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Optimizing Conventional Chemotherapy in Advanced Colorectal Cancer

Optimizing Conventional Chemotherapy in Advanced Colorectal Cancer. Axel Grothey Mayo Clinic College of Medicine Rochester, MN. Pertinent Questions in Advanced CRC. BICC-C, OPTIMOX, GISCAD. Multiple effective agents and regimens available What is the best strategic use of options?

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Optimizing Conventional Chemotherapy in Advanced Colorectal Cancer

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  1. Optimizing Conventional Chemotherapy in Advanced Colorectal Cancer Axel Grothey Mayo Clinic College of Medicine Rochester, MN

  2. Pertinent Questions in Advanced CRC BICC-C, OPTIMOX, GISCAD • Multiple effective agents and regimens available • What is the best strategic use of options? • Patients routinely live >2 years • Can and should we keep treating patients with same intensity until PD? • FOLFOX has become one of the standards of care • How can we prevent or delay the onset of sensory neurotoxicity? • Can capecitabine be a substitute for infusional 5-FU? • (Can celecoxib enhance the efficacy and/or reduce the toxicity of chemotherapy?) OPTIMOX, GISCAD OPTIMOX, XENOX BICC-C, (TREE) BICC-C

  3. 2/3 wks, not 4/6 wks Cape 1000 mg/m2 BID d1-14 Irino 250 mg/m2, q3wks BICC-C: Design • First head-to-head comparison between FOLFIRI, mIFL, and CapIri (similar design as TREE-trials) • 3x2 design to address effect of celecoxib vs placebo on efficacy and toxicity • Planned sample size N=1000, when BEV approved accrual adjusted to N=430 (Period 1) • BEV then added to FOLFIRI and mIFL arm (N=117)(Period 2, similar to TREE-2) • Primary endpoint PFS for FOLFIRI vs mIFL

  4. BICC-C: Summary NR = not reached

  5. What have we learned from BICC-C? EORTC 40015 (d/c-ed for toxicity) N=85 G3/4 Diarrhea PFS CapIri 37% 5.9 mo FOLFIRI 13% 9.6 mo Greve ASCO 2006 #3072 Capecitabine US vs RoW: RelRisk Grade 3/4 tox. 1.77 Dose reductions 1.72 Discontinuation 1.83 Haller ASCO 2006 #3514 • Celecoxib is a non-issue in advanced CRC • IFL, even in its modified form, is obsolete • CAPIRI (XELIRI) is problematic • Overlapping toxicities • What is the best capecitabine dose/schedule? • Did toxicity issues affect efficacy? • Similar effect in TREE-2? • FOLFIRI is the clear winner of the head-to-head comparison

  6. What have we learned from BICC-C? • Celecoxib is a non-issue in advanced CRC • IFL, even in its modified form, is obsolete • CAPIRI (XELIRI) is problematic • Overlapping toxicities • What is the best capecitabine dose/schedule? • Did toxicity issues affect efficacy? • Similar effect in TREE-2? • FOLFIRI is the clear winner of the head-to-head comparison

  7. What have we learned from BICC-C? • On phase II trial level and cross-trial comparison, bevacizumab increases efficacy of FOLFIRI and IFL • PFS for FOLFIRI + BEV (BICC-C) and FOLFOX + BEV (TREE-2) are both 9.9 mos* • PFS is a better parameter to appreciate differences between first-line therapies than OS • FOLFIRI + bevacizumab is one of the standard-of-care regimens in palliative first-line therapy of CRC *Hochster GI ASCO 2006

  8. Oxaliplatin-induced Neurotoxicity • Acute neuropathy: • Transient, cold-triggered paresthesia/dysesthesia • Frequent (85-95%) • Not dose-limiting • Chronic, cumulative neurotoxicity: • Predictable phenomenon, correlated with cumulative dose of oxaliplatin • Frequency of grade 3 15-20% in phase III trials • Dose-limiting toxicity of oxaliplatin • Delayed neurotoxicity

  9. 9.3 mos 5.8 mos N9741: FOLFOX4 - TTP and TTF 1 0 0 9 0 TTP TTF 8 0 7 0 63% of pts d/c-ed FOLFOX for otherreasons than PD % Event-Free 6 0 5 0 4 0 3 0 2 0 1 0 0 0 6 12 18 24 Time (mos) Green et al, GI ASCO 2005

  10. XENOX: Rationale and Design • Xaliproden: Interesting agent as potential neuroprotectant • Large, placebo-controlled trial • Problems: • Xaliproden d/c-ed 15 days after last oxaliplatin • Effect on recovery not assessable • Endpoint: Focus on grade 3/4 neurotoxicity • But grade 2 is also clinically relevant!

