Edward Chu, MD Chief Division of Hematology/Oncology University of Pittsburgh School of Medicine Deputy Director University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer This program is supported by educational grants from Image: STEVE GSCHMEISSNER/SPL/Copyright©2011 Getty Images, Inc. All Rights Reserved

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clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Colorectal Cancer: Epidemiology  CRC is third most common cancer diagnosed in US [1] –Estimated new cases in 2010 [1] –Males: 72,090 (9%) –Females: 70,480 (10%) –Age-adjusted incidence: 47.9 per 100,000 persons/yr [2]  Median age at diagnosis: 70 yrs [2]  Prevalence of CRC –In 2007, approximately 1.1 million people were alive in the US with a history of CRC [2]  At diagnosis, 50% to 55% of CRC cases are stage II/III and 20% are metastatic [2] 1. American Cancer Society Cancer Facts & Figures. 2. SEER Stat Fact Sheets: Colon and Rectum.

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Colorectal Cancer: Survival  CRC is second leading cause of all cancer deaths [1] –Estimated deaths in 2010[1] –Males: 26,580 (9%) –Females: 24,790 (9%)  CRC-related deaths have declined steadily over past 20 yrs [1] –Due to improvements in screening, early detection, and treatment Overall 5-Yr Relative Survival, [2] %65.0  White males66.0  White females65.7  Black males55.6  Black females American Cancer Society. Cancer facts & figures SEER stat fact sheets: colon and rectum

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Patient Characteristics Drive Decision Making in mCRC Treatment  Performance status  Age  Comorbid illnesses  Extent of disease  Intent of treatment: palliative vs potentially curative  Previous adjuvant therapy within 1 yr  Organ function: hepatic and renal  Underlying/uncontrolled hypertension  Bleeding risks/concerns  KRAS status

Making Optimal First-line Treatment Decisions

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Performance Status  Critical factor to consider when choosing therapy ECOG Performance Status [1] GradeCriteria 0Fully active, able to carry on all predisease performance without restriction 1Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work, office work 2Ambulatory and capable of all self-care but unable to carry out any work activities; up and about > 50% of waking hours 3Capable of only limited self-care; confined to bed or chair > 50% of waking hours 4Completely disabled; cannot carry on any self-care; totally confined to bed or chair 5Dead 1.Oken MM, et al. Am J Clin Oncol. 1982;5:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Performance Status vs Comorbid Illnesses  Treatment options should not be limited based on performance status and needs to include tumor-related symptoms –Studies have demonstrated that patients with significant symptoms from their cancer, with a performance status ≥ 2 but who are otherwise healthy, may benefit from a more aggressive therapy Comorbid IllnessesPerformance Status Debilitating health problems not related to cancer Helps to quantify general well-being; associated with cancer-related issues

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Patients With Poor Performance Status Derive Benefit From Therapy  Pooled analysis of 9 trials evaluating first-line therapy in mCRC patients (N = 6286) [1] –92% PS 0 or 1 –8% PS 2  Patients with PS 2 experience significantly higher frequency of grade ≥ 3 nausea and vomiting –Higher rate of 60-day all-cause mortality for PS 2 vs PS 0/1 patients –12.0% vs 2.8% (P <.0001)  No difference in treatment benefit for PS 0/1 vs PS 2 for any efficacy outcome –PFS—HR: 0.81 vs 0.79 for PS 0/1 vs PS 2 –P =.68 for the PS/treatment interaction –OS—HR: 0.87 vs 0.88 for PS 0/1 vs PS 2 –P =.41 for the PS/treatment interaction 1. Sargent DJ, et al. J Clin Oncol. 2009;27:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Goals of Treatment: Asymptomatic vs Symptomatic Patient  Choice of first-line mCRC therapy based on treatment goals for the patient [1] –Asymptomatic, indolent disease –Consider patient age, comorbidities, convenience, quality of life, patient preference, treatment cost –Symptomatic, aggressive disease –Combination chemotherapy with addition of biologic agents when possible to achieve rapid tumor shrinkage and symptom relief 1. Adam R, et al. Ann Oncol. 2010;21:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Goals of Treatment: Curative vs Palliative  Curative intent to treat should be considered in patients with organ-limited metastatic disease involving the liver or lung that would allow potentially curative surgical resection  Palliative treatment should be considered in patients with multiple organ involvement with the goal of increasing quality of life

