Optimizing Conventional Chemotherapy in Advanced

Colorectal Cancer

Optimizing Conventional Chemotherapy in Advanced

Colorectal Cancer

Axel Grothey

Mayo Clinic College of Medicine

Rochester, MN

Axel Grothey

Mayo Clinic College of Medicine

Rochester, MN

Pertinent Questions in Advanced CRCPertinent Questions in Advanced CRC

• 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?)

• 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?)

BICC-C, OPTIMOX, GISCAD

OPTIMOX, GISCAD

OPTIMOX, XENOX

BICC-C, (TREE)

BICC-C

BICC-C: DesignBICC-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

• 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: SummaryBICC-C: SummaryPeriod 1, no BEV Period 2, + BEV

Efficacy FOLFIRIN=144

mIFLN=141

CapIriN=145

FOLFIRIN=57

mIFLN=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 19 5 2

MI/stroke 0.7 4.4 0 1.8 0

60d mort. 2.9 5.8 3.5 1.8 6.8

NR = not reached

What have we learned from BICC-C?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

• 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: RelRiskGrade 3/4 tox. 1.77Dose reductions 1.72Discontinuation 1.83

Haller ASCO 2006 #3514

EORTC 40015 (d/c-ed for toxicity)N=85 G3/4 Diarrhea PFSCapIri 37% 5.9 moFOLFIRI 13% 9.6 mo

Greve ASCO 2006 #3072

What have we learned from BICC-C?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

• 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

• 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

• 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

What have we learned from BICC-C?What have we learned from BICC-C?

*Hochster GI ASCO 2006

Oxaliplatin-induced NeurotoxicityOxaliplatin-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

• 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

N9741: FOLFOX4 - TTP and TTFN9741: FOLFOX4 - TTP and TTF

0

10

20

30

40

50

60

70

80

90

100

0 12 18 24

% E

ven

t-F

ree

TTP TTF

6

Time (mos)

9.3 mos

5.8 mos

Green et al, GI ASCO 2005

63% of pts d/c-edFOLFOX for otherreasons than PD

XENOX: Rationale and DesignXENOX: 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!

• 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!

Xaliproden: EfficacyXaliproden: Efficacy

Logrank test, p = 0.0203HR [95% CI] = 0.61 [0.40, 0.93]

Placebo

Xaliproden

0 200 400 600 800 1000 1200 1400 1600 1800 2000Oxaliplatin cumulative dose (mg/m2)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ilit

y G

rad

e 3

Neu

roto

x

PlaceboXaliproden

Patients at risk:

Placebo 324 303 275 240 199 104 34 23 6 3 1

Xaliproden 325 308 281 248 200 119 50 23 16 5 2

% of patients

Placebon = 324

Xaliprodenn = 325

All Grades 73.5 73.2

G1 38.0 38.5

G2 18.8 23.7

G3 16.7 11.1

What should we expect from an oxaliplatin neuroprotectant?

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

• 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

yesyes

no

?

nono

?

no

Stop and Go concept - OPTIMOX1

Tournigand et al, JCO 2006

6x FOLFOX7- 12x sLV5FU2 - 6x FOLFOX7

FOLFOX4

620 pts

R

Cum. Oxali 780 1560

(%) FOLFOX4 FOLFOX7

RR 58.5 58.3PFS 9.0 8.7DDC 9.0 10.6OS 19.3 21.2G3/4 NTox 17.9 13.3

Primary endpoint

Maughan et al., Lancet 2003

“Our findings provided no clear evidence of a benefit in continuing therapy indefinitely

until disease progression”

Continuous vs Intermittent Therapy?- MRC Trial -

Continuous vs Intermittent Therapy?- MRC Trial -

OPTIMOX StudiesOPTIMOX Studies

OPTIMOX-1

FOLFOX 4 until TF

FOLFOX 7 FOLFOX 7

sLV5FU2

OPTIMOX-2

mFOLFOX 7 mFOLFOX 7

sLV5FU2

mFOLFOX 7 mFOLFOX 7

CFI

OPTIMOX-2: DesignOPTIMOX-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%) »

• 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-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-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: DDCOPTIMOX-Trials: DDC

t

T size

FOLFOX FOLFOX

PFS 1

PD Baseline progression

PFS 2

Progressionat reintroduction

DDC=PFS1+PFS2Tournigand JCO 2006

?

OPTIMOX-2: EfficacyOPTIMOX-2: Efficacy

OPTIMOX

Maintenance CFI P-value

RR (%) 61 61 n.s.

PFS (mo) 8.7 6.9 .009

DDC (mo) 12.9 11.7 n.s.

OS ? ?

How valid is DCC as endpoint without data on OS?

OPTIMOX-2 - Chemotherapy-free Interval and Prognostic Factors OPTIMOX-2 - Chemotherapy-free Interval and Prognostic Factors

0 10 20 30 400.00

0.25

0.50

0.75

1.00

Good Prog. n=30 med. 35 weeks

Poor Prog. n=57 med. 20 weeks

p=.005

weeks

probability

8.0 months

4.6 months

PS 2LDH ↑Alk Ph >3x ULN>1 site

GISCAD-Trial: DesignGISCAD-Trial: Design

• Primary endpoint: OS

• Non-inferiority: 4 months difference accepted!

• Primary endpoint: OS

• Non-inferiority: 4 months difference accepted!

R

FOLFIRIFOLFIRIFOLFIRIFOLFIRI

Evaluation

4 mos

N=336

GISCAD: SummaryGISCAD: Summary

GISCAD BICC-C

Efficacy FOLFIRICont N=163

FOLFIRIInt N=168

FOLFIRIN=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?

How does all this translate into clinical practice?

• Stop-and-Go with maintenance• Oxaliplatin: mandatory - stop before

tox!• Irinotecan: can be done

• 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

• 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 DREAMFrom OPTIMOX to DREAM

OPTIMOX-1

OPTIMOX-2

Efficacy =Toxicity

Efficacy = ?Toxicity =

DREAMBevacizumab

ErlotinibBevacizumab

No More “Lines” of TherapyNo 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

• 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

yes

yes

Re-evaluation of resectability

Observation

RRInduction Ctx (3-4 mos)

e.g. FOLF?? + BV

Maintenance

Re-Induction Ctx

“All 5 drugs”

no

Evaluation oftumor biology

CFI

Time, QOL