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Update of 2010 American Society of Clinical Oncology (ASCO) Annual Meeting: Gastrointestinal Malignancies. Michael F Driscoll, MD Chief Fellow Medical Oncology / Hematology JGBCC University of Louisville. An Update on Gastrointestinal Cancer: Overview.

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Update of 2010 American Society of Clinical Oncology (ASCO) Annual Meeting: Gastrointestinal Malignancies

Michael F Driscoll, MD

Chief Fellow

Medical Oncology / Hematology

JGBCC University of Louisville

an update on gastrointestinal cancer overview
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

crystal trial folfiri cetuximab study schema
CRYSTAL Trial FOLFIRI ± Cetuximab: Study Schema

FOLFIRI5-FU bolus 400 mg/m2, 46-hr infusion 2400 mg/m2 + Irinotecan 180 mg/m2 +Leucovorin 400 mg/m2every 2 wks

Patients with previously untreated EGFR-expressing metastatic colorectal cancer

(N = 1217)

FOLFIRI + Cetuximab5-FU bolus 400 mg/m2, 46-hr infusion 2400 mg/m2 + Irinotecan 180 mg/m2 +Leucovorin 400 mg/m2 every 2 wks +Cetuximab 400 mg/m2 initial dose, then 250 mg/m2 wkly

  • Patients stratified by region and ECOG performance score
  • Safety population: n = 1202
  • ITT population: n = 1998

Van Cutsem E, et al. ASCO 2008. Abstract 2.

crystal pfs in patients with the kras mutation
CRYSTAL: PFS in Patients With the KRAS Mutation

KRAS mutation (n = 192) HR: 1.07; P = .47

Cetuximab + FOLFIRI

1.0

FOLFIRI

0.9

Median PFS cetuximab + FOLIFIRI: 7.6 mos

0.8

Median PFS FOLIFIRI: 8.1 mos

0.7

0.6

PFS Estimate

0.5

0.4

0.3

0.2

0.1

0

0

2

4

6

8

10

12

14

16

Mos

Van Cutsem E, et al. ASCO 2008. Abstract 2.

crystal pfs in patients with wt kras
CRYSTAL: PFS in Patients With WT KRAS

WT KRAS (n = 348): HR: 0.68; P = .017

Cetuximab + FOLFIRI

1.0

FOLFIRI

0.9

Median PFS cetuximab + FOLIFIRI: 9.9 mos

0.8

Median PFS FOLIFIRI: 8.7 mos

0.7

1-yr PFS rate: 43%

0.6

PFS Estimate

0.5

0.4

0.3

1-yr PFS rate: 25%

0.2

0.1

0

0

2

4

6

8

10

12

14

16

18

Mos

Van Cutsem E, et al. ASCO 2008. Abstract 2.

kras status and efficacy of first line folfox cetuximab opus
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
OPUS: Results

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.

an update on gastrointestinal cancer overview1
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

crystal and opus objectives of pooled analysis
CRYSTAL and OPUS: Objectives of Pooled Analysis
  • Investigate the efficacy of cetuximab in KRAS wild-type tumors and according to BRAF status in patients with mCRC
    • 1063 (89%) evaluable samples from CRYSTAL
    • 315 (93%) evaluable samples from OPUS
  • Primary endpoints
    • CRYSTAL: PFS (by independent review)
    • OPUS: OR (by independent review)
  • Secondary endpoint OS in both trials

Bokemeyer C, et al. ASCO 2010. Abstract 3506.

crystal opus pooled analysis study design
CRYSTAL/OPUS Pooled Analysis:Study Design

Cetuximab + Chemotherapy

Treat until disease progression, symptomatic deterioration, or unacceptable toxicity

Patients with

EGFR-positive

mCRC

Chemotherapy

OPUS

FOLFOX4 (cycles given q2w)

Oxaliplatin 85 mg/m2 on Day 1

5-FU 400 mg/m2 bolus, then 600 mg/m2 on Days 1, 2 Leucovorin 200 mg/m2 on Day 1

Cetuximab 400 mg/m2 initial dose, then 250 mg/m2/wk

CRYSTAL

FOLFIRI (cycles given q2w)