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Role of Previous Adjuvant Therapy  Progression within 12 mos of adjuvant therapy suggests that the tumor is resistant to that treatment 1. NCCN. Clinical practice guidelines in oncology: colon cancer Recommended [1] First-line Treatment Choices for Patients Progressing < 12 mos after adjuvant FOLFOX> 12 mos after adjuvant FOLFOX, adjuvant 5-FU/LV, or adjuvant capecitabine  FOLFIRI ± bevacizumab  FOLFIRI ± cetuximab or panitumumab (KRAS wild type only)  All active chemotherapy regimens

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Adjuvant Therapy for Colon Cancer  Oxaliplatin-based chemotherapy is standard adjuvant treatment of stage III colon cancer in good performance patients [1] –FOLFOX –XELOX (capecitabine + oxaliplatin)  Fluoropyrimidine monotherapy is considered for patients who cannot tolerate more aggressive oxaliplatin-based regimens –5-FU/LV –Oral capecitabine 1. NCCN. Clinical practice guidelines in oncology: colon cancer

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Organ Function  Liver dysfunction –Poor liver function may be a result of multiple causes in mCRC patients –Preexisting liver disease (eg, viral or drug-induced cirrhosis) –Metastatic disease involving the liver –Can significantly alter pharmacokinetics of drugs metabolized by the liver –Irinotecan should be used with caution in patients with elevated serum bilirubin levels (> 2 mg/dL)

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Organ Function  Renal dysfunction –Kidneys often responsible for clearance of a wide range of anticancer agents –Oxaliplatin should not be given in patients with creatinine clearance < 20 mL/min –Patients with reduced creatinine clearance may experience increased toxicity secondary to capecitabine therapy –Dose reduction of 25% indicated with CrCl mL/min –Contraindicated in patients with CrCl <30 mL/min

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer KRAS Gene Status  ~ 40% of CRCs have mutated KRAS genotype [1] –Mutations in codons 12 and 13 of exon [2] –Results in constitutively activated KRAS protein kinase  Associated with poor response to EGFR-targeted agents [2] –EGFR inhibition may be negated by downstream KRAS constitutive activity [1] 1. Lièvre A, et al. Oncogene. 2010;29: Dahabreh IJ, et al. Ann Intern Med. 2011;154:37-49.

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Concerns Regarding Hypertension  Bevacizumab: anti-VEGF monoclonal antibody –Associated with increased incidence (10% to 15%) of grade 3/4 hypertension –Should not be used in mCRC patients with uncontrolled or severe hypertension –Associated with increased risk of stroke and/or other arterial thromboembolic events –Especially in patients 65 yrs of age or older

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Concerns Regarding Bleeding  Bevacizumab is also associated with risk of –Bleeding complications –Wound healing complications –GI perforations  Recommendations [1] –At least 4- to 6-wk interval between last bevacizumab dose and surgery –6- to 8-wk postoperative interval before initiating bevacizumab –Should not be administered to patients with serious hemorrhage or recent hemoptysis 1. NCCN. Clinical practice guidelines in oncology: colon cancer

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Comorbidities  Patient comorbidities can have a significant impact on choice of mCRC first-line therapy  Examples –Use of oxaliplatin may be limited in patients with preexisting diabetic neuropathy –Use of irinotecan may be limited in patients with preexisting bowel disorders or in those who have had previous pelvic and/or abdominal radiation therapy –Patients with preexisting cardiac disease are more susceptible to 5-FU–related cardiotoxicity

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Making First-line Treatment Choices  The practicing oncologist selects optimal first-line treatment for mCRC based on current clinical data, authoritative guidelines (NCCN), and the evidence-based recommendations of expert faculty  Clinical Care Options has developed an Interactive Decision Support Tool to help guide oncologists in making first-line treatment decisions based on the recommendation of 5 experts

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer In the IDST, the above 6 variables were used to make treatment decisions. Interactive Decision Support Tool: 1 Tool; 5 Expert Recommendations

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Participants Were Asked How They Would Treat Patients With the Following Options Chemotherapy  FOLFOX  FLOX  FOLFIRI  5-FU/LV or capecitabine  FOLFOXIRI  CapeOX (XELOX)  CapeIRI (XELIRI)  IROX  Irinotecan Targeted Therapy  Bevacizumab  Cetuximab  Panitumumab NCCN. Clinical practice guidelines in oncology: colon cancer