  11. Xaliproden: Efficacy 1 . 0 P l a c e b o 0 . 9 X a l i p r o d e n 0 . 8 0 . 7 0 . 6 Probability Grade 3 Neurotox Placebo 0 . 5 0 . 4 Xaliproden 0 . 3 0 . 2 Logrank test, p = 0.0203 HR [95% CI] = 0.61 [0.40, 0.93] 0 . 1 0 . 0 0 2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0 1 2 0 0 1 4 0 0 1 6 0 0 1 8 0 0 2 0 0 0 O x a l i p l a t i n c u m u l a t i v e d o s e ( m g / m 2 ) P a t i e n t s a t r i s k : P l a c e b o 3 2 4 3 0 3 2 7 5 2 4 0 1 9 9 1 0 4 3 4 2 3 6 3 1 X a l i p r o d e n 3 2 5 3 0 8 2 8 1 2 4 8 2 0 0 1 1 9 5 0 2 3 1 6 5 2

  12. What should we expect from an oxaliplatin neuroprotectant? • No interference with efficacy • Tolerable side-effects/ toxicity profile • Reduced overall neurotoxicity • Reduced severe neurotoxicity (grade 2/3) • Longer time on therapy • Higher cumulative dose of oxaliplatin • More rapid recovery from neurotoxicity • Reduced acute excitatory and cold-triggered phenomena yes yes no ? no no ? no

  13. FOLFOX4 R 6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7 620 pts Cum. Oxali 780 1560 Stop and Go concept - OPTIMOX1 (%) FOLFOX4FOLFOX7 RR 58.5 58.3 PFS 9.0 8.7 DDC 9.0 10.6 OS 19.3 21.2 G3/4 NTox 17.9 13.3 Primary endpoint Tournigand et al, JCO 2006

  14. Continuous vs Intermittent Therapy?- MRC Trial - “Our findings provided no clear evidence of a benefit in continuing therapy indefinitely until disease progression” Maughan et al., Lancet 2003

  15. 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

  16. OPTIMOX-2: Design • mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin • Comparison: maintenance therapy vs chemotherapy-free intervals (CFI) • Primary endpoint DDC • Planned trial size N=600, after bevacizumab approved downsized to a randomized phase II trial (N=200) • « no formal hypotheses between the two arms but sample size was enough to detect a 20% difference in 2-year survival (30 vs 50%) »

  17. OPTIMOX-2: Why DDC? • OPTIMOX-1/-2 tested sequences of regimens (or CFI) • Time-related endpoint most appropriate, not RR • OS too much influenced by subsequent lines of treatment to reliably reflect differences in initial phase • PFS captures efficacy of continuous first-line therapy very well, but not of an induction-maintenance/CFI-reintroduction strategy • Is DDC the answer?

  18. Tournigand JCO 2006 ? OPTIMOX-Trials: DDC T size DDC=PFS1+PFS2 PFS 1 PFS 2 t FOLFOX FOLFOX Progression at reintroduction PD Baseline progression

  19. OPTIMOX-2: Efficacy How valid is DCC as endpoint without data on OS?

  20. OPTIMOX-2 - Chemotherapy-free Interval and Prognostic Factors 1 . 0 0 8.0 months y G o o d P r o g . n = 3 0 m e d . 3 5 w e e k s t i 0 . 7 5 P o o r P r o g . n = 5 7 m e d . 2 0 w e e k s l i 4.6 months p = . 0 0 5 b a b 0 . 5 0 o r p PS 2 LDH ↑ Alk Ph >3x ULN >1 site 0 . 2 5 0 . 0 0 0 1 0 2 0 3 0 4 0 w e e k s

  21. GISCAD-Trial: Design • Primary endpoint: OS • Non-inferiority: 4 months difference accepted! N=336 FOLFIRI R Evaluation 4 mos

  22. GISCAD: Summary • No difference in efficacy • No difference in toxicity (surprisingly!)

  23. How does all this translate into clinical practice? • Stop-and-Go with maintenance • Oxaliplatin: mandatory - stop before tox! • Irinotecan: can be done • Chemotherapy-free intervals • Intriguing, consistent results from MRC, OPTIMOX2 and GISCAD trials • Applicable for patients with “good” tumor biology • But not standard of care yet • Endpoint validation (DDC) • Role of biologics in maintenance strategy needs to be explored in phase III trial

  24. Bevacizumab DREAM Erlotinib Bevacizumab From OPTIMOX to DREAM Efficacy = Toxicity  OPTIMOX-1 Efficacy = ? Toxicity = OPTIMOX-2

  25. No More “Lines” of Therapy • Chemotherapy regimens and agents get recycled in the course of therapy in the palliative setting • We should not think in terms of “1st-2nd-3rd line” therapy anymore, but • rather develop a treatment strategy • with emphasis on different “phases” of therapy • Defining the overall goal of therapy upfront sets the stage for treatment strategy

  26. RR Time, QOL yes no Induction Ctx (3-4 mos) e.g. FOLF?? + BV/C225 Induction Ctx (3-4 mos) e.g. FOLF?? + BV Re-evaluation of resectability Evaluation oftumor biology yes Maintenance CFI Surgery with curative intent yes “Adjuvant” Ctx Re-Induction Ctx Observation “All 5 drugs” Patient potentially curable?

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