Irinotecan 180 mg/m2 on Day 1

5-FU: 400 mg/m2 bolus, then 600 mg/m2 on Days 1, 2 Leucovorin 200 mg/m2 on Day 1

Cetuximab 400 mg/m2 initial dose, then 250 mg/m2/wk

pooled analysis of os by treatment group for patients with kras wt tumors
Pooled Analysis of OS by Treatment Group for Patients with KRAS WT Tumors

1.0

0.9

FOLFIRI/FOLFOX4 + cetuximab (n = 398) median 23.5 mosFOLFIRI/FOLFOX4: (n = 447) median 19.5 mos

0.8

0.7

0.6

HR: 0.81 (95% CI: 0.69-0.94; P = .0062)

Probability of OS

0.5

0.4

0.3

0.2

0.1

0

0

18

36

54

12

6

24

42

60

30

48

Mos

Patients, nCT + cetuximabCT

398447

356395

296313

246227

177159

128112

8367

6548

2118

42

00

Bokemeyer C, et al. ASCO 2010. Abstract 3506. Reprinted with permission.

pooled analysis of pfs by treatment group for patients with kras wt tumors
Pooled Analysis of PFS by Treatment group for Patients with KRAS WT Tumors

1.0

0.9

FOLFIRI/FOLFOX4 + cetuximab (n = 398) median 9.6 mosFOLFIRI/FOLFOX4: (n = 447) median 7.6 mos

0.8

0.7

0.6

HR: 0.66 (95% CI: 0.55-0.80; P < .0001)

Probability of PFS

0.5

0.4

0.3

0.2

0.1

0

0

12

4

8

20

16

Mos

Patients, nCT + cetuximabCT

398447

286298

154128

4624

94

10

Bokemeyer C, et al. ASCO 2010. Abstract 3506. Reprinted with permission.

crystal opus pooled analysis braf mutation associated with poor prognosis
CRYSTAL/OPUS Pooled Analysis:BRAF Mutation Associated With Poor Prognosis

*Odds ratio.

Bokemeyer C, et al. ASCO 2010. Abstract 3506. Reprinted with permission.

crystal opus pooled analysis conclusions
CRYSTAL/OPUS Pooled Analysis:Conclusions
  • Statistically significant improvements in OS, PFS, and response rate associated with adding cetuximab to standard chemotherapy for first-line treatment of patients with mCRC and wild-type KRAS
  • In patients with wild-type KRAS and BRAF mutation, addition of cetuximab to chemotherapy resulted in numeric improvement in OS, PFS, and response rate
  • Investigators concluded that based on results of this pooled analysis, BRAF mutation status cannot be used as relevant predictive marker for addition of cetuximab to chemotherapy in first-line treatment of mCRC
    • However, BRAF mutation prognostic of poor survival outcome

Bokemeyer C, et al. ASCO 2010. Abstract 3506.

an update on gastrointestinal cancer overview2
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

coin patient subsets with best responses to addition of cetuximab to ct
COIN: Patient Subsets With Best Responses to Addition of Cetuximab to CT

Continuous Chemotherapy

Administered until progression, toxicity, or patient choice

5-FU or Capecitabine + Oxaliplatin

(n = 815)

Patients

with

previously

untreated

advanced

CRC

Irinotecan-based

second-line

chemotherapy

Cetuximab + Continuous Chemotherapy

Administered until progression, toxicity, or patient choice

Cetuximab + 5-FU or Capecitabine + Oxaliplatin

(n = 815)

Regimens

OxFU administered q2w

I-folinic acid 175 mg

Oxaliplatin 85 mg/m2

5-FU 400 mg/m2 bolus, then 2400 mg/m2 over 46 hrs

OxCap administered q3w

Oxaliplatin 130 mg/m2

Capecitabine 1000 mg/m2 BID for 2 wks

Maughan TS, et al. ASCO 2010. Abstract 3502.

coin no significant difference in os pfs between treatment arms pt subsets
COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets

Maughan TS, et al. ASCO 2010. Abstract 3502.

coin prognostic effect of mutational status
COIN: Prognostic Effect of Mutational Status
  • Strong OS prognostic effect of KRAS, NRAS, and BRAF mutation status evident regardless of cetuximab use
    • Patients with wild-type KRAS have better prognosis vs mutated KRAS
    • Patients with mutated BRAF have the poorest prognosis

Chemotherapy

Chemotherapy + Cetuximab

12

Median PFS (Mos)

6

0

18

12

Median OS (Mos)

6

0

367

362

268

297

57

45

n =

289

292

340

815

366

815

Mutation Status

BRAF mutation

All patients

KRAS wild type

Any mutation

Maughan TS, et al. ASCO 2010. Abstract 3502. Reprinted with permission.

