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? 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

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 Cape 1000 mg/m2 BID d1-14 Irino 250 mg/m2, q3wks 2/3 wks, not 4/6 wks

BICC-C: Summary Period 1, no BEV Period 2, + BEV Efficacy FOLFIRI N=144 mIFL N=141 CapIri N=145 FOLFIRI N=57 mIFL N=60 RR (%) 46.6 41.9 38 54.4 53.3 PFS (mo) 7.6 5.8 5.5 9.9 8.3 OS 23.1 17.6 18.9 NR 18.7 G 3/4 (%) Diarrhea 13 19 48 11 12 Dehydr. 6 7 5 2 MI/stroke 0.7 4.4 1.8 60d mort. 2.9 3.5 6.8 NR = not reached

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mo FOLFIRI 13% 9.6 mo Greve ASCO 2006 #3072 Celecoxib is a non-issue in advanced CRC IFL, even in its modified form, is obsolete CAPIRI (XELIRI) is problematic Overlapping toxicities What is the best capecitabine dose/schedule?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 Capecitabine US vs RoW: RelRisk Grade 3/4 tox. 1.77 Dose reductions 1.72 Discontinuation 1.83 Haller ASCO 2006 #3514

What have we learned from BICC-C? Celecoxib is a non-issue in advanced CRC IFL, even in its modified form, is obsolete CAPIRI (XELIRI) is problematic Overlapping toxicities What is the best capecitabine dose/schedule?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

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

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

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

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!

Probability Grade 3 Neurotox Xaliproden: Efficacy % of patients Placebo n = 324 Xaliproden n = 325 All Grades 73.5 73.2 G1 38.0 38.5 G2 18.8 23.7 G3 16.7 11.1 1 . . 9 P l a c e b o X a l i p r o d e n . 8 . 7 . 6 Probability Grade 3 Neurotox . 5 Placebo . 4 Xaliproden . 3 . 2 Logrank test, p = 0.0203 HR [95% CI] = 0.61 [0.40, 0.93] . 1 . 2 4 6 8 1 1 2 1 4 1 6 1 8 2 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 3 2 7 5 2 4 1 9 9 1 4 3 4 2 3 6 3 1 X a l i p r o d e n 3 2 5 3 8 2 8 1 2 4 8 2 1 1 9 5 2 3 1 6 5 2

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

Stop and Go concept - OPTIMOX1 6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7 FOLFOX4 620 pts R Cum. Oxali 780 1560 (%) FOLFOX4 FOLFOX7 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

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

OPTIMOX Studies CFI OPTIMOX-1 OPTIMOX-2 FOLFOX 4 until TF FOLFOX 7 sLV5FU2 OPTIMOX-2 mFOLFOX 7 sLV5FU2 CFI

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%) »

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?

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

OPTIMOX-2: Efficacy OPTIMOX Maintenance CFI P-value RR (%) 61 n.s. PFS (mo) 8.7 6.9 .009 DDC (mo) 12.9 11.7 OS ? How valid is DCC as endpoint without data on OS?

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

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

GISCAD: Summary No difference in efficacy BICC-C Efficacy FOLFIRI Cont N=163 FOLFIRI Int N=168 FOLFIRI N=144 RR (%) 33.6 36.5 46.6 PFS (mo) 6.5 6.2 7.6 OS 17.6 16.9 23.1 G 3/4 (%) Diarrhea 3.6 3.2 13 No difference in efficacy No difference in toxicity (surprisingly!)

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

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

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

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