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer An Expert Insight Is Shown With Each Expert’s Treatment Recommendations

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer First-line FOLFOX and FOLFIRI Are Equivalent  Randomized phase III trial to determine which sequence is better (treatment switched at progression) FOLFIRIFOLFOX6 FOLFIRI Previously untreated mCRC (N = 226) Progression 1. Tournigard C, et al. J Clin Oncol. 2004;22:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer First-line FOLFOX and FOLFIRI Are Equivalent  Median PFS after first-line therapy similar –8.5 vs 8.0 mos for FOLFIRI vs FOLFOX6 (P =.26) Reprinted with permission. © 2004 American Society of Clinical Oncology. All rights reserved. Tournigard C, et al. J Clin Oncol. 2004;22: Probability Mos FOLFIRI first line FOLFOX6 first line

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer First-line FOLFOX and FOLFIRI Are Equivalent  OS similar between treatment arms (21.5 vs 20.6 mos for FOLFIRI vs FOLFOX6; P =.99) Reprinted with permission. © 2004 American Society of Clinical Oncology. All rights reserved. Tournigard C, et al. J Clin Oncol. 2004;22: Probability Mos FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer ARIES: Study Design  Community-based prospective observation cohort study  244 sites, 43 states in US FOLFOX + Bev (n = 739) FOLFIRI + Bev (n = 191) First-line mCRC (N = 1550 enrolled) PFS OS

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer ARIES Study: Clinical Efficacy Endpoint, MosFOLFOX + Bev (n = 72) FOLFIRI + Bev (n = 73) PFS OS Bendell JC, et al. GI ASCO Abstract 480.

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer N016966: Study Design  Randomized phase III trial XELOX + Placebo (n = 350) Unresectable mCRC with no previous systemic therapy for mCRC and no previous oxaliplatin or bevacizumab (N = 1401) XELOX + Bevacizumab (n = 350) FOLFOX4 + Placebo (n = 351) FOLFOX4 + Bevacizumab (n = 350) 1. Saltz LB, et al. J Clin Oncol. 2008;26:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer N016966: Efficacy Results  PFS significantly increased with addition of bevacizumab to chemotherapy Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Saltz LB, et al. J Clin Oncol. 2008;26: Mos Proportion of Patients XELOX/FOLFOX4 + bevacizumab (n = 700; 513 events) XELOX/FOLFOX4 + placebo (n = 701; 547 events) HR: 0.83 (97.5% CI: ; P =.0023)

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Case 2  A 66-yr-old female underwent colon resection in 2006 for stage III sigmoid colon cancer and received adjuvant FOLFOX4 for 6 mos  13 mos following the completion of adjuvant therapy, she was found to have a rising CEA and multiple new liver metastatic lesions in right lobe of liver  PMH is significant for hypertension and coronary artery disease with previous history of MI in 2004  Overall, feels well except for mild right upper quadrant abdominal pain  ECOG PS 1

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer First-line FOLFOX and FOLFIRI Are Equivalent  OS similar between treatment arms Reprinted with permission. © 2004 American Society of Clinical Oncology. All rights reserved. Tournigard C, et al. J Clin Oncol. 2004;22: Probability Mos FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI P =.99

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer KRAS Status in Response to Cetuximab  CRYSTAL: randomized, multicenter phase III trial [1] –Significant improvement in PFS with addition of cetuximab to FOLFIRI vs FOLFIRI alone for first-line mCRC treatment  Retrospective analysis of CRYSTAL [2] –Included only subset of KRAS-evaluable patients (N = 540) 1. Van Cutsem E, et al. N Engl J Med. 2009;360: Van Cutsem E, et al. ASCO Abstract 2. FOLFIRI* 2-wk cycle (n = 609) FOLFIRI* 2-wk cycle + Cetuximab † (n = 609) Stratified by geographic region, ECOG PS EGFR-positive patients with previously untreated mCRC (N = 1218) *FOLFIRI: irinotecan 180 mg/m 2, folinic acid 400 mg/m 2, 5-FU 400 mg/m 2 bolus, 5-FU infusion 2.4 g/m 2 over 46 hrs. † Cetuximab: 400 mg/m 2 on Day 1, then 250 mg/m 2 /wk.

