A Report from ECCO 14 Oral Chemotherapy in Colorectal Cancer John L. Marshall, MD Chief, Division of...

A Report from ECCO 14

Oral Chemotherapy in Colorectal Cancer

John L. Marshall, MDChief, Division of Hematology/OncologyAssociate Director of Clinical Research

Director, Developmental Therapeutics and GI OncologyLombardi Comprehensive Cancer Center

Georgetown University Medical CenterWashington, DC

Capecitabine in the Treatment of Colorectal Cancer

• ECCO 2007 trials of capecitabine in colorectal cancer

– Oral vs. IV 5-FU

• Adjuvant: X-ACT Trial

• First-line metastatic: COFFEE Trial (SICOG)

– First-line metastatic CRC

• First BEAT Trial

• CAIRO2 (CAPOX-B ± cetuximab)

• CAIRO (sequential vs. combination chemotherapy)

• Novel Approaches (XELOXIRI)

– Second-line mCRC

– Capecitabine dosing

Capecitabine vs. IV 5-FU

ECCO 14 Abstract 1LB

5-Year Overall Survival Update from the X-ACT Trial of Capecitabine vs. 5-FU/LV as Adjuvant

Treatment for Stage III Colon Cancer

C. Twelves, W. Scheithauer, J. McKendrick, M. Nowacki, J. Seitz, G. Van Hazel, A. Wong, E. Diaz-Rubio, J. Cassidy

X-ACT Trial Design

1° endpoint: disease-free survival (DFS)

Chemo-naïve Dukes C,

resection ≤ 8 weeks

Capecitabine1250 mg/m2 twice daily, d 1-14, q21d

(N = 1004)

Bolus 5-FU/LV5-FU 425 mg/m2 plus

LV 20 mg/m2, d 1-5, q28d(N = 983)

24 weeks

Twelves C, et al. ECCO 14. Abstract 1LB.

Standard Eligibility Criteria

• Eligible patients

– Age 18–75 years

– Histologically confirmed Dukes’ C colon cancer

– Fully recovered after surgery

– ECOG PS: ≤1

– Life expectancy ≥ 5 years

• Excluded patients

– Metastatic disease

– Prior cytotoxic chemotherapy or organ allografts

– Clinically significant cardiac disease

– Severe renal impairment

– Central nervous system disorders

– Pregnant or lactating women


Previously Presented Primary Efficacy (ITT) and Safety Findings

At a median follow-up of 3.8 years

• DFS in the capecitabine group was at least equivalent to 5-FU/LV – HR = 0.87 (95% CI: 0.75–1.00)

• OS in the capecitabine group was at least equivalent to 5-FU/LV– HR = 0.84 (95% CI: 0.69–1.01)

• Capecitabine was associated with significantly fewer adverse events than 5-FU/LV (P < 0.001)

Twelves C et al. NEJM 2005;352:2696–704.

X-ACT Disease-Free Survival 5-year update – median follow-up 6.8 years (ITT)

Est

ima

ted

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0.0

0 6 42 48 78 96

Months

HR = 0.88 (95% CI: 0.77–1.01)NI margin 1.20

12 18 24 30 36 54 60 66 72 84 90

5-yearCapecitabine (N = 1 004) 60.8%5-FU/LV (N = 983) 56.7%

Test of non-inferiority P < 0.0001Test of superiority P = 0.0682


X-ACT Overall Survival 5-year update – median follow-up 6.8 years (ITT)

5-yearCapecitabine (N = 1 004) 71.4%5-FU/LV (N = 983) 68.4%1.0

0.8

0.6

0.4

0.2

0.0

0 6 42 48 78 9612 18 24 30 36 54 60 66 72 84 90

Est

imat

ed P

rob

abil

ity

Months

HR = 0.86 (95% CI: 0.74–1.01)NI margin 1.14

Test of non-inferiority P = 0.000116Test of superiority P = 0.06


5-year Overall Survival Subgroup Analysis

ITT population

MaleFemale

< 40 40–69 years old≥ 70

pN1pN2

Baseline CEA < ULNBaseline CEA > ULN

1987

1074912

761513396

1389593

1672155

N

Hazard Ratio and 95% CI

Favours Capecitabine

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Favours 5-FU


Multivariate Analysis of Overall Survival

FactorHazard Ratio 95% CI P-value

Age (years) 1.010 1.001–1.019 0.0238

Gender (female vs. male) 0.770 0.654–0.908 0.0018

Regional lymph nodes (PN1 vs. PN0, PN2, PNx) 0.577 0.489–0.682 < 0.0001

Baseline CEA (< vs. ≥ ULN) 0.401 0.320–0.503 < 0.0001

Time from surgery to randomisation (days) 1.004 0.997–1.012 0.2418

Treatment effect (capecitabine vs. 5-FU/LV) 0.828 0.705–0.971 0.0203


Treatment Duration and Intensity

Capecitabine(N = 995)

Bolus 5-FU/LV(N = 974)

Completed full course of treatment

84% 88%

Needed dose reduction 42% 44%

Needed dose reduction, interruption or delay

57% 52%


Safety Profile of Capecitabine vs. Bolus 5-FU/LV (All Grades)

*P < 0.001†Laboratory value

Treatment-related AEs

Capecitabine (N = 993)

Bolus 5-FU/LV (N = 974)

*

*

*

*

Diarrhea Stomatitis Hand-foot Neutropenia† Nausea / Alopeciasyndrome vomiting

100

80

60

40

20

0

*

*

Pat

ien

ts (

%)

Scheithauer W et al. Ann Oncol 2003;14:1735–43.

