challenging cases in cancer: integration of findings from asco 2007 colorectal cancer

Challenging Cases in Cancer:Integration of Findings from ASCO 2007

Colorectal Cancer

Metastatic Colorectal CancerAxel Grothey, MD

Senior Associate Consultant Division of Medical Oncology

Mayo Clinic College of MedicineRochester, MN

Case 3: First-line Colorectal Cancer

• Patient was treated with adjuvant 5-FU/LV after R hemicolectomy for T3N1M0 stage III colon cancer

• Two years later he relapses with rising CEA and 2 lung metastases plus 3 liver metastases

• He is treated with modified FOLFOX6 plus bevacizumab for 12-cycles (six months) but develops grade 3 neuropathy

• CT scan shows all lesions more than 50% smaller


• Which treatment option would you recommend? Continue therapy (unchanged) Hold all treatment until tumor progression Stop oxaliplatin and continue therapy with 5-FU/LV and

bevacizumab Stop oxaliplatin and continue therapy with bevacizumab

alone Switch therapy to an irinotecan-based regimen


• Which treatment option would you recommend? Continue therapy (unchanged) Hold all treatment until tumor progression Stop oxaliplatin and continue therapy with 5-FU/LV and

bevacizumab Stop oxaliplatin and continue therapy with bevacizumab

alone Switch therapy to an irinotecan-based regimen

• Recommended approach – Stop oxaliplatin and continue therapy with 5-FU/LV and

bevacizumab

Pertinent Issues for Case 3

• Metachronous metastases after 2-years to lung and liver– Should always consider resectability even with extrahepatic

disease• In this case situation it was deemed unresectable

• Good response to chemotherapy with FOLFOX + BEV, but grade 3 neurotoxicity after 12-cycles

• Should patient have a “chemo-holiday”?

Definition of “Chemo-Holiday”

• Stop of:– All medical therapy (chemo/biologics), no “maintenance”

(OPTIMOX2)

– Certain components of medical therapy, continuation of “chemo-light” (+/- biologics) (OPTIMOX1, CONcePT)

– Conventional chemotherapeutics, continuation of biologics (DREAM)

Definition of “Chemo-Holiday”

• Stop can occur:– After pre-defined number of cycles

– When “best response” is achieved

– When long-lasting SD has been documented

– When toxicity threshold is reached

• Restart/re-intensify therapy:– After pre-defined interval (OPTIMOX1, CONcePT)

– When “relevant” tumor progression noted (OPTIMOX2)

N9741: FOLFOX4 - TTP and TTF

0

10

20

30

40

50

60

70

80

90

100

0 12 18 24

% E

vent

-fre

e

TTP TTF

6

Time (mos)

9.3 mos

5.8 mos

Green et al., GI ASCO 2005

63% of pts stoppedFOLFOX for otherreasons than PD

OPTIMOX Studies

OPTIMOX-1N = 620

FOLFOX4 until TF

FOLFOX7 FOLFOX7

sLV5-FU2

OPTIMOX-2N = 202

mFOLFOX7 mFOLFOX7

sLV5-FU2

mFOLFOX7 mFOLFOX7

CFI

Tournigand et al, JCO 2006

Maindrault-Goebel et al, ASCO 2007 Abstract #4013

Stop and Go Concept - OPTIMOX1

Tournigand et al., JCO 2006

6x FOLFOX7- 12x sLV5-FU2 - 6x FOLFOX7

FOLFOX4

620 pts

R

Cum. Oxali 780 1,560

(%) 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

OPTIMOX2 - 5-FU/LV Maintenance vs Chemo-Free Intervals

MaintenanceN = 99

CFIN = 103

P

Initial RR (%) 60 59

RR reintro. (%) 21 25

PFS (wks) 36 29 0.08

DDC (wks) 52 39 0.39

OS (mos) 26 19 0.0549


0 10 20 30 40 50 60 70 80 90 100

0.0

0.2

0.4

0.6

0.8

1.0

36 weeks

29 weeks

Maintenance

CFI

P = 0.08

weeks

OPTIMOX2: Progression-free Survival


0 10 20 30 40 50

0.0

0.2

0.4

0.6

0.8

1.0

26 months

19 months

Maintenance

CFI

P = 0.0549

months

Lesson from OPTIMOX2: Don’t stop treatment before progression!

