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ASCO 2011 - Updates in Colorectal Cancer -

ASCO 2011 - Updates in Colorectal Cancer -. Axel Grothey Professor of Oncology Mayo Clinic Rochester. Noteworthy at ASCO for CRC?. No practice-changing information, but confirmation of standards of care Early rectal cancer:

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ASCO 2011 - Updates in Colorectal Cancer -

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  1. ASCO 2011- Updates in Colorectal Cancer - Axel Grothey Professor of Oncology Mayo Clinic Rochester

  2. Noteworthy at ASCO for CRC? No practice-changing information, but confirmation of standards of care • Early rectal cancer: • Capecitabine can be used as radiosensitizer in neoadjuvant therapy • Addition of oxaliplatin more toxic, no increase in pCR rate • Is there a role for TNT (Total Neoadjuvant Therapy)?

  3. Noteworthy at ASCO for CRC? • Early colon cancer: • Value of oxaliplatin as adjuvant therapy in stage II cancers debatable • Palliative therapy of CRC: • IGF-R1 inhibitors conclusively ineffective • Not all KRAS mutations are created equal • Aflibercept (VEGF-TRAP) is active and improves OS in 2nd line added to FOLFIRI(to be presented in Barcelona)

  4. The Impact of Capecitabine and Oxaliplatin in the Preoperative Multimodality Treatment of Patients with Carcinoma of the Rectum: NSABP R-04 MS Roh, GA Yothers, MJ O'Connell, RW Beart, HC Pitot, AF Shields, DS Parda, S Sharif, CJ Allegra, NJ Petrelli, JC Landry, DP Ryan, A Arora, TL Evans, GS Soori, L Chu, RV Landes, M Mohiuddin, S Lopa, N Wolmark 1400 Patients

  5. Adenocarcinoma of rectum amenable to surgical resection located < 12 cm from anal verge STRATIFICATION Gender Clinical Tumor Stage II or III Intent for Type of Surgery (sphincter saving; non-sphincter saving) RANDOMIZATION Group 1 5FU (CVI 225mg/m2 5d/week) + 4600cGy + 540-1080cGy Group 2 5FU (CVI 225mg/m2 5d/week) + Oxaliplatin 50 mg/m2/week X 5 + 4600cGy + 540-1080cGy Group 3 Capecitabine 825 mg/m2 PO BID + 4600cGy + 540-1080cGy Group 4 Capecitabine 825 mg/m2 PO BID + Oxaliplatin 50 mg/m2/week X 5 + 4600cGy + 540-1080cGy SURGERY Roh et al. ASCO 2011

  6. Gastrointestinal Toxicity5-Fu or CAPE vs addition of Oxaliplatin **CTCAE Version 3.0 No Oxali Oxali 0.04 0.08 0.12 0.16 0.2 Roh et al. ASCO 2011

  7. 5-FU Cape 0.15 0.2 0.25 0.3 Surgical Downstaging (SD) by Treatment5-FU vs Capecitabine *Restricted to patients without pre-trial intent for SSS Roh et al. ASCO 2011

  8. No Oxali Oxali 0.1 0.15 0.2 0.25 0.3 0.35 Surgical Downstaging (SD) by TreatmentOxaliplatin vs None *Restricted to patients without pre-trial intent for SSS Roh et al. ASCO 2011

  9. 5-FU Cape 0.14 0.16 0.18 0.2 0.22 0.24 0.26 Pathologic Complete Response by Treatment5-FU vs Capecitabine Roh et al. ASCO 2011

  10. No Oxali Oxali 0.16 0.18 0.2 0.22 0.24 0.26 Pathologic Complete Response by TreatmentOxaliplatin vs None Roh et al. ASCO 2011

  11. NSABP R-04Conclusions Roh et al. ASCO 2011 • Administration of capecitabine with preoperative RT achieved rates similar to continuous infusion 5-FU for • Surgical downstaging • Sphincter saving surgery • Pathologic complete response • Addition of oxaliplatin did not improve outcomes and added significant toxicity • Longer follow up will be needed to assess local-regional tumor relapse, DFS and OS

