A Report from ASCO 2007 First-Line Metastatic Colorectal Cancer

A Report from ASCO 2007

First-Line Metastatic Colorectal Cancer

Edward Chu, MDProfessor, Medicine & PharmacologyChief, Section of Medical Oncology

Deputy Director, Yale Cancer CenterYale Cancer Center

Yale University School of MedicineNew Haven, CT

CRC Treatment Review

• Chemotherapy for advanced disease– Oral vs. IV 5-FU

– Sequential vs. combination

– Continuous vs. intermittent

• Targeted therapies– Anti-angiogenesis inhibitors

• Bevacizumab

– EGFR inhibitors

• Cetuximab

Chemotherapy for Advanced Disease

Abstract 4029

Efficacy and Safety from a Phase III, Randomized Study of Capecitabine plus

Oxaliplatin (XELOX) vs. Infusional 5-FU/LV plus Oxaliplatin (FOLFOX6) as First-Line

Treatment for Metastatic Colorectal CancerM. Ducreux, J. Bennouna, M. Hebbar, M. Ychou, G. Lledo,

T. Conroy, A. Adenis, R. Faroux, C. Rebischung, J. Douillard

Phase III Study of XELOX vs. FOLFOX6 as First-Line Treatment of mCRC

• Primary Endpoint: Non-inferiority of XELOX to FOLFOX on best RR• Secondary Endpoints: PFS; OS; Safety; QoL; Pharmacoeconomics

FOLFOX6 12 cycles(N = 150)

Metastatic/advancedcolorectal cancer,

previously untreatedby chemotherapy

(N = 306)

RANDOMIZE

XELOX 8 cycles(N = 156)

Ducreux M, et al. ASCO 2007. Abstract #4029.


Grade 3/4 Hematologic Toxicity



Clinical Activity

Response (%)

XELOX(N = 156)

FOLFOX6 (N = 150)

ORR (independent review) 42 46

ORR (investigator) 44 44

PFS 8.8 mos. 9.3 mos.

OS 19.9 mos. 20.5 mos.


Abstracts 4028 and 4030

Bevacizumab in Combination with XELOX or FOLFOX4: Updated Efficacy Results from

XELOX-1/NO16966, a Randomized Phase III Trial in First-Line Metastatic Colorectal Cancer

Abstract 4028: L. Saltz et al.Abstract 4030: J. Cassidy et al.

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-controlled design after bevacizumab

phase III data became available (N = 1,401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

Phase III NO16966 Trial: XELOX ± Bevacizumab vs. FOLFOX4 ± Bevacizumab


Study Objectives

• Main endpoint: progression-free survival (PFS)

• Two primary objectives– XELOX is non-inferior to FOLFOX– Bevacizumab + chemotherapy is superior to placebo +

chemotherapy

Saltz L, et al. ASCO 2007. Abstract #4028.Cassidy J, et al. ASCO 2007. Abstract #4030.

XELOX vs. FOLFOX: PFS 2-Arm Study Only (ITT)

FOLFOX N = 317; 294 events XELOX N = 317; 285 events

HR = 0.96 [97.5% CI: 0.80–1.16] (ITT)HR = 0.98 [97.5% CI: 0.81–1.18] (EPP)

1.0

0.8

0.6

0.4

0.2

0

Sur

viva

l

0 5 10 15 20 25 30

Months

7.77.3


XELOX/BV vs. FOLFOX/BV: PFS (ITT)

FOLFOX + bevacizumab N = 349; 255 events XELOX + bevacizumab N = 350; 258 events

HR = 1.01 [97.5% CI: 0.83–1.23] (ITT)HR = 1.04 [97.5% CI: 0.84–1.27] (EPP)

9.49.3

PFS

Est

imat

e

0 5 10 15 20 25Months

1.0

0.8

0.6

0.4

0.2

0


FOLFOX vs. XELOX: Safety ProfileFOLFOX (N = 649)

XELOX(N = 655)

Grade 3/4 AEs 78.3% 71.5%Diarrhea grade 3/4 11.2% 20.2%Neutropenia grade 3/4 43.8% 7.0%Febrile neutropenia grade 3/4 4.8% 0.9%Hand-foot syndrome grade 3 1.2% 6.1%Neurosensory toxicity grade 3/4 16.5% 17.4%Venous thromboembolic events grade 3/4 6.3% 3.8%Cardiac disorders grade 3/4 1.4% 0.9%