OPTIMOX2: Overall Survival


Take-home Messages OPTIMOX2

• A strategy with complete chemotherapy-free intervals (CFI) leads to inferior outcome compared to an induction-maintenance-reintroduction approach

• If PFS is the primary endpoint of your trial, do not stop treatment before progression (see NO16966)

• DDC is NOT an appropriate endpoint in CRC

In advanced CRC, the default treatment strategy should be “treatment to progression”

Recommendation for Case 3

• In palliative situation, goal of therapy is to extend duration and maintain the quality of life as long as possible

• Do not “waste” potentially active agents unnecessarily (no irinotecan here!)

• Maintenance therapy should be default position– Infusional 5-FU/LV + BEV or capecitabine + BEV should be

considered

– No role so far for BEV single agent as maintenance therapy


• 52-year-old healthy restaurant owner presents with increasing pain on bowel movement and complains of several weeks of diarrhea and weight loss of 10 pounds

– Finally cannot move bowels and begins to vomit

• CT scan shows 12 cm mass in the LLQ with multiple liver nodules and an elevated CEA level of 60 ng/mL

• GI evaluation with colonoscopy shows a nearly obstructing sigmoid mass – cannot pass scope – biopsy shows adenocarcinoma


• Undergoes sigmoid colon resection with primary anastomosis and a wedge biopsy of the left lobe of the liver

• Pathology reveals a mucinous adenocarcinoma of the sigmoid colon metastatic to lymph nodes and liver

• Now referred for consideration of chemotherapy


• Which chemotherapy would you recommend? 5-FU/LV or capecitabine FOLFOX CAPOX (XELOX) FOLFIRI IROX FOLFOXIRI


• Which targeted agent would you add? None Bevacizumab Cetuximab Panitumumab Bevacizumab + cetuximab Bevacizumab + panitumumab


• Which targeted agent would you add? None Bevacizumab Cetuximab Panitumumab Bevacizumab + cetuximab Bevacizumab + panitumumab

• Recommended approach– FOLFOX + bevacizumab or FOLFIRI + bevacizumab


• Palliative situation with unresectable, scattered liver metastases

• Symptomatic primary (obstruction) → resection of primary warranted

• What is optimal chemotherapy?

• And should a biologic be added upfront?

New Agents Have Significantly Improved Treatment and Patient Outcomes

RegimenFirst Line

Second Line

FDA-Approval Year

5-FU √ √ 1962

Irinotecan (monotherapy) √ 1996

IFL/irinotecan + infusional 5-FU/LV* √ 2000

Capecitabine (monotherapy) √ 2001

Oxaliplatin + infusional 5-FU/LV† √ √Second-line, 2002

First-line, 2004

Cetuximab (with or without irinotecan) √ 2004

Bevacizumab + IV 5-FU-based regimens‡ √ √First-line, 2004

Second-line 2006

Panitumumab (single agent) Salvage 2006

Modified from Venook A. Oncologist. 2005.

More regimens provide more options formultiple lines of therapy to extend survival

* FOLFIRI† FOLFOX‡ IFL, FOLFIRI, FOLFOX, and 5-FU/LV

NCCTG/Intergroup Trial N9741

IFL:Irinotecan +

5-FU/LV

IROX: Irinotecan + oxaliplatin

FOLFOX4: Oxaliplatin + 5-FU/LV

Goldberg et al., JCO 2004

795 patients

RANDOMIZATION

NCCTG/Intergroup Trial N9741Efficacy

Goldberg et al., JCO 2004

IFL FOLFOXP

P-value

OS 15.0 mo 19.5 mo 0.0001

TTP 6.9 mo 8.7 mo 0.0014

RR 31% 45% 0.002

Tournigand Trial (N = 220)