  12. Capecitabine versus 5-fluorouracil-based (neo-)adjuvant chemo-radiotherapy for locally advanced rectal cancer: Long term results of a randomized phase III trial R. Hofheinz, F. Wenz, S. Post, A. Matzdorff, S. Laechelt, J. Hartmann, L. Müller, H. Link, M. H. Moehler, E. Kettner, E. Fritz, U. Hieber, H. W. Lindemann, M. Grunewald, S. Kremers, C. Constantin, M. Hipp, D. Gencer, I. Burkholder, A. Hochhaus, on behalf of the German MARGIT study group

  13. Treatment regimen Arm A Chemoradiotherapy 50.4 Gy + Cape 1,650 mg/m² days 1 – 38 N=197 plus 5 cycles of Cape 2,500 mg/m² d 1 – 14, rep. d 22 S I: 2 x Cape  CRT  3 x Cape S II: CRT  TME surgery (4 – 6 weeks after CRT)  Cape x 5 Arm BChemoradiotherapy 50.4 Gy + 5-FU 225 mg/m² c.i. daily [S I] or N=195 5-FU 1,000 mg/m² c.i. d 1 – 5 and 29 – 33 [S II] plus 4 cycles of bolus 5-FU 500mg/m² d 1 – 5, rep. d 29 S I: 2 x 5-FU  CRT  2 x 5-FU S II: CRT  TME surgery (4 – 6 weeks after CRT)  5-FU x 4 Cape: capecitabine; CRT: chemoradiotherapy; TME: total mesorectal excision; 5-FU: 5-fluorouracil Hofheinz et al. ASCO 2011

  14. Treatment regimen Adjuvant stratum S I Arm A Capecitabine 2,500mg/m²/day (during radiotherapy 1,650mg/m²/day) Radiotherapy 50.4 Gy Week 1 5 9 13 17 21 Radiotherapy 50.4 Gy 5-FU 500mg/m² day 1 – 5 (during radiotherapy 225 mg/m²/day) Arm B Hofheinz et al. ASCO 2011

  15. Capecitabine 2,500mg/m²/day (during radiotherapy 1,650mg/m²/day) Surgery Radiotherapy 50.4Gy Week 1 5 10 16 20 24 28 Radiotherapy 50.4Gy Surgery 5-FU 500mg/m² day 1 – 5 (during radiotherapy 1000 mg/m² d 1 – 5, d 29 – 33) Treatment regimen Neodjuvant stratum S I Arm A Arm B Hofheinz et al. ASCO 2011

  16. Neoadjuvant stratumComparison Arm A & Arm B pCR: pathological complete remission Hofheinz et al. ASCO 2011

  17. Neoadjuvant stratum – Trend of improved downstaging with Capecitabine Patients receiving capecitabine exhibited • less ypN-positive tumors (p = 0.09) • improved T-downstaging (i.e. ypT0 – 2) (p = 0.07) • more pCR (ypT0 ypN0): 13.2 % vs. 5.4% (p = 0.16) Hofheinz et al. ASCO 2011

  18. Disease free survival (DFS)Secondary endpoint (Median Follow-up 52 mon.) Hofheinz et al. ASCO 2011

  19. Overall survival (OS)Primary endpoint (Median Follow-up 52 mon.) Hofheinz et al. ASCO 2011

  20. Conclusions • Both treatment regimens were well tolerated. Cape patients had more all grade HFS, proctitis, diarrhea and fatigue, while alopecia and leukopenia were more frequently observed with 5-FU. • In the neo-adjuvant stratum Cape led by trend to improved downstaging and a numerical higher rate of pCR. • Cape was non-inferior to 5-FU regarding 5-year survival. • Exploratory test for superiority was borderline significant. • 3-year DFS was significantly better with Cape. • HFS indicated superior 3-year DFS and 5-year OS. • Capecitabine may replace 5-FU in the perioperative treatment of locally advanced rectal cancer. Hofheinz et al. ASCO 2011