Discontinuations due to AE 24.8% 26.0%

All-cause 60-day mortality 2.3% 3.4%

Treatment-related mortality up to 28 days after last dose 1.7% 2.1%


XELOX vs. FOLFOX: Conclusions

• XELOX and FOLFOX are equivalent in terms of clinical efficacy (RR, PFS, and OS)

• Safety profiles of XELOX and FOLFOX are similar– Increased grade 3/4 myelosuppression and neutropenic fever

with FOLFOX– Increased incidence of hand-foot syndrome with XELOX

• XELOX should be considered a standard treatment option in first-line setting


Capecitabine-Based RegimensIssues to Consider

• What is the optimal dose of capecitabine when used in combination with oxaliplatin?– 1,000 mg/m2 bid 2 weeks on / 1 week off– Lower doses, 750-850 mg/m2 bid– Fixed dose

• What is the optimal schedule for capecitabine-based regimens?– 2 weeks on / 1 week off (every 3 weeks)– 1 week on / 1 week off (every 2 weeks)

Capecitabine Dosing U.S. vs Europe

• European trials – Capecitabine 1,000-1,250 mg/m2 bid (d1-14, q3w)

• United States trials – Capecitabine 1,250 mg/m2 bid dose too toxic (d1-14, q3w)– 1,000 mg/m2 bid more tolerable, but still toxic– Lower doses more tolerable in U.S. (850 mg/m2 bid)

• Reasons for discrepancy?– United States diet fortified with folic acid– Vitamin/nutritional supplements

• Folic acid exacerbates capecitabine toxicity– Pharmacogenetic differences in folate metabolism, DPD?– Other?

Abstract 4012

Sequential Compared to Combination Chemotherapy with Capecitabine, Irinotecan,

and Oxaliplatin in Advanced Colorectal Cancer: A Dutch Colorectal Caner Group (DCCG)

Phase III StudyC. J. Punt, M. Koopman, J. Douma, J. Wals, A. H. Honkoop, F. L. Erdkamp, R. S. de Jong, C. J. Rodenburg, L. Mol, N. F. Antonini

CAIRO Study Design

• Primary Endpoint: Survival• Secondary Endpoints: PFS, RR, Safety, QoL• Sample Size: 1,298 patients in 221 centers

CAPIRI(N = 378)

Capecitabine(N = 397)

mCRC No prior therapy

(N = 820)

CAPOX(N = 213)

Irinotecan(N = 251)

CAPOX(N = 143)

Punt CJ, et al. ASCO 2007. Abstract #4012.

CAIRO StudyClinical Efficacy

Combination Sequence P-value

OS (mos.) 17.4 16.3 n.s.

1-yr Survival 67% 64% n.s.

PFS (mos.) 7.8 5.8 0.0002

RR (%) 41% 20% < 0.0001


CAIRO StudyConclusions

• Median OS equivalent between sequential and combination strategies

• Highlights the role of effective salvage treatments in mCRC

• Sequential therapy is a reasonable treatment option for patients with mCRC– Consider in good risk patients– Role of biologics in improving clinical efficacy and maintaining

safety profile


Abstract 4013

Final Results of OPTIMOX2, a Randomized Phase II Study of Maintenance Therapy of Chemotherapy-Free Intervals (CFI) after

FOLFOX in Patients with Metastatic Colorectal Cancer

F. Maindrault-Goebel, G. Lledo, B. Chibaudel, L. Mineur, T. Andre, M. Bennamoun, M. Mabro, P. Artru, C. Louvet, A. de Gramont

OPTIMOX1 Study

Tournigand et al, JCO 2006.