All wild type

KRAS mutation

coin conclusions
COIN: Conclusions
  • No improvement in OS or PFS with addition of cetuximab to oxaliplatin-based chemotherapy for first-line treatment of advanced CRC
    • Response rate improved among patients with wild-type KRAS tumors
  • KRAS, BRAF, and NRAS mutation status strongly prognostic regardless of cetuximab treatment
    • Patients with mutated BRAF had poorest prognosis
    • Patients with wild-type KRAS, BRAF, and NRAS had the best prognosis

Maughan TS, et al. ASCO 2010. Abstract 3502.

an update on gastrointestinal cancer overview3
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

n0147 adjuvant mfolfox cetuximab in resected stage iii colon cancer
N0147: Adjuvant mFOLFOX ± Cetuximab in Resected Stage III Colon Cancer

12 cycles

mFOLFOX6

Oxaliplatin 85 mg/m2 +

Leucovorin 400 mg/m2 +

5-FU 2400 mg/m2

(infused over 46 hrs) q2w

(n = 1283)

Patients with

stage III colon cancer

(N = 2581)

mFOLFOX6 + Cetuximab

400 mg/m2 loading dose then 250 mg/m2 on Days 1, 8

(n = 1298)

Goldberg RM, et al. ASCO 2010. Abstract 3508.

n0147 duration of therapy shorter with cetuximab addition vs mfolfox6 alone
N0147:Duration of Therapy Shorter With Cetuximab Addition vs mFOLFOX6 Alone

Wild-Type KRAS

Mutant KRAS

Goldberg RM, et al. ASCO 2010. Abstract 3508. Reprinted with permission.

trend toward improved dfs os with mfolfox6 vs mfolfox6 cetuximab
Trend Toward Improved DFS, OS With mFOLFOX6 vs mFOLFOX6 + Cetuximab

Goldberg RM, et al. ASCO 2010. Abstract 3508.

pts with mutant kras more likely to have disease progression or death
Pts With Mutant KRAS More Likely to Have Disease Progression or Death

Goldberg RM, et al. ASCO 2010. Abstract 3508.

n0147 targeting egfr in stage iii colorectal cancer
N0147:Targeting EGFR in Stage III Colorectal Cancer
  • Cetuximab does not improve adjuvant chemotherapy for rates of DFS and OS in resected stage III colon cancer
    • Increased toxicity
  • KRAS mutation associated with poor prognosis vs wild-type KRAS
  • EGFR-targeted antibodies likely not feasible as part of adjuvant regimens for stage III colon cancer

Goldberg RM, et al. ASCO 2010. Abstract 3508.

prognostic and or predictive value of kras in crc
Prognostic and/or Predictive Value of KRAS in CRC

1. Bokemeyer C, et al. J Clin Oncol. 2009;27:663-671. 2. Van Cutsem E, et al. N Engl J Med. 2009;360:1408-1417. 3. Amado RG, et al. J Clin Oncol. 2008;26:1626-1634.4. Douillard J, et al. ASCO 2010. Abstract 3528. 5. Andreyev HJ, et al. J Natl Cancer Inst. 1998;90:675-684. 6. Andreyev HJ, et al. Br J Cancer. 2001;85:692-696. 7. Richman SD, et al. J Clin Oncol. 2009;27:5931-5937. 8. Maughan TS, et al. ASCO 2010. Abstract 3502. 9. Goldberg RM, et al. ASCO 2010. Abstract 3508. 10. Karapetis CS, et al. N Engl J Med. 2008;359:1757-1765. 11. Tol J, et al. N Engl J Med. 2009;360:563-572. 12. Hecht JR, et al. J Clin Oncol. 2009;27:672-680.

