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Individualizing Therapy for Metastatic Colorectal Cancer

Individualizing Therapy for Metastatic Colorectal Cancer. ASCO Educational Session. 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

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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

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