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer KRAS Status in Response to Cetuximab  Retrospective analysis of CRYSTAL [1] –PFS and ORR benefit of FOLFIRI + cetuximab only observed in mCRC patients with wild-type KRAS 1. Van Cutsem E, et al. ASCO Abstract 2. OutcomeWild-Type KRAS (n = 348) Mutated KRAS (n = 192) Median PFS, mos  FOLFIRI + cetuximab  FOLFIRI  HR0.68*1.07 † ORR, %  FOLFIRI + cetuximab59.3 ‡ 36.2  FOLFIRI *P =.017; † P =.75; ‡ P =.0025

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer KRAS Status in Response to Cetuximab  CRYSTAL and OPUS meta-analysis [1] –Pooled efficacy analysis of two randomized phase III trials –CRYSTAL: FOLFIRI + cetuximab vs FOLFIRI alone [2] –OPUS: FOLFOX + cetuximab vs FOLFOX alone [3] –After 90% of samples were subjected to KRAS genotype testing, HRs for benefit of addition of cetuximab shown to be highly statistically significant in patients with wild-type KRAS –PFS—HR: 0.66 (P <.0001) –OS—HR: 0.81 (P =.0062) 1. Bokemeyer C, et al. ASCO Abstract Van Cutsem E, et al. N Engl J Med. 2009;360: Bokemeyer C, et al. J Clin Oncol. 2009;27:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer PRIME Study: KRAS Status in Response to Panitumumab  Randomized, global, open-label, phase III trial Douillard JY, et al. J Clin Oncol. 2010;28: Panitumumab 6.0 mg/kg q2w + FOLFOX4 q2w (n = 593) FOLFOX4 q2w (n = 590) Stratified by ECOG PS (0-1 vs 2) and geographic region (Western Europe, Canada, and Australia vs all other locations) Patients with previously untreated mCRC (N = 1183)

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer PRIME Study: Efficacy Results  PFS significantly improved with FOLFOX4 + panitumumab only in wild-type KRAS patients  Worse PFS outcome with panitumumab addition in mutated KRAS patients Douillard JY, et al. J Clin Oncol. 2010;28:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer KRAS Testing: What Are the Recommendations?  NCCN guidelines [1] –Strongly recommends KRAS testing in all patients with mCRC at the time of diagnosis of metastatic disease –Testing should be performed in a CLIA-certified lab –Testing can be performed on either primary or metastatic tissue  ASCO Provisional Clinical Opinion [2] –All patients with mCRC who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory  In both cases, anti-EGFR agents (cetuximab and panitumumab) are recommended for wild-type KRAS patients only [1,2] 1. NCCN. Clinical practice guidelines in oncology: colon cancer Allegra CJ, et al. J Clin Oncol. 2009;27:

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Summary: Good PS Patients, Mutant KRAS  In previously untreated patients, oxaliplatin-based regimens are equivalent to irinotecan-based regimens –FOLFOX –XELOX –FOLFIRI –XELIRI  In patients previously treated with FOLFOX as adjuvant therapy, consider irinotecan-based regimens –FOLFIRI –XELIRI  Bevacizumab is the biologic agent of choice

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Summary: Good PS Patients, Wild-Type KRAS  In previously untreated patients, oxaliplatin-based regimens are equivalent to irinotecan-based regimens –FOLFOX –XELOX –FOLFIRI –XELIRI  In patients previously treated with FOLFOX as adjuvant therapy, consider irinotecan-based regimens –FOLFIRI –XELIRI

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Summary: Good PS Patients, Wild-Type KRAS  Bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab are reasonable biological agents to consider as part of the treatment regimen  In patients who are potentially surgically resectable, cetuximab may be the optimal biological agent as it yields increased response rates when combined with cytotoxic chemotherapy

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Summary: Poor PS Patients, Mutant KRAS  In previously untreated patients, fluoropyrimidine monotherapy is appropriate –5-FU/LV –Capecitabine  Bevacizumab is the biologic agent of choice in the absence of contraindications

clinicaloptions.com/oncology Expert Insight Into the First-line Treatment of Metastatic Colorectal Cancer Summary: Poor PS Patients, Wild-Type KRAS  In previously untreated patients, fluoropyrimidine monotherapy is appropriate –5-FU/LV –Capecitabine  Consider using bevacizumab or the anti-EGFR antibodies cetuximab or panitumumab

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