6x FOLFOX7 → 12x sLV5FU2 → 6x FOLFOX7

FOLFOX4

620 pts

R

Cum. Oxaliplatin 780 1,560

(%) FOLFOX4 FOLFOX7

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

Primary endpoint

OPTIMOX Studies

OPTIMOX1

FOLFOX 4 until TF

FOLFOX7 FOLFOX7

sLV5FU2

OPTIMOX2

mFOLFOX7 mFOLFOX7

sLV5FU2

mFOLFOX7 mFOLFOX7

CFICFI: Chemotherapy-Free Interval

OPTIMOX2 StudyContinuous vs. Intermittent Chemotherapy

• mFOLFOX7: no bolus 5-FU, 100 mg/m2 oxaliplatin• Comparison: maintenance therapy vs. chemotherapy-

free intervals (CFI)• Primary endpoint: Duration of disease control (DDC) • Planned trial size, N = 600

– After bevacizumab approved downsized to a randomized phase II trial (N = 200)

Maindrault-Goebel F, et al. ASCO 2007. Abstract #4013.

FOLFOX Regimens

600600FOLFOX4

B 400FOLFOX6

2,400FOLFOX7

200B 400

85200

400100

2,400-3,000

400130

B 400

mFOLFOX7 400100

3,000


OPTIMOX2Clinical Efficacy

OPTIMOX

Maintenance5-FU/LV

Chemo-Free Interval P-value

RR (%) 60 61 n.s.

PFS (mo) 8.3 6.7 0.008

DDC (mo) 12.0 9.0 n.s.

OS (mo) 26.0 19.0 0.0549


OPTIMOX2Conclusions

• Stop-and-go with maintenance is associated with prolonged OS and DDC vs. chemotherapy-free interval

• Incidence of grade 3 neurotoxicity similar between 2 arms• Break in chemotherapy not recommended

– May consider for patients with “good” tumor biology – Role of biologics in maintenance strategy needs to be explored in

phase III trials (Dream Study)


Targeted Therapy

VEGF Inhibitors

Abstracts 4028 and 4030

Bevacizumab in Combination with XELOX or FOLFOX4: Updated Efficacy Results from

XELOX-1/NO16966, a Randomized Phase III Trial in First-Line Metastatic Colorectal Cancer

Abstract 4028: L. Saltz et al.Abstract 4030: J. Cassidy et al.

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-controlled design after bevacizumab

phase III data became available (N=1,401)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005


XELOX/BV vs. FOLFOX/BV: PFS (ITT)

FOLFOX + bevacizumab N = 349; 255 events XELOX + bevacizumab N = 350; 258 events

HR = 1.01 [97.5% CI: 0.83–1.23] (ITT)HR = 1.04 [97.5% CI: 0.84–1.27] (EPP)

9.49.3

PFS

Est

imat

e

0 5 10 15 20 25Months

1.0

0.8

0.6

0.4

0.2

0


XELOX vs. FOLFOX4 ± Bevacizumab Safety Profile

FOLFOX/XELOX + Placebo(N = 675)

FOLFOX/XELOX + Bevacizumab

(N = 694)

Grade 3/4 AEs 74.8% 80.0%

Gastrointestinal perforations grade 3/4 0.3% 0.6%

Bleeding grade 3/4 1.2% 1.9%

Arterial thromboembolic events grade 3/4 1.0% 1.7%

Hypertension grade 3/4 1.2% 3.7%

Proteinuria grade 3/4 – 0.6%

Wound-healing complication grade 3/4 0.3% 0.1%

Discontinuations due to AE 20.7% 30.7%

All-cause 60-day mortality 1.6% 2.0%

Treatment-related mortality up to 28 days after last dose 1.5% 2.0%


Effect of Bevacizumab on PFS

XELOX + Placebo(X+P)

FOLFOX-4 + Placebo(F+P)

XELOX + Bevacizumab(X+A)

FOLFOX-4 + Bevacizumab(F+A)

VS.

