Best of ASCO Colorectal & Pancreatic Cancers

Best of ASCO – Colorectal & Pancreatic Cancers

Best of ASCOColorectal & Pancreatic Cancers

Ali Shamseddine, MDProfessor of Medicine

Head of Hematology/Oncology DivisionAmerican University of Beirut Medical Center


Adjuvant Chemotherapy in Colorectal Cancer


Survival Results of NSABP C-07

FULV5-FU 500 m2 IV bolus weekly x 6 +

LV 500 mg/m2 IV weekly x 6 of each 8-week cycle x 3

(n = 1209)

FLOX FULV + Oxaliplatin 85 mg/m2 IV on

Weeks 1, 3, and 5 of each 8-week cycle x 3

(n = 1200)

Patients with stage II or III carcinoma of the colon

stratified by number of positive lymph nodes

(N = 2409)

Wolmark N, et al. ASCO 2008. Abstract LBA4005.

Primary endpoint: DFS


C-07: Disease-Free Survival

3-Year DFS 5-Year DFS

FLOX (n = 1200)

76.1% 69.4% P = .002

HR: 0.81 (95% CI: 0.70-0.93)

FULV (n = 1209)

71.5% 64.2%

∆ 4.6% 5.2%



C-07: Overall Survival

Deaths, n 3-Year OS 5-Year OS

FLOX (n = 1200)

259 80.3% 77.7% P = .06

HR: 0.85 (95% CI: 0.72-1.01)

FULV (n = 1209)

301 78.3% 73.5%

∆ 42 2.0% 4.2%



Initial Safety Report of NSABP C-08

Arm AmFOLFOX6 every 2 wks x 12 doses

(n = 1356)

Arm B: mFOLFOX6 + Bevacizumab

5 mg/kg every 2 wks x 26 doses (n = 1354)

Patients with stage II or III colon adenocarcinoma

with ECOG performance score of 0/11(N = 2710)

Patients were stratified by the number of positive lymph nodes and were randomized between Days 29 and 50 postoperatively

mFOLFOX6 regimen: leucovorin 400 mg/m2 IV, 5-FU 400 mg/m2 IV, 5-FU 2400 mg/m2 over 46 hrs; oxaliplatin 85 mg/m2 IV

Primary endpoint: DFSAllegra CJ, et al. ASCO 2008. Abstract 4006.


C-08: Grade 3/4 Toxicities Significantly Increased With BevacizumabAdverse Event mFOLFOX, % mFOLFOX +

Bevacizumab,%P Value

Hypertension 1.8 12.0* < .0001

Any pain 6.3 11.1 < .0001

Proteinuria 0.8 2.7 < .0001

Wound complications

0.3 1.7† < .0001

Allegra CJ, et al. ASCO 2008. Abstract 4006.

*5 patients had grade 4 hypertension.†All grade 3.

Median time on study: 22.4 months No significant increases in GI perforation, hemorrhage, arterial, or venous thrombotic

events, or deaths have been observed with the addition of bevacizumab


Metastatic Colorectal Cancer


CONcePT Trial Design

Grothey A, et al. ASCO 2008. Abstract 4010.

*Treat to failure. †8 cycles with oxaliplatin, 8 cycles without oxaliplatin, 8 cycles with oxaliplatin.

Patients with metastatic

colorectal cancer

(N = 140)

Continuous Oxaliplatin*mFOLFOX7 + Bevacizumab +

Placebo(n = 34)

Continuous Oxaliplatin*mFOLFOX7 + Bevacizumab +

Ca2+/Mg2+

(n = 35)

Intermittent Oxaliplatin†

mFOLFOX7 + Bevacizumab +Placebo(n = 36)

Intermittent Oxaliplatin†

mFOLFOX7 + Bevacizumab +Ca2+/Mg2+

(n = 35)


CONcePT: Treat-to-Failure

Treat-to-failure

– Continuous oxaliplatin (CO): 4.2 months (95% CI: 3.7-5.5)

– Intermittent oxaliplatin (IO): 5.6 months (95% CI: 4.7-7.0)

Unstratified (IO relative to CO): P = .002*

Stratified by CaMg (IO relative to CO): P = .003*


*Log-rank test.


