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Individualizing Therapy for Metastatic Colorectal Cancer

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  1. Individualizing Therapy for Metastatic Colorectal Cancer ASCO Educational Session

  2. Session Agenda • Axel Grothey • How to optimize the sequence and duration of treatment for metastatic colorectal cancer? • Heinz-Josef Lenz • Established biomarkers guiding treatment decisions in colorectal cancer • Lee Ellis • Promising future biomarkers for colorectal cancer

  3. How to optimize the sequence and duration of treatment for metastatic colorectal cancer? Axel Grothey Professor of Oncology Mayo Clinic Rochester

  4. Disclosures • Consulting activities (honoraria went to the Mayo Foundation) • Amgen • Bayer • Pfizer • Roche/Genentech • Sanofi-Aventis

  5. Personalized Medicine- Decision Tools - • New: Molecular Biomarkers • Patient-based (Pharmacogenomics) • Tumor-based • Old: Clinical parameters • Patient-based • Age, PS, co-morbidities, experience with prior therapies, financial implications… • Tumor-based • Stage, differentiation, number and sites of metastases… • Goal oriented approach to therapy

  6. 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

  7. 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 Median OS (mo) P =.0001 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005

  8. Different Philosophies… FOLFOXIRI PACCE Piling up Sequencing FOCUS CAIRO

  9. Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced Colorectal Cancer * externally reviewed; †67% 2nd line FOLFOX Falcone et al., JCO 2007

  10. Randomize Arm B Arm A capecitabine N=397 capecitabine + irinotecan N=398 1st line irinotecan N=251 (62%) capecitabine + oxaliplatin N=213 (53%) 2nd line capecitabine + oxaliplatin N=143 (36%) 3rd line CAIRO: Trial Design Koopman et al., Lancet 2007

  11. CAIRO: Overall Survival Median OS 17.4 vs 16.3 mos Koopman et al., Lancet 2007

  12. Take-Home Messages CAIRO/FOCUS • CAIRO (and FOCUS) validate the importance of post- first-line therapies for overall survival • But the OS survival is shorter than what we like to see nowadays • Likelihood of patients to receive all active agents is higher with combination therapy upfront • FOLFOXIRI (OS 22.6 mos) vs CAIRO/FOCUS approach • What about potentially resectable metastases? • How do targeted agents fit in here?  Start with single agent and subsequent sequential therapy can be an option in select patients, but should NOT be the standard of care

  13. 2nd line:62% 2nd line:74% Tournigand-Trial (N=220) Tournigand et al., JCO 2004

  14. 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

  15. Evolution in CRC Treatment Paradigm • Old paradigm • Distinct lines of non–cross-resistant therapy initiated at each disease progression • New paradigm: continuum of care • Comprehensive, strategic, long-term, and individualized disease management • Exposure to all active agents and modalities • Maximal OS and QOL by minimizing toxicity and unnecessary treatment • No more distinct “lines of therapy” Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

  16. 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

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

  18. BICC-C Trial Period 1: Progression Free Survival mIFL CapeIRI 1 0 . 9 0 . 8 0 . 7 0 . 6 Proportion of Progression Free Survival 0 . 5 0 . 4 0 . 3 FOLFIRI 0 . 2 0 . 1 0 0 5 1 0 1 5 2 0 2 5 3 0 Months Primary endpoint! Fuchs et al., JCO 2007

  19. BICC-C: Summary Fuchs et al., JCO 2007, JCO 2008

  20. 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 et al., JCO 2008 1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646)

  21. FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events PFS chemotherapy + bevacizumab superiority: primary objective met 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

  22. 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 5 10 15 20 25 0 5 10 15 20 25 Months Months PFS chemotherapy + bevacizumab superiority: XELOX and FOLFOX subgroups PFS estimate 8.6 9.4 7.4 9.3 FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT) p = 0.0026 FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT) p = 0.1871 Saltz et al., JCO 2008

  23. Why did BEV not increase PFS when added to FOLFOX in NO16966? • No synergistic/additive effect with FOLFOX? • No, see E3200 (second-line) • Ceiling effect of first-line chemotherapy? • Perhaps… • Failure to OPTIMOXize? • Very likely!

  24. Treatment-Free Intervals • Rationale • Decrease intensity of therapy • Reduce toxicity • Prevent discontinuation of therapy • Preserve ability to administer later therapy • Maximize time on treatment • Increase QOL • Recognize drug toxicities • Proactively determine therapeutic strategy • Assess acute and cumulative toxicity • Develop strategies to avoid or minimize toxicity

  25. Chemo-Holidays • Types of treatment breaks • Treatment break with maintenance regimen • OPTIMOX-1 • CONcePT • Complete Chemotherapy-free intervals (CFI) • OPTIMOX-2 • When to interrupt therapy • After pre-planned number of cycles • When toxicity reaches a certain grade • Stop 1 drug or all? Goldberg. Oncologist. 2007;12:38; Grothey. ASCO 2007 Educational Book.