  • Predictive of treatment response
    • Anti-EGFR antibodies not beneficial in patients with KRAS mutations[1-4]
  • Prognostic of outcome
    • Yes: RASCAL,[5,6] FOCUS,[7] COIN,[8] N0147[9]
    • No: cetuximab and panitumumab monotherapy trials,[3,10] CAIRO-2,[11] PACCE[12]
      • Maybe: CRYSTAL[2]
an update on gastrointestinal cancer overview4
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

macro maintenance bev vs continued bev xelox in patients with mcrc
MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC

XELOX + Bevacizumab

(n = 239)

Induction

Therapy

XELOX +

Bevacizumab

6 cycles

Disease progression, severe toxicity, or consent withdrawal

Patients with

previously

untreated mCRC

(N = 480)

Bevacizumab

(n = 241)

Maintenance cycles administered q3w:

Oxaliplatin 130 mg/m2 IV on Day 1

Capecitabine 1000 mg/m2 BID PO on Days 1-14

Bevacizumab 7.5 mg/kg IV on Day 1

Tabernero J, et al. ASCO 2010. Abstract 3501.

macro duration of pfs comparable between bev vs xelox bev
MACRO: Duration of PFS Comparable Between Bev vs XELOX + Bev

*Median follow-up: 20.4-21.1 mos.

  • No significant difference between treatment arms in any efficacy outcome
  • Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed
    • The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32

Tabernero J, et al. ASCO 2010. Abstract 3501.

macro conclusions
MACRO: Conclusions
  • After bevacizumab + XELOX induction therapy for patients with mCRC, maintenance bevacizumab comparable to continued bevacizumab + XELOX
    • No significant difference in any efficacy outcome between arms
  • Single-agent bevacizumab may be a feasible option for patients receiving bevacizumab + XELOX as induction therapy

Tabernero J, et al. ASCO 2010. Abstract 3501.

an update on gastrointestinal cancer overview5
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

prime first line panitumumab folfox4 vs folfox4 in mcrc
PRIME: First-line Panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

Stratified by

ECOG PS (0-1 vs 2) and geographic region

Panitumumab 6.0 mg/kg every 2 wks + FOLFOX4

(n = 593)

Patients with previously untreated

mCRC

(N = 1183)

FOLFOX4

(n = 590)

FOLFOX4 (cycles given q2w)

Oxaliplatin 85 mg/m2 on Day 1

5-FU 400 mg/m2 bolus, then 600 mg/m2 on Days 1, 2 Leucovorin 200 mg/m2 on Day 1

Douillard J, et al. ASCO 2010. Abstract 3528.

prime pfs os by kras status
PRIME: PFS, OS by KRAS Status

Douillard J, et al. ASCO 2010. Abstract 3528.

prime exploratory analysis efficacy of panitumumab folfox4 by skin toxicity
PRIME Exploratory Analysis: Efficacy of Panitumumab + FOLFOX4 by Skin Toxicity

*Landmark analysis of patients with PFS duration ≥ 28 days.

Douillard J, et al. ASCO 2010. Abstract 3528.

prime conclusions
PRIME: Conclusions
  • In patients with previously untreated mCRC receiving panitumumab + FOLFOX4, grade 2-4 skin toxicity associated with significantly longer PFS and OS vs grade 0/1 skin toxicity, regardless of KRAS mutationstatus
  • Panitumumab + FOLFOX4 associated with significantly improved PFS in patients with KRAS wild-type tumors, significantly worse PFS in patients with KRAS-mutated tumors
    • Similar trends in OS; no differences in objective response rate between groups

Douillard J, et al. ASCO 2010. Abstract 3528.

an update on gastrointestinal cancer overview6
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

nasbp protocol c10
NASBP Protocol C10
  • 74% of patients with stage IV CRC not eligible for curable resection
    • Asymptomatic primary tumor present in 75% of those patients
  • Study evaluated intact primary tumor-related morbidity in patients with stage IV CRC with asymptomatic primary tumor receiving mFOLFOX6 plus bevacizumab who have not undergone resection
  • Primary endpoint
    • Primary tumor events requiring surgery
      • Bleeding
      • Perforation or fistula formation
      • Obstruction
    • Primary tumor events leading to death

McCahill LE, et al. ASCO 2010. Abstract 3527.