  21. Preoperative chemoradiotherapy and postoperative chemotherapy with 5-FU and oxaliplatin versus 5-FU alone in locally advanced rectal cancer: First results of CAO/ARO/AIO-04 C. Rödel, H. Becker, R. Fietkau, U. Graeven, W. Hohenberger, C. Hess, T. Hothorn, M. Lang-Welzenbach, T. Liersch, L. Staib, C. Wittekind, R. Sauer German Rectal Cancer Study Group

  22. Phase III: CAO/ARO/AIO-04 Best arm of CAO/ARO/AIO-94: T M E RT 50.4 Gy + 5-FU1000 mg/m² days 1-5 + 29-33 5-FU500 mg/m² d 1-5, q29 4 cycles (4 months) Based on phase I/II trials: RT 50.4 Gy + 5-FU/OXOx: 50 mg/m² d 1, 8, 22, 29 5-FU: 250 mg/m² d 1-14 + 22-35 Note:Chemo gap 3rd week of RT ! mFOLFOX6Oxaliplatin: 100 mg/m² d1,q15 Folinic Acid:400 mg/m² d15-FU: 2400 mg/m² d1-28 cycles (4 months) Rödel et al. ASCO 2011

  23. Main InclusionCriteria • Carcinomaofrectum • Within 12 cm above anal verge • ECOG PS 0-2 • cT3/4 and/orcN+, cM0 • Staging: EUS+CT and/or MRI Rödel et al. ASCO 2011

  24. Rödel et al. ASCO 2011

  25. TME good TME moderate TME poor ventral view dorsal view peritoneal fold distal resectionmargin Rödel et al. ASCO 2011

  26. *p= 0.045 (unplanned, exploratory) Rödel et al. ASCO 2011

  27. 1Aschele et al., J Clin Oncol 2009;27:170s abstr CRA4008; 2Gérard. et al., J Clin Oncol 2010;28:1638-44 Rödel et al. ASCO 2011

  28. 1Aschele et al., J Clin Oncol 2009;27:170s abstr CRA4008; 2Gérard. et al., J Clin Oncol 2010;28:1638-44 Rödel et al. ASCO 2011

  29. Conclusions: CAO/ARO/AIO-04 • 5-FU/OX-CRT with one week chemo gap • - well tolerated, high compliance • - increased pCR-rates • Quality assurance program: • - Good TME quality 74% • - Lymph nodes examined per specimen: 15 (median) • Oxaliplatinincludedbothpre- andpostop • - 73% started, 60% completed adjuvCTx in both arms • Longer follow-up needed for primary endpoint • - Disease-free survival Rödel et al. ASCO 2011

  30. Optimal Duration of Neoadjuvant Therapy in Rectal Cancer Garcia-Aguilar, et al. ASCO 2011

  31. Pathologic Response Garcia-Aguilar, et al. ASCO 2011

  32. Pathologic Response • No increase in surgical or non-surgical complications • Higher pCR rate with prolonged neoadjuvant therapy and inclusion of FOLFOX • Results generate interest in: • TNT (total neoadjuvant therapy – all treatment upfront) • Role of neoadjuvant chemotherapy – see Intergroup-Alliance trial Garcia-Aguilar, et al. ASCO 2011

  33. NCCTG N1048-CALGB 81001-ACOSOG Z6092A Phase II/III Trial of Neoadjuvant FOLFOX with Selective Use of Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal Excision • Inclusion criteria: • Candidate for sphincter-sparing surgery • Clinical staging: T1N1, T2N1, T3N0, T3N1 (5-12 cm from anal verge) • Physical exam by primary surgeon • MRI or ERUS (MRI preferred) • CT scan of C/A/P • Radiologic definition of N1 and N2 • 1 or more nodes >=5mm=N1 • 4 or more >10mm nodes=N2