FOLFOXFOLFOX FOLFIRI FOLFIRI FOLFOXFOLFOX (1st line 2nd line) (1st line 2nd line)

N pts 111 69 109 81

RR 54% 4% 56%15%

Resection ofHepatic Metastases 21%21% 9%

PFS (mos) 8.1 2.5 8.5 4.2

Median OS (mos) 20.6 21.5 Tournigand et al., JCO 2004

2nd line:62%

2nd line:74%

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5,768 Patients

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5,768 Patients

OS (mos)=13.2 + (% 3 drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005

0 10 20 30 40 50 60 70 80

Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV

LV5-FU2

FOLFOXIRI

CAIRO

22

21

20

19

18

17

16

15

14

13

12

Med

ian

OS

(m

o)

Patients with 3 drugs (%)

P =.0001

First-Line Therapy

Multivariate analysis:Effect on OS P

First-line doublet 0.69All 3 drugs 0.005

2007

Murine Ab“momab”

ChimericMouse-Human Ab

“ximab”

Humanized Ab“zumab”

Fc

Fab

Human Ab“mumab”

Biologic Agents in Colorectal Cancer Monoclonal Antibodies

(17-1A) Cetuximab Matuzumab Bevacizumab

PanitumumabEGFR

VEGF

Cetuximab as Salvage Therapy for CRC

*P <0.05

Saltz 2001 Saltz 2002 Cunningham 2003

Phase II Phase II Rand. Phase II

Cetux. + CPT Cetux. Cetux. + CPT Cetux.

N 121 57 218 111

RR (%) 22.5 11 23* 11

RR+SD (%) 46 35 56* 32

Med. TTP (mos) -- -- 4.1* 1.5

Med. OS (mos) -- > 4 8.6 6.9

CRYSTAL Study (First-line)

FOLFIRI + Cetuximab

FOLFIRI

EGFR-expressingmetastatic CRC PFS

Stratified by:• Regions• ECOG PS

• Primary Endpoint: PFS (independent review)

• Secondary Endpoints: RR, DCR, OS, Safety, QoL

• Sample Size: 1,217 patients randomized, ITT: 1,198 pts

N = 599

N = 599

Van Cutsem et al., ASCO 2007 Abstract #4000

R

Progression-free survival time (months)

PF

S e

stim

ate

1.0

0.8

0.9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 2 4 6 8 10 12 14 16 18 20

HR = 0.851; 95% CI = [0.726-0.998]

Stratified log-rank P-value = 0.0479

8.9 mo

8.0 mo

FOLFIRI, N = 599

Cetuximab + FOLFIRI, N = 599

1-year PFS rate23% vs 34%

Subjects at risk

FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI

599 499 392 298 196 103 58 29 12 5 1

CRYSTAL Trial: Primary Endpoint PFS ITT Population Independent Review


CRYSTAL Trial:Independent Assessment of Response

CRYSTAL Trial:Independent Assessment of Response

38.7

46.9

0

10

20

30

40

50

60

Response rate

Pe

rce

nta

ge

(%

)

FOLFIRI alone, N = 599Cetuximab + FOLFIRI, N = 599

P-value* = 0.0038

FOLFIRI

%

Cetuximab

+ FOLFIRI

%

CR

PR

SD

PD

0.3

38.4

46.7

9.0

0.5

46.4

37.4

8.8

ORR95%CI

38.7[34.8 - 42.8]

46.9[42.9 - 51.0]

DCR** 85.5 84.3

*Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate Van Cutsem et al., ASCO 2007 Abstract #4000

CRYSTAL Trial:Subgroup Analysis of PFS Time by

On-study Skin Reactions: Cetuximab + FOLFIRI

Skin reaction grade 0 or 1, n=244

*There were no grade 4 skin reactions

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Progression-free survival time (months)

1.00

0.75

0.50

0.25

0.00

PF

S e

stim

ate

Skin reaction grade 2, n=243

Skin reaction grade 3*, n=112

11.3 mo5.4 mo 9.4 mo


KRAS Mutation Status Predictive of Response to Cetuximab?

