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Colorectal Cancer

Colorectal Cancer. Axel Grothey Professor of Oncology Mayo Clinic Rochester. Disclosures. Consulting activities (honoraria went to the Mayo Foundation) Amgen Bayer Pfizer Roche/Genentech BMS Imclone /Eli-Lilly

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Colorectal Cancer

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  1. Colorectal Cancer Axel Grothey Professor of Oncology Mayo Clinic Rochester

  2. Disclosures • Consulting activities (honoraria went to the Mayo Foundation) • Amgen • Bayer • Pfizer • Roche/Genentech • BMS • Imclone/Eli-Lilly I WILL include discussion of investigational or off-label use of a product in my presentation.

  3. CRC as worldwide health problem • CRC Global Statistics: • 3rd highest incidence rate (~ 1,200,000/yr) • 4th highest mortality rate (~ 608,000/yr) Developed Worldwide Developing CA: A Cancer Journal for Clinicians 2011;61:69-90

  4. Familial Hereditary AC-1 without MMR (Familial CRC of syndrome “X”) Lynch Syndrome Sporadic FAP; AFAP Mixed Polyposis Syndrome Ashkenazi I1307K CHEK2 (HBCC) MYH TGFBR1 PJSFJP CD BRRS = as yet undiscovered hereditary cancer variants Hamartomatous Polyposis Syndromes

  5. US Preventative Services Task Force Screening Recommendations (October 2008) The USPSTF recommends CRC screening for men and women aged 50–75* using high-sensitivity fecal occult blood testing (FOBT), sigmoidoscopy, or colonoscopy. The decision to be screened after age 75 should be made on an individual basis. • High-Sensitivity FOBT – once a year • Flexible Sigmoidoscopy – every 5 years • Colonoscopy – every 10 years Other screening tests in use or being studied (not recommended by the USPSTF ) • Double-Contrast Barium Enema • Virtual Colonoscopy • Stool DNA Test *no upper age limit in all other guidelines http://www.cdc.gov/cancer/colorectal/basic_info/screening/tests.htm

  6. CRC:Demographics and Presentation • Estimated 2009 U.S. incidence (new cases): 147,000 • Estimated 2008 U.S. mortality: 49,900 12% stage I* 18.6% stage IV* 24.5% stage II* 32.6% stage III* 12.3% of patients presented with recurrent CRC.*2002 data. American Cancer Society, 2005; Datamonitor, 2003.

  7. TNM / AJCC v7 Effective Jan 2010 AJCCv6 TNM Staging Definitions Primary tumor (T) Tis Carcinoma in situ T1 Tumor invades submucosa T2 Tumor invades muscularispropria T3 Tumor invades through muscularispropria or subserosa T4 Tumor directly invades other organs or structures Regional lymph nodes (N) N0 No regional lymph node metastases     N1 Metastases in 1–3 regional lymph nodes     N2 Metastases in 4 or more regional lymph nodes Distant metastases (M)     M0 No distant metastases     M1 Distant metastases T4a: perf. visceral peritoneum T4b: invasion of organs N1a: 1 N+ N1b: 2-3 N+ N2a: 4-6 N+ N2b: >7 N+ AJCC = American Joint Committee on Cancer. National Comprehensive Cancer Network (NCCN), 2008; Greene et al., 2002.

  8. AJCC v7 Stage III Stage II Gunderson et al, JCO 2009

  9. History of adjuvant therapy of colon cancer • 5-FU/LV superior to 5-FU/lev • 6- and 12-month treatment cycles equivalent • Lev unnecessary • High-dose and low-dose LV equivalent • Monthly and weekly treatment equivalent • 5-FU/lev superior to surgery alone • LV5FU2 and monthly bolus equivalent • 5-FU/LV superior to surgery alone 1990 1994 1998 2002 Moertel et al. Ann Intern Med. 1995;122:321. Francini et al. Gastroenterol. 1994;106:899. Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract O’Connell et al. J Clin Oncol. 1998;16:295. Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982. Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.

  10. Recurrence rate over time 83% of recurrences occur within the first 3 years Sargent et al., ASCO 2009

  11. Beyond 5-FU in the adjuvant setting Completed studies: • Capecitabine (X-ACT) • Oxaliplatin (MOSAIC, NSABP C-07, XELOXA) • Irinotecan (CALGB 89803, ACCORD-2, PETACC-3) • Bevacizumab (NSABP C-08, AVANT) • Cetuximab in KRAS wt CC (N1047, PETACC-8) Ongoing studies: • QUASAR2 (Cape +/- BEV)

  12. X-ACT: Cape vs Mayo - 5-year DFS (median follow-up 6.8 years) 1.0 0.8 0.6 0.4 0.2 0 5-year n DFS (%) Capecitabine 1,004 60.8 5-FU/LV 983 56.7 Estimated probability HR=0.88 (95% CI: 0.77–1.01) NI margin 1.20 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority p<0.0001 Test of superiority p=0.0682 ITT population Twelves C, et al. Eur J Cancer Suppl2007;5:1 (Abstract 1LB) ITT (intent-to-treat) population; NI = non-inferiority

