting KRAS mutational status epidermal growth factor receptor WT KRAS Mutant KRAS Mutant KRAS Wild-Type KRAS 34/113 (30%) 79/113 (70%) 6% 28%Responders 2/34 (6%)* 22/79 (28%)† 45% 32%Nonresponders 32/24 (94%) † 57/79 (72%)† 62% 27% *P < .05 (P = .029). BRAF mutational status WT BRAF Mutant BRAF † P < .05 (P = .011). on WT KRAS tumors 0% Mutant BRAF WT BRAF 68/79 32% 27% 11/79 (14%) (86%) 41% Responders 0/11 (0%)* 22/68 (32%)* 27% 73% Nonresponders 11/11 (100%)* 46/68 (68%)*Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712. PR SD PD
  • 71. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer clinicaloptions.com/oncology Patients With WT KRAS and Mut BRAF Fare Worse With Anti-EGFR MoAbs vs WT BRAF PFS OS 100 100Alive Without Progression (%) WT BRAF WT BRAF 90 90 Mutant BRAF Mutant BRAF 80 80 P = .0010 P < .0001 70 70 Alive (%) 60 60 50 50 40 40 30 30 20 20 10 10 0 0 0 100 200 300 400 500 600 700 800 900 0 200 400 600 800 1,0001,2001,400 Days Since Start of Treatment Days Since Start of Treatment Di Nicolantonio F, et al. J Clin Oncol. 2008;26:5705-5712.
  • 72. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer clinicaloptions.com/oncology Anti-EGFR MoAbs in mCRC With WT KRAS ± BRAF V600E Mutation: Survival  In patients with KRAS WT tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but strongly associated with shorter PFS (P < .001) and shorter OS (P < .001). 1.00 1.00Probability of PFS Probability of OS 0.75 V600E mutation 0.75 V600E mutation Non-mutated Non-mutated 0.50 0.50 0.25 0.25 0 0 0 8 16 24 32 40 48 56 64 72 80 88 96 0 6 12 18 24 30 36 42 48 Wks Since Treatment Wks Since Treatment Pts at Risk, n Pts at Risk, n M 5 4 1 0 0 0 0 0 0 0 0 0 0 M 5 3 0 0 0 0 0 0 0 NM 109 104 80 66 44 26 17 9 6 3 3 2 1 NM 110 99 68 45 27 14 6 3 1 Laurent-Puig P, et al. J Clin Oncol. 2009;27:5924-5930.
  • 73. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology CRYSTAL: OS by BRAF Mutation Status 1.0 Median Overall Survival (proportion) Events (months) 95% CI FOLFIRI BRAF MT (n = 33) 33 10.3 8.4 to 14.9 0.8 Cetuximab + FOLFIRI BRAF MT (n = 26) 22 14.1 8.5 to 18.5 0.6 FOLFIRI BRAF WT (n = 289) 229 21.6 20.0 to 24.9 Cetuximab + FOLFIRI BRAF WT (n = 277) 207 25.1 22.5 to 28.7 0.4 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Time (months)  “There was no evidence of an independent treatment by tumor BRAF mutation status interaction. Thus, with the current data set, BRAF mutation status cannot be shown to be predictive of treatment effects of cetuximab plus FOLFIRI.”Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019.
  • 74. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Current “Cutting Edge” Dana-Farber Cancer Center OncoMap
  • 75. Cost (Dollars) 10,000 1000 100,000 10,000,000 100,000,000 1,000,000 Jul 01 Oct 01 Jan 02 Apr 02 clinicaloptions.com/oncology Jul 02 Oct 02 Jan 03 Apr 03 Jul 03 Oct 03 Jan 04 Apr 04 Jul 04 Oct 04 Jan 05 Apr 05 Jul 05 Oct 05 Jan 06 Apr 06 Jul 06Date Oct 06 Jan 07 Study of the CRC Genome Cost per Genome Apr 07 Jul 07 Oct 07 Jan 08 Apr 08 Jul 08 Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer Oct 08 Jan 09 Apr 09 Jul 09 Oct 09 Jan 10 Apr 10 Jul 10 Oct 10 Jan 11 Moore’s Law Rapid Technology Improvement Enables Apr 11 Jul 11 Oct 11
  • 76. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancer clinicaloptions.com/oncology The “Cutting Edge” in the Near Future Double-stranded DNA Exome Sequencing Fragmentation Exonof Genomic DNA Intron P P Linker Hybridization on P capture array for Ligation of target enrichment Linker Target-enrichment and amplification Sequence DNA AcGTCTA AcGTCTA Timmerman B, et al. PLoS One. 2010;5:e15681.
  • 77. Treating the Patient With Newly Diagnosed Metastatic Colorectal Cancerclinicaloptions.com/oncology Conclusions  The understanding of the implications of KRAS and BRAF mutations in CRC is evolving and currently uncertain  The preponderance of data at the current time suggests that patients with KRAS G13D–mutated tumors may respond to EGFR antibodies – Although not all studies support this conclusion  Patients with BRAF V600E–mutated tumors have a worse prognosis than patients with BRAF WT tumors – This effect is probably independent of response to EGFR antibody therapy
  • 78. Go Online for More Education on Metastatic Colorectal CancerInteractive Decision Support Tool: 5 experts make treatmentrecommendations for newly diagnosed mCRC based on specificpatient and disease characteristicsCCO inPractice™ Chapter, “ColorectalCancer: Medical Management”Comprehensive point-of-care referenceauthored by John L. Marshall, MDclinicaloptions.com/oncology