Lievre et al., Cancer Res 2006

• 30 patients with CRC on cetuximab

• PR: 11/30 patients (37%)• KRAS mutation in

• 0/11 responders• 13/19 non-responders

(68%)• P = 0.0003

• Increased EGFR gene copy number in 10%

• significantly associated with response (P = 0.04)

16.3 mo

6.9 mo

Agents Targeting the VEGF PathwayAgents Targeting the VEGF Pathway

VEGFR-2VEGFR-1P

PPPP

PPP

Endothelial cellSmall-molecule

VEGFR inhibitors (Vatalanib, sunitinib, sorafenib)

Anti-VEGFR antibodies(IMC-1121b)

Soluble VEGF

receptors(VEGF-TRAP)

VEGF

Anti-VEGF antibodies

(bevacizumab)

Phase III Trial of Bevacizumab in MCRC: Efficacy

IFL+ Placebo (N = 411)

IFL+ Bevacizumab(N = 402)

P-value

Median survival (mo) 15.6 20.3 0.00004

PFS (mo) 6.2 10.6 < 0.00001

ORR (%)

CR

PR

35

2.2

32.5

45

3.7

41.2

0.0036

Duration of resp. (mo) 7.1 10.4 0.0014

Hurwitz et al., N Engl J Med 2004

Phase III Trial of IFL ± Bevacizumab in mCRC: Survival

Phase III Trial of IFL ± Bevacizumab in mCRC: Survival

HR = 0.66, P = 0.00004

Median survival: 15.6 vs. 20.3 mo

Duration of survival (mo)

Pro

port

ion

su

rviv

ing

0.2

200 10 30 400

0.8

1.0

0.4

0.6

Treatment Group

IFL + placeboIFL + bevacizumab

Hurwitz et al., N Engl J Med 2004

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 5 10 15 20 25 30

BICC-CPeriod 2: Overall Survival

BICC-CPeriod 2: Overall Survival

Pro

port

ion

of P

atie

nts

Who

Sur

vive

d

Survival Time (months)

RegimenMedian OS (Months)

1 YearHR

(95% CI)P-value

FOLFIRI+ BEV Not Reached 87% -- --

mIFL + BEV 19.2 61% 2.3(1.3,4.1)

0.007

mIFL + bevacizumab

FOLFIRI + bevacizumab

Fuchs et al., ASCO GI 2007

BICC-C: SummaryPeriod 1, no BEV Period 2, + BEV

EfficacyFOLFIRIN = 144

mIFLN = 141

CapIriN = 145

FOLFIRIN = 57

mIFLN = 60

RR (%) 46.6 41.9 38 57.9 53.3

PFS (mo) 7.6 5.9 5.8 11.2 8.3

OS 23.1 17.6 18.9 NR 19.2

G 3/4 (%)

Diarrhea 14 19 48 11 12

Dehydr. 6 7 19 5 2

MI/stroke 0.7 4.4 0 1.8 0

60d mort. 3.4 5.1 3.5 1.8 6.8

NR = not reachedFuchs et al., ASCO GI 2007

XELOX + placebo N = 350

FOLFOX4 + placebo N = 351

XELOX + bevacizumab

N = 350

FOLFOX4 + bevacizumab

N = 350

XELOX N = 317

FOLFOX4 N = 317

Initial 2-arm open-label study (N = 634)

Protocol amended to 2x2 placebo-controled design after bevacizumab phase III data1 became available (N = 1401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

XELOX vs FOLFOX ± Bevacizumab Roche NO16966 Study Design

1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy et al., ESMO 2006

0 5 10 15 20 25 30Months

PF

S e

stim

ate

PFS XELOX Non-inferiority: Primary Objective Met Based on ITT

HR = 1.04 [97.5% CI 0.93-1.16]