  26. FOLFOX4 R 6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7 620 pts Cum. Oxali 780 1560 Stop and Go concept - OPTIMOX1 Primary endpoint Tournigand et al, JCO 2006

  27. OPTIMOX 1: neurotoxicity FOLFOX4 vs 7 25 FOLFOX4 Grade 3 neurotoxicity FOLFOX7 20 15 Percentage of patients 10 5 0 1 3 5 7 9 11 13 15 17 19 21 23 Cycles Tournigand et al, JCO 2006

  28. mFOLFOX 7 mFOLFOX 7 sLV5FU2 OPTIMOX-2 mFOLFOX 7 mFOLFOX 7 CFI OPTIMOX Studies FOLFOX 4 until TF OPTIMOX-1 FOLFOX 7 FOLFOX 7 sLV5FU2 Maindrault-Goebel et al, ASCO 2006

  29. Maintenance 1 . 0 36 weeks P =0.08 0 . 8 29 weeks CFI 0 . 6 0 . 4 0 . 2 0 . 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 OPTIMOX2: Progression-free Survival Lesson from OPTIMOX2: If PFS is the primary endpoint of your trial, don’t stop treatment before progression! weeks Maindrault-Goebel et al, ASCO 2007

  30. NO16966 Study Drug Exposure – Median Months of Treatment * Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine + placebo or bevacizumab. Patients could also remain on a fluoropyrimidine alone or placebo or bevacizumab alone but not oxaliplatin alone Saltz et al., ASCO GI 2007

  31. NO16966 PFS Subgroup Analyses:On-Treatment Population XELOX Group FOLFOX Group 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Survival Survival 7.0 m 9.5 m 8.4 m 10.6 m 0 100 200 300 400 500 0 100 200 300 400 500 Study day Study day HR = 0.61 [97.5% CI 0.48–0.78] P ≤ .0001 HR = 0.65 [97.5% CI 0.50–0.84] P = .0002 XELOX + placebo XELOX + Bev FOLFOX4 + placebo FOLFOX-4 + Bev VS VS Saltz et al., ASCO GI 2007

  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. 1.0 CO 0.9 IO 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 Censored data. CONcePT: Results TTF PFS 1.0 0.9 0.8 0.7 0.6 Proportion of Patients Proportion of Patients 0.5 P=0.002 P=0.044 0.4 0.3 0.2 0.1 7.3 12 4.2 5.6 0.0 0 2 4 6 8 10 12 14 16 Months Months Grothey et al, ASCO 2008

  34. Should Bevacizumab Be Continued Beyond Progression?

  35. BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP) Evaluablepatients(n=1953) BRiTE: Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo 1st Progression (n=1445) Physician decision - no randomization No Post-PD Treatment(n=253) No BBP(n=531) BBP(n=642) Grothey et al. JCO 2008

  36. BRiTE: Patient Outcome Based on Treatment Post 1st PD No Post-PD Treatment(n=253) No BBP(n=531) BBP(n=642) Grothey et al. JCO 2008

  37. SWOG/NCCTG S600/iBET- Revised - (FOLF) IRI + BEV (FOLFOX orXELOX orOPTIMOX) + BEV R KRAS wt (FOLF) IRI + C225 N = 620 Primary EP: PFS (HR 1.3, 5 -> 6.5 mos for BEV arm) Secondary EP: OS (HR 1.3, 12 -> 15.6 mos in BEV arm)

  38. AIO 0504Multinational European Trial Any-OX+ BEV Any-IRI+ BEV R R Any-IRI Any-IRI+ BEV Any-OX Any-OX+ BEV N = 820 Primary EP: OS

  39. Optimized Medical Therapy of Advanced CRC • Identify the goal of therapy • RR only matters for • conversion therapy of liver metastases or • if patient is symptomatic from his tumor burden • For most patients gain of time and maintaining QOL is more important • Treat to progression (and perhaps beyond?) • Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops • Some select patients can have CFI

  40. Optimized Medical Therapy of Advanced CRC • Expose patients to all potentially active agents • These agents are the oncologist’s tools to keep patients alive • Use fluoropyrimidine-based combinations as default backbone, reserve sequential single agent therapy for select patients • Reutilize chemotherapeutic agents (in different combinations?) in the course of the therapy • Continuum of care vs distinct lines of therapy • Keep in mind that personalized medicine in colorectal cancer did not start with KRAS