CONcePT: Progression-Free Survival

Treat-to-failure

– Continuous oxaliplatin (CO): 7.3 months (95% CI: 6.9-NE)

– Intermittent oxaliplatin (IO): 12.0 months (95% CI: 8.2-NE)

Unstratified (IO relative to CO): P = .044*

Stratified by CaMg (IO relative to CO): P = .030*


*Log-rank test.


Clinical practice*: Hepatic metastasectomy in patients with liver disease only

Cassidy, et al. ASCO 2008 (poster)*BEAT: largest prospective trial with a predefined analysis for resectability (non-randomised study)

n=107 n=71 n=33

15.2

20.3

14.3

n=85

12.1

n=54

15.5

n=27

11.7

25

20

15

10

5

0

Pat

ien

ts (

%)

Hepatic metastasectomy with no residual disease (R0)Hepatic metastasectomy

Avastin + CTx All

(n=704)

Avastin + CTxIncluding oxaliplatin

(n=349)

Avastin + CTxIncluding irinotecan

(n=230)


Clinical practice*: Significant improvement in 2-year OS for patients who underwent hepatic metastasectomy with R0 resection

*BEAT (non-randomised study) OS = overall survival Cassidy, et al. ASCO 2008 (poster)

1.00

0.75

0.50

0.25

0

OS

est

imat

e

0 5 10 15 20 25 30Months

Hepatic metastasectomy and R0 resection (n=114)

Hepatic metastasectomy total (n=145)

No hepatic metastasectomy (n=1,791)

p<0.001

47%

89%

86%


FDG-PET Improves Selection of Patients With CRC Liver Metastases

Wiering B, et al. ASCO 2008. Abstract 4004.

CT imaging only

(n = 75)

CT imaging + FDG-PET(n = 75)

Patients with colorectal cancer liver metastases

selected for surgical treatment by imaging

with CT scan

(N = 150)

Laparotomy

Laparotomy

Excluded by PET

Findings at laparotomy

and F/U

Findings at laparotomy

and F/U

Patients were followed for at least 3 yrs for OS and DFS–No standard chemotherapy was given postoperatively


Primary endpoint: futile laparotomies, defined as a laparotomy that

– Did not result in complete tumor treatment

– Revealed benign disease

– Did not result in DFS longer than 6 months

Secondary endpoint: OS and DFS

FDG-PET Improves Selection of Patients With CRC Liver Metastases



Number of futile laparotomies was reduced from 45% to 28%

Addition of FDG-PET to the workup for surgical resection of colorectal liver metastases prevents unnecessary surgery in 1 out of 6 patients

No significant differences in OS or DFS were noted in the first 3 yrs of follow-up

FDG-PET in CRC Liver Metastases: Conclusions



KRAS Status and Efficacy in Metastatic Colorectal Cancer


KRAS Status and Efficacy of First-Line FOLFOX ± Cetuximab: OPUS Genomic DNA was isolated from archived tumor material

KRAS mutation status of codons 12/13 was determined using a sensitive, quantitative PCR-based assay

Population with tissue available for KRAS analysis (n = 233) was representative of overall ITT population (n = 337) in terms of demographics and efficacy parameters

KRAS mutations detected in 42% (99/233) of evaluable samples

Bokemeyer C, et al. ASCO 2008. Abstract 4000.


OPUS: Results

KRAS Status

Median PFS Cetuximab + FOLFOX,

Mos

Median PFS

FOLFOX, mos

HR (P Value)

Overall RR Cetuximab + FOLFOX,

%

Overall RR FOLFOX, %

P Value

WT 7.7 (n = 61) 7.2 (n = 73) 0.57 (.02) 61 37 .01

Mutation 5.5 (n = 52) 8.6 (n = 47) 1.83 (.02) 33 49 .11

PFS and Response Rates by KRAS Mutation Status

The benefit from addition of cetuximab to standard treatment is higher forthe population with WT KRAS

No benefit could be shown of adding cetuximab to FOLFOX for patients with KRAS mutations

Bokemeyer C, et al. ASCO 2008. Abstract 4000.