1.0

0.8

0.6

0.4

0.2

0

8.58.0

Upper limit ≤ 1.23 (non-inferiority margin)

FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N = 1017; 826 events

XELOX/XELOX+placebo/XELOX+bevacizumab N = 1017; 813 eventsCassidy et al., ESMO 2006

PFS Chemotherapy + Bevacizumab Superiority: Primary Objective Met

PFS Chemotherapy + Bevacizumab Superiority: Primary Objective Met

0 5 10 15 20 25

Months

PF

S e

stim

ate

HR = 0.83 [97.5% CI 0.72–0.95] (ITT)P = 0.0023

9.48.0

1.0

0.8

0.6

0.4

0.2

0

FOLFOX+placebo/XELOX+placebo N = 701; 547 events

FOLFOX+bevacizumab/XELOX+bevacizumab N = 699; 513 eventsCassidy et al., ESMO 2006

XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT)

P = 0.0026

9.37.4

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Months

PF

S e

stim

ate

XELOX+placebo N = 350; 270 events XELOX+bevacizumab N = 350; 258 events

FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT)

P = 0.1871

9.48.6

FOLFOX+placebo N = 351; 277 events FOLFOX+bevacizumab N = 349; 255 events

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25

Months

PFS Chemotherapy + Bevacizumab Superiority: XELOX and FOLFOX Subgroups

PFS Chemotherapy + Bevacizumab Superiority: XELOX and FOLFOX Subgroups

Cassidy et al., ESMO 2006

NO16966 Response Rate

Saltz et al., ASCO GI 2007

Chemo + Chemo placebo + Bev

FOLFOX+ FOLFOX

placebo + Bev

XELOX+ XELOX

placebo + Bev

Investigator

report

49% 47% 50% 47% 48% 46%

P = 0.90 P = 0.88 P = 0.91

IRC data38% 38% 36% 38% 39% 37%

P = 0.99 P = 0.49 P = 0.48

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!

NO16966 Study Drug Exposure – Median Months of Treatment

FOLFOX+Placebo

(N = 336)

FOLFOX+Bev

(N = 341)

XELOX+Placebo

(N = 339)

XELOX+Bev

(N = 353)

Oxaliplatin 6.0 6.0 5.5 5.8

Fluoropyrimidine 6.3 6.7 5.6 6.3

Placebo or Bev 6.3 6.0 5.5 6.0

* 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


NO16966 PFS Subgroup Analyses:On-treatment Population


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 + placeboFOLFOX4 +

placeboXELOX + Bev

FOLFOX4 + Bev

VS. VS.

XELOX Group FOLFOX Group

Su

rviv

al

1.0

0.8

0.6

0.4

0.2

00 100 200 300 400 500

Study day

1.0

0.8

0.6

0.4

0.2

00 100 200 300 400 500

Su

rviv

al

Study day

10.6 m8.4 m9.5 m7.0 m

Rationale for Combining EGFR- and Angiogenesis- Inhibitors

EGFR Inhibitors• Tumor cell growth • Synthesis of angiogenic

proteins

• Response of endothelial cells to angiogenic proteins

Tumor

Angiogenesis Inhibitors

Angiogenic proteinsbFGFVEGFTGF-

Endothelial cells

Herbst et al., J Clin Oncol. 2005;23:2544.

- - -

Targets

BOND-2 Trial - Efficacy (Historic Comparison with BOND-1)

BOND-1 BOND-2 BOND-1 BOND-2

Cetux.Cetux.+

BEVCetux.+

CPTCetux.+ CPT

+BEV

N pts 111 40 218 41

Previous Oxaliplatin (%) 64 90 62 85

RR (%) 11 20 23 37

TTP (mos) 1.5 5.6 4.1 7.9

Med. OS (mos) 6.9 10.2 8.6 18.0

Saltz et al., ASCO 2005; Lenz et al., ASCO GI 2007

PACCE Study SchemaPACCE: Panitumumab Advanced Colorectal Cancer Evaluation

Randomized, Open-Label, Controlled Phase 3b Trial

Stratification Factors: ECOG score, prior adjuvant Tx, disease site,Ox doses/Iri regimen, number of metastatic organs