nasbp protocol c10 low rate of tumor events requiring surgery
NASBP Protocol C10: Low Rate of Tumor Events Requiring Surgery
  • 10 patients (11.6%) required surgery
      • Obstruction: n = 8
      • Perforation: n = 1
      • Pain: n = 1
  • 2 patients (2.3%) died
      • Perforation: n = 1
      • Obstruction: n = 1
  • At Month 24, estimated cumulative incidence of major morbidity associated with intact primary tumor: 16.3% (95% CI: 7.6% to 25.1%)

McCahill LE, et al. ASCO 2010. Abstract 3527.

nasbp protocol c10 conclusions
NASBP Protocol C10: Conclusions

In patients with unresectable stage IV colorectal cancer with an asymptomatic primary tumor, treatment with mFOLFOX6 plus bevacizumab associated with a low rate of primary tumor events requiring surgery or leading to death

Median OS: 19.9 mos

Low rate of primary events (13.9%) suggests these patients can be spared initial noncurative resection of primary tumor

McCahill LE, et al. ASCO 2010. Abstract 3527.

an update on gastrointestinal cancer overview7
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

prodige 4 accord 11 trial design
PRODIGE 4/ACCORD 11 Trial Design

RANDOMIZE

for both arms:

FOLFIRINOX (n = 171)

CT scans: obtained every 2 mons

Patients with metastaticpancreaticcancer

(N = 342)

6 mos of chemotherapy recommended

Gemcitabine

(n = 171)

Stratified by

  • Center
  • Performance score 0 vs 1
  • Location of the tumor: head vs other location of the primary

Conroy T, et al. ASCO 2010. Abstract 4010. Reprinted with permission.

prodige 4 accord 11 progression free survival
PRODIGE 4/ACCORD 11: Progression-Free Survival

Median PFS, Mos

6.4

3.3

1.00

FOLFIRINOX

Gemcitabine

0.75

HR: 0.47 (95% CI: 0.37-0.59; P < .0001)

Probability

0.50

0.25

0

0

3

6

9

12

15

18

21

24

27

30

33

36

Mos

Patients at Risk, nGemcitabineFOLFIRINOX

171171

88121

2685

842

517

27

04

01

01

Conroy T, et al. ASCO 2010. Abstract 4010.

prodige 4 accord 11 overall survival
PRODIGE 4/ACCORD 11: Overall Survival

Median OS, Mos

11.1

6.8

1.00

FOLFIRINOX

Gemcitabine

0.75

HR: 0.57 (95% CI: 0.45-0.73)

Stratified log rank test P < .0001

Probability

0.50

0.25

0

0

3

6

9

12

15

18

21

24

27

30

33

36

Mos

Patients at Risk, nGemcitabineFOLFIRINOX

171171

134146

89116

4881

2862

1434

720

613

39

35

23

22

22

Conroy T, et al. ASCO 2010. Abstract 4010.

prodige 4 accord 11 safety
PRODIGE 4/ACCORD 11: Safety

Conroy T, et al. ASCO 2010. Abstract 4010.

prodige 4 accord 11 conclusions
PRODIGE 4/ACCORD 11: Conclusions
  • In patients with metastatic pancreatic cancer FOLFIRINOX associated with significant improvements in PFS and OS vs gemcitabine
    • Median OS: 11.1 mos; reduced risk of disease progression by 53%
  • FOLFIRINOX associated with significantly increased incidence of adverse events, although significantly (P = .001) delays QoL degradation vs gemcitabine
  • Investigators asserted that FOLFIRINOX potential new standard of care in this setting

Conroy T, et al. ASCO 2010. Abstract 4010.

an update on gastrointestinal cancer overview8
An Update on Gastrointestinal Cancer: Overview

CRYSTAL/OPUS pooled analysis investigating the efficacy of cetuximab in KRAS wild-type tumors in patients with mCRC

COIN: identification of patients with strongest responses to cetuximab + CT

N0147: adjuvant mFOLFOX ± cetuximab in resected stage III colon cancer

MACRO: maintenance Bev vs continued Bev + XELOX in mCRC

PRIME: first-line panitumumab + FOLFOX4 vs FOLFOX4 in mCRC

NASBP Protocol C10: evaluation of patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection

PRODIGE 4/ACCORD 11: FOLFIRINOX vs gemcitabine as first-line treatment for metastatic pancreatic cancer

Phase II randomized comparison of modified DCF vs DCF in metastatic gastric cancer

phase ii randomized comparison of modified dcf vs dcf
Phase II Randomized Comparison of Modified DCF vs DCF

To develop a DCF-like regimen that is more tolerable than parent DCF, to which a targeted agent could be safely added

Modified DCF

(n = 56)

Patients with previously untreated metastatic gastric/GEJ adenocarcinoma

(N = 87)

R

DCF + G-CSF

(n = 31)

Stratified by

  • GEJ/gastric
  • Measurable/nonmeasurable

Shah MA, et al. ASCO 2010. Abstract 4014.

modified dcf vs dcf treatment arms
Modified DCF vs DCF: Treatment Arms

Shah MA, et al. ASCO 2010. Abstract 4014.

modified dcf vs dcf overall survival
Modified DCF vs DCF: Overall Survival

1.00

Median follow-up: 10.3 mos

0.75

Modified DCF

DCF + G-CSF

0.50

Fraction Surviving

0.25

12.6 mos

15.1 mos

0

15

20

30

35

0

5

10

25

Mos

Shah MA, et al. ASCO 2010. Abstract 4014.

modified dcf vs dcf time to treatment failure
Modified DCF vs DCF: Time to Treatment Failure

1.00

Median follow-up: 10.3 mos

0.75

Modified DCF

DCF + G-CSF

0.50

Fraction Without Treatment Failure

0.25

5.9 mos

8.6 mos

0

7.5

10.0

15.0

22.5

0

2.5

5.0

12.5

20.0

17.5

Mos

Shah MA, et al. ASCO 2010. Abstract 4014.

modified dcf vs dcf grade 3 4 toxicity
Modified DCF vs DCF: Grade 3/4 Toxicity

Shah MA, et al. ASCO 2010. Abstract 4014.

modified dcf vs dcf conclusions
Modified DCF vs DCF: Conclusions
  • Modified DCF vs DCF plus G-CSF
    • Comparable OS and time to treatment failure
    • Modified DCF had improved toxicity profile vs DCF + G-CSF
  • Modified DCF feasible 3-drug regimen for metastatic gastric cancer

Shah MA, et al. ASCO 2010. Abstract 4014.

summary
Summary
  • CRYSTAL/OPUS pooled analysis: cetuximab plus chemotherapy associated with significant improvements in OS, PFS, and response rate in patients with mCRC and KRAS wild-type tumors
    • BRAF mutation not predictive of response to cetuximab plus chemotherapy, but is prognostic of poor survival outcome
  • COIN: no improvement in OS or PFS with addition of cetuximab to oxaliplatin-based chemotherapy previously untreated advanced CRC
    • KRAS, BRAF, and NRAS mutation status strongly prognostic; those with mutated BRAF had poorest prognosis
summary1
Summary
  • N0147: adjuvant mFOLFOX + cetuximab does not improve rates of DFS, OS in resected stage III colon cancer vs mFOLFOX
  • MACRO: after bevacizumab + XELOX induction therapy for patients with mCRC, maintenance bevacizumab comparable to continued bevacizumab + XELOX
  • PRIME: in patients with mCRC, first-line panitumumab + FOLFOX4 associated with significantly improved PFS in patients with KRAS wild-type tumors, significantly worse PFS in patients with KRAS-mutated tumors vs FOLFOX4
    • Grade 2-4 skin toxicity associated with significantly longer PFS and OS vs grade 0/1 skin toxicity, regardless of KRAS mutationstatus
summary2
Summary
  • NASBP Protocol C10: in patients with stage IV CRC and asymptomatic primary tumors receiving mFOLFOX6 plus Bev without resection, low rate of primary events suggests these patients can be spared initial noncurative resection of primary tumor
  • PRODIGE 4/ACCORD 11: FOLFIRINOX associated with significant improvements in PFS, OS and increased incidence of AEs vs gemcitabine as first-line treatment for metastatic pancreatic cancer
  • Phase II randomized comparison of modified DCF vs DCF demonstrated comparable OS and time to treatment failure in metastatic gastric cancer
    • Modified DCF had improved toxicity profile vs DCF + G-CSF
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