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

0 3 6 9 12 15 18 21Months

PFS

Est

imat

e

9.4 8.0

1.0

0.8

0.6

0.4

0.2

0

Effect of Bevacizumab on PFS XELOX and FOLFOX Subgroups

0 5 10 15 20 25

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

0

Months

PFS

Est

imat

e

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

Phase III NO16966 Trial Conclusions

• First study to show that XELOX and FOLFOX regimen are clinically equivalent

• Provides first evidence that bevacizumab confers clinical benefit to FOLFOX chemotherapy

• Safety profile in line with previous trial results in CRC• Supports the use of bevacizumab in combination with

standard first-line chemotherapy


Abstract 4027

Updated Results of BICC-C Study Comparing First-Line

Irinotecan/Fluoropymidine Combinations with or without Celecoxib in mCRC

C. Fuchs, J. Marshall, E. Mitchell, R. Wierzbicki, V. Ganju, M. Jeffery, J. Schultz, D. A. Richards, R. Soufi-Mahjoubi, J. Barrueco

Phase III Study of Three Irinotecan Regimens in First-Line mCRC (BICC-C)

Fuchs C, et al. ASCO 2007. Abstract #4027.

Original Design (Period 1: 2/03-4/04)

Irinotecan 180 mg/m2 D 1 q 2wk5-FU 400 mg/m2 (bolus) D1 q 2 wkLV 400 mg/m2 D 1 q 2 wk5-FU 400 mg/m2 bolus/2.4 g/m2 (46 hr infusion)D 1 q 2 wk ARM B: Modified Saltz

Irinotecan: 125 mg/m2

5-FU: 500 mg/m2

LV: 20 mg/m2 D 1, 8, q 3 wks

Irinotecan: 250 mg/m2 d1 q 3 wksCapecitabine: 1,000 mg/m2 bid d1-14 q 3 wks

± Celecoxib400 mg bid

N = 1,000 (430)

3 x 2 design

RANDOMIZATION



ARM A: FOLFIRI

ARM C: XELIRI

Phase III Study of Three Irinotecan Regimens in First-Line mCRC (BICC-C)

N = 1172 x 2 design Fuchs C, et al. ASCO 2007. Abstract #4027.

ARM B: Modified SaltzIFL + BV

This arm was discontinued

Amended Design (Period 2: 5/04-12/04)

ARM C: XELIRI


ARM A: FOLFIRI + BV± Celecoxib400 mg bid

RANDOMIZATION

BICC-C StudyClinical Efficacy

FOLFIRI +Bevacizumab

mIFL + Bevacizumab

P-value

Median PFS 11.2 mos. 8.3 mos. 0.28

Median OS Not reached 19.2 mos. 0.01

Fuchs C, et al. ASCO 2007. Abstract #4027.

BICC StudyUpdate on Clinical Efficacy

TTP(months)

OS(months)

FOLFIRI + BV≤ 65> 65

11.2 11.1

Not reached

FOLFIRI≤ 65> 65

7.6 7.5

24.3 20.1

Barrueco J, et al, ASCO 2007, Abstract #4076.

FOLFIRI + BV vs. FOLFOX + BVClinical Efficacy

FOLFIRI + BV

OS NR

PFS 11.2 mos.

RR 54%

FOLFOX + BV

21.3 / 26 mos.

9.4 / 9.9 mos.

47% / 53%

BICC-C Trial NO16966 / TREE-2 Trials

Bevacizumab TherapyConclusions

• Bevacizumab can be safely and effectively used in combination with 5-FU-, irinotecan-, and oxaliplatin-based chemotherapy for the first-line treatment of mCRC

• VEGF and the VEGF-signaling pathway are rational targets for anticancer therapy

• Agents in clinical development target the VEGF ligand, VEGF receptors, and VEGFR-TK

Bevacizumab Therapy Arterial Thromboembolic Events

Chemotherapy alone

Bevacizumab + Chemotherapy

Arterial TE events* 2.0% (15/741) 4.5% (45/1004)

• Risk factors for arterial thromboembolic events* included:– History of prior arterial thromboembolic events such as stroke or

heart attack– Age of 65 years or older

*Pooled analysis of 5 randomized trials

BevacizumabRecommendations

• Recommended dose is 5 mg/kg every 14 days as an IV infusion until disease progression

• Bevacizumab therapy should not be initiated for at least 28 days following surgery

• Bevacizumab should be permanently discontinued in patients who develop:– Gastrointestinal perforation– Wound dehiscence requiring medical intervention– Serious bleeding– Nephrotic syndrome– Hypertensive crisis

Bevacizumab TherapyIssues

• Should bevacizumab be continued at time of disease progression?

• What dose of bevacizumab should be used in second-line and disease refractory setting?

• What are the biomarkers of response to bevacizumab therapy?