  34. Study Schema No Progression TME FOLFOX x 6 “selective arm” Progression FOLFOX x 6 Restage 5FUCMT TME FOLFOX x 2 RANDOMIZE: 1:1 5FUCMT TME FOLFOX x 8 “standard arm”

  35. Value of Oxaliplatin as Part of Adjuvant Therapy in Stage II Colon Cancer?- Pooled Analysis of NSABP Trials - Yothers et al. ASCO 2011

  36. Adjusted* KM-Estimate of DFS Stage II Yothers et al. ASCO 2011

  37. Oxaliplatin HR by Risk Group Stage II Yothers et al. ASCO 2011

  38. 5-Year Adjusted Estimates Yothers et al. ASCO 2011

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

  40. 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

  41. 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

  42. KRAS as Biomarker for Panitumumab Response in Metastatic CRC • PFS log HR significantly different depending on K-ras status (P < .0001) • Percentage decrease in target lesion greater in patients with wild-type KRAS receiving panitumumab Patients With Wild-Type KRAS Patients With Mutant KRAS Pmab + BSC 1.0 Meanin Wks 1.0 Medianin Wks BSC alone Pmab + BSC Events/N (%) 0.9 Meanin Wks Medianin Wks 0.9 BSC alone Events/N (%) 0.8 19.0 12.3 0.8 115/124 (93) 9.3 7.3 0.7 114/119 (96) 9.9 7.4 76/84 (90) 0.7 10.2 0.6 7.3 95/100 (95) 0.6 HR: 0.45 (95% CI: 0.34-0.59) Proportion With PFS 0.5 Proportion With PFS Stratified log rank test: P < .0001 0.5 HR: 0.99 (95% CI: 0.73-1.36) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 40 44 40 44 6 8 10 12 14 16 18 22 24 26 28 30 34 36 38 42 46 48 50 52 6 8 10 12 14 16 18 22 24 26 28 30 34 36 38 42 46 48 50 0 2 4 20 32 2 4 20 32 52 0 Weeks Weeks Amado et al. JCO 2008

  43. 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

  44. 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

  45. 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 Months Van Cutsem et al. NEJM 2009

  46. CRYSTAL - KRAS wild-type mCRC (N=348): PFS FOLFIRI + Cetuximab: 9.9 mos FOLFIRI: 8.7 mosHR=0.68, p=0.017 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 Van Cutsem et al. NEJM 2009

  47. Anti-EGFR Antibodies and KRAS mutations Anti-EGFR Antibody EGFR WT KRAS MT KRAS 79% Others Codon 12 ? 18% ~40% MT BRAF 5-10% Codon 13 3% Codons 61,146 ,others Bekaii-Saab, T . Adapted from multiple sources: 1- Wheeler DL, et al Nat Rev Clin Oncol 2010 7(9) : 493-507;2- De Roock et al . Lancet Oncology, 2010 11: 753-762; 3- Frattini M , BJC 2007 97; 1139-1145; 4- Di Nicolantonio F et al . Journal of Clin Oncol 2008 26(35); 5705-5712; 5- Loupakis F et al. BJC 2009 101;715-721;

  48. In Vitro and In Vivo Effects of the G13D Mutation Effect of Cetuximab on Cellular Proliferation in Isogenic Cell Lines Proliferation Assay on Isogenic Cell lines Effect of Cetuximab on Growth of Tumor De Roock, W. et al. JAMA 2010;304: e-suppl.

  49. Are All KRAS Mutations Created Equal? – G13D • Retrospective analysis • Patients treated within and outside of clinical trials • Some trials randomized, some not • Various lines of therapy • Cetuximab single agent (n=10) and with chemo (n=22) • And still only 45 patients total! De Roock et al., JAMA 2010

  50. Are All KRAS Mutations Created Equal? – G13D Pooled analysis of OPUS and CRYSTAL Tejpar et al., ASCO 2011

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