Tumor assessments: Q12w until disease progression or intolerability

Panitumumab 6 mg/kg Q2W

Ox-CTBevacizumab

Ox-based CT(e.g., FOLFOX)

N = 800Inv choice

Iri-based CT(e.g., FOLFIRI)

N = 200Inv choice

Ox-CTBevacizumab

Panitumumab 6 mg/kg Q2W

Iri-CTBevacizumab

Iri-CTBevacizumab

RANDOMIZE

1:1

1:1

SCREENING

Hecht et al., World GI Barcelona 2007

Objective Response Rate By Cohort(Central Review)

pmab+ bev/Ox-CT(N = 407)

%

bev/Ox-CT(N = 405)

%

pmab+ bev/Iri-CT(N = 68)

%

bev/Iri-CT(N = 67)

%

Best ORR 39 41 38 31

Complete response 0 <1 0 0

Partial response 39 40 38 31

Stable disease 31 33 26 37

Progressive disease 6 4 9 4

Not done/Unevaluable* 24 22 26 27

ITT set*Included missing and unreadable scans

Oxaliplatin Irinotecan


Months

413 267 92 21 3

410 298 96 21 1

0 5 10 15 20

Pmab+bev/Ox-CT N

bev/Ox-CT N

Patients at risk:

Limited Update of PFS – Ox-CT Cohort(Central Review, Apr 2007 Data Cutoff)

# PFS events (%)

Median (95%CI), mos

206 (50) 9.0 (8.5-10.4)

172 (42) 10.5 (9.7-11.6)Pmab+bev/Ox-CT

Bev/Ox-CT

HR= 1.29 (95% CI: 1.05-1.58)

Pro

po

rtio

n P

rog

ress

ion

-Fre

e 100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

ITT set Hecht et al., World GI Barcelona 2007

73 10 076 6 0

407 318 194405 333 184

Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 4 8 12 16 20

Pmab+bev/Ox-CTbev/Ox-CT

Pts at risk:

413 342 224 85 9 0410 357 234 96 6 0

Pmab+bev/Ox-CTbev/Ox-CT

Months

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25Pts at risk:

Unplanned Interim OS (Ox-CT Cohort)

# OS events (%)

Median(95%CI), mos

127 (31) 18.6 (16.4- 20.6)

95 (23) NE

Pro

po

rtio

n A

liv

e

HR= 1.44 (95% CI: 1.10-1.88)

*Interpretation of statistical significance is limited by the lack of a prespecified significance boundary

Pmab+bev/Ox-CT

Bev/Ox-CT

HR= 1.56 (95% CI: 1.11-2.17)

Oct 2006 Data Cutoff* Apr 2007 Data Cutoff # OS events

(%)Median (95%CI),

mos

83 (20) 18.4 (13.8-NE)

58 (14) NE

Pro

po

rtio

n A

liv

e

Pmab+bev/Ox-CT

Bev/Ox-CT

NE = not estimatable; ITT set


PACCE: Grade 3/4 AEs of Interest(Ox-CT Cohort)

Pmab+bev/Ox-CT

(N = 401), %

bev/Ox-CT(N = 392), %

Gr 3 Gr 4 Gr 3 Gr 4

Skin toxicity 33 <1 1 0

Diarrhea 21 2 12 1

Dehydration 14 2 4 1

Hypokalemia 8 2 3 1

Hypomagnesemia 3 1 0 0

Neutropenia 12 10 17 7

Neuropathy 9 <1 10 <1

Nausea 10 0 4 <1

Infectionsa 16 2 7 2

Deep venous thrombosis 6 0 7 0

Pulmonary embolismb 0 6 0 4

MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0aGrade 5 infections occurred in 2 (1%) pmab + bev/Ox-CT pts and 3 (1%) bev/Ox-CT ptsbGrade 5 pulmonary embolism occurred in 2 (1%) pmab + bev/Ox-CT pts Hecht et al., World GI Barcelona 2007