  13. Primary end-point: disease-free survival Secondary end-points: safety, overall survival • n=2246 • Enrollment:Oct 1998–Jan 2001 (146 centres; 20 countries) • Completely resected colon cancer • Stage II, 40%; Stage III, 60% • Age 18–75 years • KPS ≥60 • No prior chemotherapy MOSAIC: Study Design (n=1123) FOLFOX4 (LV5FU2 + oxaliplatin 85 mg/m²) R LV5FU2 (n=1123) Andre NEJM 2004 LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

  14. MOSAIC: Disease-free Survival - Final Update Data cut-off: June 2006 Δ7.5 Δ7.2 Andre JCO 2009

  15. MOSAIC: OS: Stage II and Stage III 0.1% 4.4% Andre JCO 2009

  16. Long-term Safety Peripheral Sensory Neuropathy Data cut-off: January 2007 Andre JCO 2009

  17. Should patients with stage II colon cancer receive adjuvant therapy?

  18. QUASAR: OS in patients with “no clear indication for chemo” (mostly stage II)5-FU/LV vs surgery alone 100 Observation (n=1622) Chemotherapy (n=1617) 80 60 5-yr OS difference: 2.9% % of Patients 40 P = .02 5-year OS, Observation = 77.4% vs Chemotherapy = 80.3% Relative risk = 0.83 (95% CI, 0.71-0.97) 20 0 0 1 2 3 4 5 6 7 8 9 10 Years QUASAR group, Lancet 2007

  19. “High-risk” Stage II Colon Cancer • Clinical-pathological parameters • T4 tumors • Less than 10 (12) LNs examined • Obstruction/perforation • Lymphatic or vascular invasion • Undifferentiated histology • Molecular parameters • Single marker vs signature - TBD

  20. Defective MMR (dMMR) - Colon cancer Characterized by presence of MSI & loss of MLH1, MSH2, MSH6 or PMS2 expression ~15% of Sporadic CC, >90% loss of MLH1 Clinical Correlations: Right sided, female, early stage, excellent prognosis! Tumors: Poorly differentiated, Signet-ring-cell, Lymphocytic infiltration, near diploid dMMR cells resistant to 5-FU1,2 1Carethers, 1999; 2Arnold 2003

  21. Decision Algorithm in Adjuvant Therapy Resected Colon Ca Stage II Stage III yes T4 and/or<12 LNs High-Risk * no yes Low-Risk FOLFOXXELOX dMMR no Intermed. Risk 5-FU/LV or Capecitabine * No therapy! ? Marker signature? *pts not considered candidates for oxaliplatin Grothey, Oncology 2010

  22. What is the Standard Adjuvant Therapy in Colon Cancer ? • FOLFOX(or XELOX) is standard adjuvant therapy in • stage III and • can be considered in high-risk stage II colon cancer • very consistent results for oxaliplatin across trials • Capecitabine (or 5FU/LV)for • patients who are not considered candidates for oxaliplatin (elderly?) • unselected stage II, pMMR • Irinotecan, bevacizumab, and cetuximab have failed!

  23. median overall survival Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 Best supportive care (BSC) 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab

  24. Treatment paradigms for mCRC • Some patients with stage IV disease can be cured by an interdisciplinary approach • In the palliative setting: FOLFOX = XELOX = FOLFIRI (XELIRI has problems with toxicity) • Most patients tolerate a chemotherapy doublet, but not all need it • The addition of biologics to chemotherapy has improved outcomes, but not as much as we hoped • We are on the verge of individualized therapy based on molecular predictive factors

  25. Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients 22 21 20 19 18 17 16 15 14 13 12 First-Line Therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2 FOLFOXIRI CAIRO Median OS (mo) P =.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) 2007 OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005

  26. EGFR Biologic Agents in Colorectal Cancer = Monoclonal Antibodies Fab Fc Murine Ab “momab” Chimeric Mouse-Human Ab “ximab” Humanized Ab “zumab” Human Ab “mumab” (17-1A) Cetuximab Bevacizumab Panitumumab VEGF

  27. Nomenclature of Monoclonal Antibodies Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab

  28. Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy Hurwitz et al. N Engl J Med 2004

  29. Phase III Trial of IFL +/-Bevacizumab in MCRC: PFS 1.0 HR=0.54, P<0.00001 Median PFS: 6.2 vs 10.6 mo 0.8 0.6 Proportion progression-free 0.4 Treatment Group 0.2 IFL + placebo IFL + bevacizumab 0 0 10 20 30 Progression-free survival (mo) Hurwitz et al. N Engl J Med 2004

  30. XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design RecruitmentJune 2003 – May 2004 RecruitmentFeb 2004 – Feb 2005 XELOX N=317 XELOX + placebo N=350 XELOX + bevacizumab N=350 FOLFOX4 N=317 FOLFOX4 + placebo N=351 FOLFOX4 + bevacizumab N=350 Protocol amended to 2x2 placebo-controled design after bevacizumab phase III data1 became available (N=1401) Initial 2-arm open-label study (N=634) Cassidy & Saltz, JCO 2008 1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

