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Treating Advanced Colorectal Cancer: 15 minutes, 13 abstracts

Treating Advanced Colorectal Cancer: 15 minutes, 13 abstracts. Richard M Goldberg MD Professor and Chief of Heme/Onc Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill. Topics: Chemotherapy N = 2241. First-line chemotherapy comparisons

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Treating Advanced Colorectal Cancer: 15 minutes, 13 abstracts

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  1. Treating Advanced Colorectal Cancer: 15 minutes, 13 abstracts Richard M Goldberg MD Professor and Chief of Heme/Onc Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill

  2. Topics: ChemotherapyN = 2241 • First-line chemotherapy comparisons • BICC (Fuchs et al): mIFL, CapeIRI, FOLFIRI • Ducreux et al: Xelox to FOLFOX • NO 16966 (Cassidy et al): Xelox to FOLFOX • GONO (Falcone et al): 5-FU/IRI to FOLFOXIRI • Second-line chemotherapy comparisons • Rothenberg et al: Xelox to FOLFOX

  3. FOLFIRI mIFL CapeIRI BICC-C: Fuchs et al: n = 547 R A N D O M I Z A T I O N 1st-line mCRC N = 1000

  4. Efficacy in 430 Patients

  5. Period 1: Progression Free Survival 1.0 0.9 0.8 0.7 0.6 Proportion of Progression Free Survival 0.5 0.4 0.3 0.2 FOLFIRI mIFL 0.1 CapeIRI 0 0 10 20 30 Time (months)

  6. FOLFIRI mIFL CapeIRI Period 1: OS as ofMay 1st, 2007 1 0.9 0.8 0.7 0.6 Proportion of Patients Who Survived 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 Survival Time (months)

  7. Period 1: Grade 3-4 AEs

  8. Question answered: What is currently the best combination of irinotecan and 5-FU? • FOLFIRI What about toxicity? • Beware the CapeIRI regimen used in this study • No more IFL, mIFL

  9. Xelox vs FOLFOX: Ducreux et alEquivalence StudyN= 306 XELOX Randomization FOLFOX6

  10. Efficacy

  11. Progression-free & Overall survival

  12. Toxicity (n=304) * *p<0.05, Chi-square test * *

  13. Questions Answered: Does XELOX ≈ FOLFOX-6 in terms RR, Median PFS and OS? • Yes What about comparative toxicity? • XELOX offers significantly less grade 3/4 neuropathy, neutropenia, and febrile neutropenia than FOLFOX-6.

  14. Xelox vs FOLFOX: Cassidy et al RecruitmentJune 03 – May 04 RecruitmentFeb 04 – Feb 05 XELOX n=317 XELOX + placebo n=350 XELOX + bevacizumab n=350 FOLFOX-4 n=317 FOLFOX-4 + placebo n=351 FOLFOX-4 + bevacizumab n=349 n=1400 n=634

  15. Efficacy

  16. OS for XELOX vs. FOLFOX-4 in the 2-arm part of the study FOLFOX-4 n=317, 262 events Proportion of patients XELOX 1.0 n=317, 250 events 0.9 0.8 0.7 HR = 0.90 [97.5% CI: 0.74–1.10] (ITT) HR = 0.92 [97.5% CI: 0.75–1.13] (EPP) 0.6 0.5 0.4 0.3 0.2 0.1 17.7 18.8 0.0 0 5 10 15 20 25 30 35 40 45 Months X X/P X/BV F F/P F/BV

  17. Questions Answered: Do XELOX and FOLFOX-4 yield ≈ OS? • Yes What about XELOX and FOLFOX-4 toxicities? • As expected.

  18. 5-FU/IRI vs FOLFOXIRI: Falcone et alN = 244 5-FU/Iri Douillard Randomization FOLFOXIRI

  19. FOLFOXIRI Schedule Day 1 Day 2 Day 3 CPT-11 165 mg/m2 Oxaliplatin 85 mg/m2 L-LV 200 mg/m2 5FU flat continuous infusion 3200mg/m2 1 hour 2 hours 48 hours Repeated every 14 days

  20. Efficacy

  21. Post-ChemoRx Resections (patients with liver mts only) * p=0.017

  22. Progression Free & Overall Survival Medians Douillard: 6.9 mos FOLFOXIRI: 9.9 mos P= 0.0009 Medians Douillard: 16.7 mos FOLFOXIRI: 23.6 mos P= 0.042

  23. Grade 3-4 Toxicity (N=122) (N=122) p =0.0006

  24. Survival improves with availability of three active drugs * FOLFOXIRI P=0.0001 Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442.

  25. Questions Answered/Raised Is FOLFOXIRI more active than 5-FU/IRI? • Yes, including better resection rates Is FOLFOXIRI too toxic? • Generally not How do 3 drug regimens compare?