OPUS: PFS according to K-Ras statusPFS – K-Ras mutant PFS – K-Ras wild-type

Progression-free time (months)

Kap

lan

-Mei

er

esti

ma

te

0 2 4 6 8 10 12 0 2 4 6 8 10 12

Cetuximab + FOLFOX

FOLFOX

Cetuximab + FOLFOX

FOLFOX

K-Ras mutant: HR=1.83; p=0.0192 Cetuximab + FOLFOX: 5.5 monthsFOLFOX: 8.6 months

Kap

lan

-Mei

er

esti

ma

te

Progression-free time (months)

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

K-Ras wild-type: HR=0.57; p=0.016 Cetuximab + FOLFOX: 7.7 monthsFOLFOX: 7.2 months

Bokemeyer, et al. ASCO 2008


KRAS and Efficacy of Irinotecan and Cetuximab in mCRC: EVEREST

Patients with irinotecan-refractory metastatic

cancer

Cetuximab 400 mg/m2 initial dose then

250 mg/m2/wk + Irinotecan 180 mg/m2

Q2W

Control Standard Cetuximab

regimen (250 mg/m2/wk)

(n = 23)

Dose Escalation Cetuximab dose

increasesof 50 mg/m2 Q2W up to

maximum 500 mg/m2/wk

(n = 31)

Nonrandomized Standard Cetuximab

regimen (250 mg/m2/wk)

SCREENING

Day 22

Randomized:skin toxicity grade 0/1

Not eligible for randomization:

skin toxicity grade 2/3 All patients continued to receive

irinotecan Treatment until progression,

unacceptable toxicity or withdrawal of consent

Skin and tumor biopsy at baseline, Week 3, and at maximum cetuximab dose in dose-escalation arm

Tejpar S, et al. ASCO 2008. Abstract 4001.


EVEREST: PFS (ITT Population)

0

0.2

0.4

0.6

0.8

1.0

0 200 400 600Days

PF

S E

stim

ate

800

P < .0001

KRAS mutant

WT KRAS

KRAS mutation present

83 days (95% CI: 75.9-90.2)

173 days (95% CI: 141.3-204.7)

Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.


EVEREST: PFS by Treatment Group and KRAS Status

0.0

0.2

0.4

0.6

0.8

1.0

0 200 400 600 800

0.0

0.2

0.4

0.6

0.8

1.0

0 200 400 600 800

0.0

0.2

0.4

0.6

0.8

1.0

0 200 400 600 800

Days Days Days

KRAS mutantWT KRAS

ControlKRAS mutation present

P = .014

KRAS mutantWT KRAS

Dose EscalationKRAS mutation present

KRAS mutantWT KRAS

NonrandomizedKRAS mutation present

P < .001 P = .020

Tejpar S, et al. ASCO 2008. Abstract 4001. Reproduced with permission.

PF

S

Est

ima

te

PF

S

Est

ima

te

PF

S

Est

ima

te


Pancreatic Cancer


Treatment of Advanced Pancreatic Cancer

Targeted Therapy beyond ErlotinibTreatment of Gemcitabine-Refractory Disease


Primary endpoint = overall survival

Stratified according to country, KPS (<80 vs ≥80), albumin level (<2.9g/dL vs ≥2.9g/dL)

PD

PDPreviously untreated metastatic

pancreatic cancer(n=600)

Tarceva (100mg) +gemcitabine +

Avastin (5mg/kg every 2 weeks)

Tarceva (100mg) +gemcitabine +

placebo

KPS = Karnofsky performance statusPD = progressive disease

AVITA: study design


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 3 6 9 12 15 18 21 24

Ove

rall

surv

ival

pro

bab

ility

Time (months)

7.16.0

HR=0.89, p=0.2087 (95% CI: 0.74–1.07)

Gemcitabine + Tarceva + Avastin (n=221 with events)

Gemcitabine + Tarceva (n=233 with events)

Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I):214s (Abs. 4507)

AVITA: overall survival


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

PF

S p

rob

abili

ty

HR=0.73, p=0.0002(95% CI: 0.61–0.86)

4.63.6

Vervenne W, Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl. 15 Pt I):214s (Abs. 4507)

PFS = progression-free survival

Gemcitabine + Tarceva + Avastin (n=257 with events)

Gemcitabine + Tarceva (n=278 with events)

0 3 6 9 12 15 18 21 24Time (months)

AVITA: PFS

Best of ASCO Colorectal & Pancreatic Cancers

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