  31. FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events PFS chemotherapy + bevacizumab superiority: primary endpoint 1.0 0.8 0.6 0.4 0.2 0 HR = 0.83 [97.5% CI 0.72–0.95] (ITT) p = 0.0023 PFS estimate 8.0 9.4 0 5 10 15 20 25 Months Saltz et al., JCO 2008

  32. CONcePT study: IO arm 5-FU Cumulative oxaliplatin Months LV 200 2400 OX 85 BEV 5 x 8 680 mg/m2 4 200 2400 5 x 8 680 mg/m2 8 200 2400 85 5 x 8 1360 mg/m2 12 etc. Grothey et al, ASCO 2008

  33. AIO 0504 / Roche ML18147Multinational European Trial Any-OX+ BEV Any-IRI+ BEV R R Any-IRI Any-IRI+ BEV Any-OX Any-OX+ BEV Accrual completed May 31, 2010 N = 820 Primary EP: OS

  34. AIO 0504 / Roche ML18147Multinational European Trial January 26, 2012: Press release. Trial met primary endpoint of improvedoverall survival! ASCO 2012! Any-OX+ BEV Any-IRI+ BEV R R Any-IRI Any-IRI+ BEV Any-OX Any-OX+ BEV Accrual completed May 31, 2010 N = 820 Primary EP: OS

  35. Pertinent Side-Effects of Anti-VEGF Therapy • Hypertension • Arterial thrombotic/ thromboembolic events (ATEs) • Gastrointestinal perforation (GIP) • Bleeding • Delayed wound healing • (Proteinuria)

  36. Safety and Effectiveness Outcomes, by Age Subgroup in BRiTE (US Patient Registry) Kozloff et al. Oncology 2010

  37. mAbs Target Tumor Cell-Bound EGFR Ligand Extracellular EGF-R Ras PI3K Raf PTEN Intracellular Akt MEK MAPK Cell survival Cell Motility DNA Proliferation Angiogenesis Metastasis

  38. mAbs Target Tumor Cell-Bound EGFR Ligand Extracellular EGF-R Ras PI3K Raf PTEN Intracellular Akt MEK MAPK Cell survival Cell Motility DNA Proliferation Angiogenesis Metastasis

  39. NCIC CTG CO.17: Randomized Phase III Trial in mCRCCetuximab vs BSC (no cross-over) <0.0001 <0.0001 <0.0001 0.0046 Karapetis et al. NEJM 2008

  40. CRYSTAL Study (1st Line) FOLFIRI + Cetuximab N = 599 EGFR-expressingmetastatic CRC PFS R Stratified by: • Regions • ECOG PS FOLFIRI N = 599 • Primary Endpoint: PFS (independent review) • Secondary Endpoints: RR, DCR, OS, Safety, QoL • Sample Size: 1217 patients randomized, ITT: 1198 pts Van Cutsem et al. NEJM 2009

  41. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 5-FU/LV/IRI (FOLFIRI) ± Cetuximab: PFSNon-KRAS adjusted 1.0 Subgroupeffect No benefit FOLFIRI + Cetuximab HR = 0.851 P = 0.0479 8.0 vs 8.9 mos FOLFIRI PFS estimate PFS (mos) Van Cutsem et al, 2009

  42. KRAS wild-type (n=348) HR=0.68; p=0.017mPFS Cetuximab + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months 1.0 0.9 0.8 0.7 0.6 1-yr PFS rate 25% vs 43% Progression-free survival estimate 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Months Cetuximab + FOLFIRI FOLFIRI Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS wild-type Van Cutsem et al. NEJM 2009

  43. CRYSTAL: Efficacy UpdateAfter Additional KRAS Testing HR 0.7 HR 0.8 Van Cutsem et al. JCO 2011

  44. IRI OX OX OX OX OX IRI IRI 1st Line 2nd Line Grothey & Lenz, JCO 2012

  45. CAIRO2: Study design CapOx + BEV (COB, n=368) Primary endpoint • Progression-free survival Secondary endpoints • RR • OS time • Toxicity • Translational research EGFR-detectable mCRC R CapOx + BEV + Cetuximab(COB-C, n=368) Oxaliplatin d/c’d after 6 cyclesi.e. after 18 weeks = 4.5 mos Tol et al. NEJM 2009

  46. CAIRO2 - KRAS genotyping (n=501) Tol et al. NEJM 2009

  47. Bevacizumab vs EGFR Antibodies in Advanced CRC - Simplified

  48. Large molecule VEGF inhibitors PlGF VEGF-B VEGF-C, VEGF-D VEGF-A Y Bevacizumab Ramucirumab Y Aflibercept (VEGF Trap) VEGF-R1 (Flt-1) Migration Invasion Survival VEGF-R2 (KDR/Flk-1) Proliferation Survival Permeability VEGF-R3 (Flt-4) Lymphangio- genesis Functions

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