  26. Xelox vs FOLFOX 2nd Line: Rothenberg et alN = 627 Xelox Randomization FOLFOX

  27. Efficacy

  28. Progression-free survival XELOX FOLFOX-4 Estimated probability 1.0 0.8 0.6 0.4 0.2 0 4.7 4.8 0 5 10 15 20 25 Months

  29. Overall Survival XELOX FOLFOX-4 Estimated probability 1.0 0.8 0.6 0.4 0.2 0 11.9 12.6 0 5 10 15 20 25 30 35 40 Months

  30. Questions Answered/Raised Does XELOX ≈ FOLFOX-6 in terms RR, Median PFS and OS in second line? • Yes Were there any unexpected toxicities? • No Do we need another XELOX/FOLFOX study in MCRC? No, 1561 patients reported on in this session

  31. Topics: BiologicsN = 5379 • Chemotherapy + Bevacizumab • BICC (Fuchs et al): mIFL or FOLFIRI +/- Bev • NO 16966 (Saltz et al) Xelox or FOLFOX +/- Bev • Schmiegel et al: CapeOx or CapeIri + Bev • EGFR Antibodies: • Rash/Response • Humbet et al: Panitumumab rash/response • EVEREST (Tejpar et al) Iri + Cetuximab escalation trial • OPUS (Bokemeyer et al) FOLFOX +/- cetuximab

  32. BICC-C Part 2:N= 114 FOLFIRI + Bev Randomization mIFL + Bev

  33. Efficacy

  34. PFS 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Did Not Progress 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 0 0 10 20 30 Time to Progression (months)

  35. OS 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Survived 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 0 0 10 20 30 40 Survival Time (months)

  36. Period 2: Grade 3-4 AEs

  37. Questions Answered/Raised Does FOLFIRI + bev = mIFL + bev • FOLFIRI + bev > mIFL + bev Is a 6.8% 60-day mortality acceptable in PS 0,1 pts? • No, but this is a small study with wide confidence intervals What will the OS be for FOLFIRI/Bev? What is the best chemo partner for Bev?

  38. Xelox vs FOLFOX+/- Bev: Saltz et al RecruitmentFeb 04 – Feb 05 XELOX n=317 XELOX + placebo n=350 XELOX + bevacizumab n=350 FOLFOX-4 n=317 FOLFOX-4 + placebo n=351 FOLFOX-4 + bevacizumab n=349 n=1400 n=634

  39. Efficacy

  40. PFS XELOX / FOLFOX-4 + bevacizumab n=699 (513 events) XELOX / FOLFOX-4 + placebo n=701 (547 events) 1.0 0.8 0.6 0.4 0.2 0 HR=0.83 [97.5% CI 0.72–0.95] p=0.0023 PFS estimate 8.0 9.4 0 5 10 15 20 25 Months

  41. Figure 3. Separation after ~6 months in bevacizumab-containing arms between ‘general’ and ‘on treatment’ PFS XELOX / FOLFOX-4 + bevacizumab XELOX / FOLFOX-4 + placebo 1.0 0.8 0.6 0.4 0.2 0 ON TREATMENT: HR=0.63 (97.5% CI 0.52–0.75, p<0.0001) PFS estimate GENERAL: HR=0.83 (97.5% CI 0.72–0.95, p=0.0023) 0 5 10 15 20 Months

  42. 6 12 18 24 30 36 Figure 4. Overall survival XELOX / FOLFOX-4 + bevacizumab n=699 (420 events) XELOX / FOLFOX-4 + placebo n=701 (455 events) 1.0 HR=0.89 (97.5% CI 0.76–1.03) p=0.0769 0.8 Survival estimate 0.6 0.4 0.2 19.9 21.3 0 0 Months

  43. Questions Answered/Raised Does Bevacizumab add to oxaliplatin based regimens? • Not as dramatically as in irinotecan studies Should chemotherapy + bev be continued when oxaliplatin must be stopped? • Yes, probably Why no difference in response rates? Does this mean we are not optimizing 1st line Rx?

  44. CapeOx + Bev vs CapeIRI + Bev:Schmiegel et al; N= 233 CapeOX + Bev Randomization CapeIRI + Bev

  45. Treatment protocol Arm A: d 1 d 15 Oxaliplatin 130mg/m2, 120min i.v. Bevacizumab 7,5 mg/kg i.v. Capecitabine 1000mg/m2 p.o., 2x daily Arm B: (*) Irinotecan 200mg/m2, 30min i.v. Bevacizumab 7,5 mg/kg i.v. Capecitabine 800mg/m2 p.o., 2x daily q 3wks note dose reduction of CapIri compared to previous trials for safety reasons

  46. Efficacy

  47. CTC grade 3 and 4 Toxicities (n=229)

  48. Questions Answered/Raised Is 800 mg/m2 bid a better dose for CapeIRI? • Likely Final results?

  49. OPUS: Bokemeyer et al, N = 337Phase II “Superiority trial” FOLFOX Randomization FOLFOX + Cetuximab

  50. Efficacy

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