CALGB/SWOG Intergroup Trial 80405CALGB/SWOG Intergroup Trial 80405

Bevacizumab

Cetuximab

Bevacizumab +Cetuximab

FOLFOXor FOLFIRI

“Dealer’s Choice”

R

N = 2,289 Primary endpoint: OSHR 1.25 (22 vs 27.5 months)

http://www.cancer.gov protocol ID CALGB-80405

http://www.cancer.gov/

Case 5: Previously Treated Colorectal Cancer

• Patient has metastatic colorectal cancer

• Has been treated with FOLFOX and bevacizumab for 4 months but now CEA is rising and CT scan shows new and increasing liver lesions


• Palliative situation with unresectable metastases

• Relatively short initial therapy with FOLFOX + BEV, tumor shows PD after 4 months

• Irinotecan-based regimen appropriate

• FOLFIRI or irinotecan-mono?

• Should a biologic be added right away or sequentially?

• If yes, which one?– Cetuximab (or panitumumab)?

– Bevacizumab?


• Which treatment option would you recommend? Irinotecan (or FOLFIRI) until progression followed by

irinotecan and cetuximab FOLFIRI or irinotecan + bevacizimab FOLFIRI or irinotecan + cetuximab FOLFIRI or irinotecan + bevacizumab and cetuximab


• Which treatment option would you recommend? Irinotecan (or FOLFIRI) until progression followed by

irinotecan and cetuximab FOLFIRI or irinotecan + bevacizimab FOLFIRI or irinotecan + cetuximab FOLFIRI or irinotecan + bevacizumab and cetuximab

• Recommended approach – FOLFIRI or irinotecan + cetuximab

NCIC CTG CO.17: Cetuximab vs. BSCProgression-free Survival

CETUXIMAB + BSCCETUXIMAB + BSCCENSOREDCENSORED

BSCBSCCENSOREDCENSORED

Pro

port

ion

Pro

gres

sion

-fre

eP

ropo

rtio

n P

rogr

essi

on-f

ree

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

MONTHSMONTHS

00 33 66 99 1212 1515

HR 0.68 (95% CI =0.57 – 0.80)

Stratified log rank P < 0.0001

Study armStudy arm Med PFS Med PFS (months)(months) 95% CI95% CI

Cetuximab + BSCCetuximab + BSC 1.91.9 1.8 – 2.11.8 – 2.1

BSC aloneBSC alone 1.81.8 1.8 – 1.91.8 – 1.9

Jonker et al., AACR 2007

CETUXIMAB + BSCCENSORED

BSCCENSORED

SUBJECTS AT RISK

CET+BSC 287 217 136 78 37 14 4 0 0 0

BSC 285 197 85 44 26 12 8 2 1 0

Pro

port

ion

Aliv

eP

ropo

rtio

n A

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHS

0 3 6 9 12 15 18 21 24 27

NCIC CTG CO.17: Overall Survival

HR 0.77 (95% CI =0.64 – 0.92)

Stratified log rank P = 0.0046

Study armStudy arm MS MS (months)(months) 95% CI95% CI

Cetuximab + BSCCetuximab + BSC 6.16.1 5.4 – 6.75.4 – 6.7

BSC aloneBSC alone 4.64.6 4.2 – 4.94.2 – 4.9

Jonker et al., AACR 2007

Eve

nt-f

ree

Pro

babi

lity

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization

0 8 16 24 32 40 48 56

Hazard ratio = 0.54 (95% CI: 0.44, 0.66)

Stratified log-rank testP < .000000001

Only a Subgroup of Patients Benefit From EGFR Targeted Therapy

Panitumumab vs. BSC: PFS

Panitumumab

BSC

Van Cutsem et al., JCO 2007

No diff. in OS (75% cross-over!)