Targeted Therapy

EGFR Inhibitors

Abstract 4000

Randomized Phase III Study of Irinotecan and 5-FU/FA with or without Cetuximab in the First-

Line Treatment of Patients with Metastatic Colorectal Cancer (mCRC): The CRYSTAL Trial

E. Van Cutsem, M. Nowacki, I. Lang, S. Cascinu, I. Shchepotin, J. Maurel, P. Rougier, D. Cunningham, J. Nippgen, C. Köhne

CRYSTAL TrialStudy Design

FOLFIRI q2w

FOLFIRI q2w + Cetuximab

mCRC EGFR positive

(N = 1,217)PFS

Primary Endpoint: PFSSecondary Endpoints: ORR, OS, QoL, Safety

Van Cutsem E, et al. ASCO 2007. Abstract #4000.

CRYSTAL TrialGrade 3/4 Toxicity

FOLFIRIN = 602, %

Cetuximab + FOLFIRIN = 600, %

Any 59.5 78.0

Neutropenia 23.3 26.7

Febrile neutropenia 2.2 2.7

Diarrhea 10.5 15.2

Vomiting 5.0 4.5

Fatigue 4.5 5.0

Skin reactions 0.2 18.7

Infusion-related reactions 0 2.3


Progression-Free Survival (months)

PFS

Est

imat

e

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]Log-rank P-value = 0.0479

8.9 mos.8.0 mos.

FOLFIRI (N = 608)Cetuximab + FOLFIRI (N = 609)

1-year PFS rate34% vs. 23%


CRYSTAL TrialProgression-Free Survival

FOLFIRI (N = 609)

Cetux + FOLFIRI(N = 608)

P-value

PFS 8.0 8.9 0.0479

PFS, grade 0/1 ST - 5.4 (N = 244)

PFS, grade 2 ST - 9.4 (N = 243)

PFS, grade 3 ST - 11.3 (N = 112)

ORR, % 38.7 46.9 0.0038

R0 resection, % 1.5 4.3 0.0034

R0, liver mets only, % 4.5 (N = 134) 9.8 (N = 122) -


CRYSTAL TrialClinical Efficacy

CRYSTAL Trial Surgery with Curative Intent

Liver Metasteses Only Population (exploratory)

4.5

9.8

0

2

4

6

8

10

12

No residual tumor in patients with liver metastases

N = 134 / N = 122

Per

cent

age

(%)


ITT Population (pre-planned)

2.5

1.5

6

4.3

0

1

2

3

4

5

6

7

Per

cent

age

(%)

P = 0.0034odds ratio = 3.0

Surgery with curative intent

N = 599

No residual tumor after resection

N = 599

Cetuximab + FOLFIRIFOLFIRI

CRYSTAL Trial Conclusions

• Cetuximab can be safely and effectively combined with FOLFIRI in the first-line setting

• Addition of cetuximab to FOLFIRI improves RR and PFS• Skin reactions correlate with clinical activity• Significant 3-fold increase in R0 resection rate for

patients with initially unresectable disease• QoL and biomarker analysis is ongoing• Cetuximab should be considered for first-line and

neoadjuvant therapy, esp. in liver-limited disease


Phase III CALGB/SWOG 80405 Trial First-Line mCRC

Primary endpoint: OSSecondary endpoint: PFS, RR

RANDOMI

Z ATION

FOLFOXFOLFIRI

N = 2,289 (600+ enrolled)

Bevacizumab + Cetuximab

Bevacizumab

Cetuximab

Anti-EGFR AbstractConclusions

• Cetuximab has been safely and effectively combined with irinotecan and oxaliplatin for first-, second-, and third-line treatment

• Cetuximab is a reasonable treatment alternative to bevacizumab in the first-line and neoadjuvant setting (liver-limited disease)

• CALGB/SWOG 80405 currently enrolling patients to confirm role of cetuximab, bevacizumab, and cetuximab/bevacizumab in first-line setting

• Panitumumab active in the disease refractory setting• Panitumumab can not be reasonably substituted for

cetuximab in combination with chemotherapy – Await further clinical studies

A Report from ASCO 2007 First-Line Metastatic Colorectal Cancer

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