EPIC Study (Second-line)

Irinotecan + Cetuximab

Irinotecan

Failure of Oxaliplatin-Based

TherapySurvival

Stratified by:Stratified by:• Study site Study site • ECOG PS (0 - 1, 2)ECOG PS (0 - 1, 2)

• Primary Endpoint: SurvivalPrimary Endpoint: Survival

• Secondary Endpoints: PFS, RR, DCR, Safety, QoLSecondary Endpoints: PFS, RR, DCR, Safety, QoL

• Sample Size: 1,298 patients in 221 centersSample Size: 1,298 patients in 221 centers

N = 648 N = 648

N = 650 N = 650

Sobrero et al., AACR 2007

R

EPIC Results

IrinotecanIrinotecan/ Cetuximab

P-value

RR (%) 4.2 16.4 < 0.0001

PFS (mos) 2.6 4 < 0.0001

OS (mos) 10 10.7 0.71

OS (mos) w/o post-study cetux.

6.2 10.2Exploratory

analysis!

50% cross-over to cetuximab!

Sobrero et al., AACR 2007

If We Cannot Increase First-line PFS, Why Does OS Increase?

10 months 17 months

1st PFS

OS 27 Months

• More effective use of all active agents?• Continuum of care…

• Use of EGFR-mAbs?

• Use of bevacizumab beyond PD?

Post-1st PD Survival

BBP(N = 642)

No BBP(N = 531)

No Post-PD Treatment(N = 253)

Evaluablepatients

(N = 1953)

1st Progression(N = 1445)

BRiTE:Total N = 1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo

Physician decision: no randomization

BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)

Grothey et al., ASCO 2007 Abstract #4036

BRiTE: Patient Outcome Based on Treatment Post 1st PD

BBP(N = 642)

No BBP(N = 531)

No Post-PD Treatment(N = 253)

# of deaths (%)168

(66%)306

(58%)260

(41%)

Median OS (mo) 12.6 19.9 31.8

1-yr OS rate (%) 52.5 77.3 87.7

OS after 1st PD (mo) 3.6 9.5 19.2


Limitations of the Analysis

• Patients were not randomized

• Actual administration dates for BV and CT not collected; missing BV and CT stop dates

• Potential bias that patients who survived longer had a greater potential to be treated with BBP

• Possibility of unmeasured factors that may have biased these results


SWOG/NCCTG/NCIC Second-line Trial: S0600/iBET (Intergroup BEV Continuation Trial)

(FOLF)IRI/CETUX

mCRC pretreated with FOLFOX + BEV or CAPOX + BEV orOPTIMOX + BEV

(FOLF)IRI/CETUX+ BEV 10 mg/kg

N = 1,260

Primary endpoint: OS (HR 1.30; 12 15.6 mos)

PIs: Phil Gold, Axel Grothey

(FOLF)IRI/CETUX+ BEV 5 mg/kg

Open since June 15

Treatm

ent Continuum

Patient Potentially Curable?

Induction Ctx (3-4 mos)e.g. FOLF?? + BEV/CETUX

Surgery with curative intent

“Adjuvant” Ctx

yes

Yes

yes

Re-evaluation of resectability

Observation

RR

Induction Ctx (3-4 mos)e.g. FOLF?? + BEV

Maintenance

Re-Induction Ctx

“All 5-drugs”

No

Evaluation oftumor biology

CFI ??

Time, QOL

Curative A

pproach

Conclusion

• Optimize treatment strategies, mainly in the palliative setting with the idea that we should keep patients on some sort of maintenance therapy

• Refined approaches in the adjuvant setting confirming the survival benefit at six years for a stage III patient with FOLFOX

• Proof of efficacy of a perioperative chemotherapy approach in resectable stage IV disease

Future Direction

• mTOR inhibitors

• Biomarker driven trials

• KRAS

• Tailored treatment approaches

challenging cases in cancer: integration of findings from asco 2007 colorectal cancer

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