Systemic Treatments ( 2%) Given at Relapse

TreatmentCapecitabine(N = 1004)

5-FU/LV(N = 983)

5-FU 22% 20%

Oxaliplatin 15% 15%

Irinotecan 17% 19%

Capecitabine 5% 10%

Raltitrexed 2% 2%

Cetuximab 2% 2%


Locoregional Procedures ( 2%) at Relapse

Treatment or procedureCapecitabine(N = 1004)

5-FU/LV(N = 983)

Patients with 1 treatment, N 343 (34%) 350 (36%)

Radiotherapy 7% 8%

Partial hepatectomy 3% 4%

Laparotomy 3% 2%

Malignant tumour excision 2% 3%

Partial colectomy <1% 2%

Lobectomy (lung) 1% 2%


X-ACT and MOSAICOverall Survival in Stage III Patients (ITT)

Est

imat

ed P

rob

abil

ity

0 1 2 3 4 5 6 7 80.4

0.6

0.8

1.0

Years

X-ACTBolus 5-FU/LV (N = 983)

Capecitabine (N =1 004)

MOSAIC1

LV5FU2 (N = 675)

FOLFOX (N = 672)

1De Gramont A et al. J Clin Oncol 2007;25(18S):4007.


NO16968 Study Update

XELOX (N = 938)Capecitabine 1000mg/m2 bid d1–14 q3w

+ Oxaliplatin 130mg/m2 IV d1 q3w

5-FU/LV (N = 926)• Mayo Clinic bolus 5-FU/LV• Roswell Park bolus 5-FU/LV

Stage III Colon Cancer

• XELOX is feasible and safe

– Similar tolerability to bolus 5-FU/LV and FOLFOX4

– Better tolerability than FLOX

• Efficacy data are due at end of 2008

Schmoll H-J et al. J Clin Oncol 2007;25:102–9.

X-ACT 5-year Survival UpdateConclusions

• Capecitabine is known to be an effective and better tolerated alternative to bolus 5-FU/LV in the adjuvant treatment of stage III colon cancer

• Update shows that capecitabine is at least equivalent to bolus 5-FU/LV with a trend to superiority (P = 0.06) in terms of 5-year overall survival

• First indication in the adjuvant setting from a cross-trial comparison showing that capecitabine is equivalent to infusional 5-FU


ECCO 14 Abstract P#3044

Capecitabine or Folinic acid/Fluorouracil IV Bolus Plus Eloxatin Evaluation (COFFE trial) in

Metastatic Colorectal Carcinoma (MCRC): Final Results of the Southern Italy Cooperative Oncology Group (SICOG) Phase III Trial 0401

P. Comella, B. Massidda, G. Filippelli, A. Farris, D. Natale, L. Maiorino, G. Condemi, S. Palmeri, S. Leo, A. Gambardella

COFFEE Trial Study Design

• Primary Endpoint: Response rate (WHO criteria)• Secondary Endpoints: PFS, QoL

OXXELOxaliplatin 100 mg/m2 d1 +

Capecitabine 1,000 mg/m2 twice daily, d 1-11q 2-weeks (N = 150)

OXAFAFUOxaliplatin 85 mg/m2 d1 + Bolus 5-FU/FA

5-FU 850 mg/m2 + FA 250 mg/m2, d 2, q 2-weeks(N = 156)

mCRCPrior adjuvant therapy

(N = 306)to disease progression

Comella P, et al. ECCO 14. Abstract P#3044.

COFFEE Trial Baseline CharacteristicsOXAFAFU(N = 164)

OXXEL(N = 158)

Characteristic N % N %

Male/Female 89/75 54/46 104/54 66/34

Median age, years (range) 65 (37-79) 64 (39-84)

Age ≥ 70 years 64 39 51 32

ECOG PS:

0 99 60 96 61

1-2 65 40 62 39

Primary tumor site:

Colon 115 76 114 72

Rectal 49 24 44 28

Number of sites:

1 74 45 79 50

2 55 33 45 29

3+ 35 21 34 21

Previous surgery 125 76 114 72

Previous adjuvant chemotherapy 41 25 39 25


COFFEE Trial Treatment Disposition

OXAFAFU(N = 164)

OXXEL(N = 158)


Total number of cycles 1,272 1,243

Median cycles/patient (range) 8 (1-12) 8 (1-12)

Patients treated with:

≥ 4 cycles 145 88 140 89

≥ 8 cycles 95 58 96 61

≥ 12 cycles 46 28 44 28

Patients still on therapy 7 4 7 4

Patients off treatment for:

Protocol (CR, PD during treatment, or planned cycles)

110 67 100 63

Refusal 13 8 16 10

Toxicity 10 6 22 14

Disease complication 14 8 5 3

Physician’s decision 10 6 8 5


COFFEE Trial Hematologic Toxicity

0%

10%

20%

30%

40%

50%

OXAFAFU (N = 164)

OXXEL (N = 158)

% o

f P

atie

nts

27%

10%13%

6%

3% 4%1% 3%

Neutro

penia

Febrile

Neutro

penia

Throm

bocy

tope

nia

Anem

ia

P < 0.001

P < 0.043


COFFEE Trial Non-Hematologic AEs

0%

10%

20%

30%

40%

50%

OXAFAFU (N = 164)

OXXEL (N = 158)

% o

f P

atie

nts

Vomitin

g

Diarrh

ea

Stom

atitis

Fatigu

e

Neuro

logica

lHFS

Hepat

ic


COFFEE Trial Efficacy

OXAFAFU(N = 164)

OXXEL(N = 158)


Complete response 6 4 11 7

Partial response 48 29 42 27

Stable disease 57 35 57 36

Progression 37 22 29 18

Not assessed 16 10 19 11

Overall response rate, % (95% CI)

33 (25-41) 34 (26-42)


COFFEE Trial Progression-Free Survival


COFFEE Trial Conclusions

• OXXEL regimen produced a similar RR and PFS compared to OXAFAFU

– RR: 34% vs. 33%

– PFS: 6.2 mos. vs. 6.3 mos.

• Occurrence of severe adverse events was significantly lower with OXXEL regimen (32% vs. 43%)

– Although more patients went off therapy for toxicity in the OXXEL vs. OXAFAFU arm (14% vs. 6%)

• OXXEL regimen resulted in significantly lower incidence of severe neutropenia (10% vs. 27%) and febrile neutropenia (6% vs. 13%), but GI symptoms were significantly more pronounced

• These data provide additional support for capecitabine as an effective alternative to IV 5-FU/LV in the treatment of colorectal cancer


Capecitabine in First-Line Metastatic CRC


Preliminary Efficacy of Bevacizumab with First-Line FOLFOX, XELOX, FOLFIRI and

Fluoropyrimidines for mCRC: First BEAT Trial

S. Berry, D. Cunningham, M. Michael, A. Kretzschmar, F. Rivera, M. DiBartolomeo, M. Mazier, B. Lutiger, E. Van Cutsem

First BEAT Trial Study Design

• 1,965 mCRC patients from 41 countries – Accrued from June 2004 – February 2006

• First-line chemotherapy with bevacizumab until disease progression (physicians choice) – Bevacizumab at 5 mg/kg q2w for 5-FU-based CT

– Bevacizumab at 7.5 mg/kg q3w with capecitabine-based CT

• Regimens – FOLFOX (28%)

– FOLFIRI (26%)

– XELOX (18%)

– 5-FU/capecitabine (15%)

Berry S, et al. ECCO 14. Abstract P#3020.

First BEAT Trial Results

Regimen Median Progression-Free Survival (mos.)

Overall (1,110 events) 10.7

FOLFOX + Bev 10.6

XELOX + Bev 10.7

FOLFIRI + Bev 11.3

5-FU/Capecitabine + Bev 9.1

Berry S, et al. ECCO 14. Abstract P#3020.

• Median TTP 11.1 mos. (1,026 events)

• OS data immature; 614 patients died

ECCO 14 Abstract O#3000

Randomised Phase III Study of Capecitabine, Oxaliplatin and Bevacizumab (CAPOXB) with or without Cetuximab in Advanced Colorectal

Cancer (ACC), the CAIRO2 Study of the Dutch Colorectal Cancer Group (DCCG).

An Interim Safety Analysis J. Tol, M. Koopman, C.J. Rodenburg, A. Cats, G.J. Creemers,

C.A.M. de Swart, F.L.G. Erdkamp, L. Mol, N.F. Antonini, C.J.A. Punt

CAIRO2 Study Design

• Target Accrual: 755 patients• Efficacy results pending maturation of data

CAPOX-B + Cetuximab(N = 186)

Advanced CRC No prior therapy

(N = 381)

CAPOX-B(N = 195)

Tol J, et al. ECCO 14. Abstract P#3000.

CAIRO2 Study Interim Safety Analysis

Grade 3/4 Toxicity CAPOX-B

(N = 195)

CAPOX-B + Cetuximab

(N = 186)

Overall incidence 66% 76%

Hand-foot syndrome 12% 13%

Diarrhea 16% 23%

Vomiting 7% 6%

Febrile neutropenia 1% 0%

Hypertension 4% 2%

Cardiovascular events 4% 3%

Thrombembolic events 5% 7%

Allergic reactions 3% 6%

GI perforations 2% 1%

• None of these differences were statistically significantTol J, et al. ECCO 14. Abstract P#3000.


• Cetuximab associated toxicities (occurring only in the CAPOX-B + Cetuximab arm)– Acneiform skin reaction:

• Grade 3: 80%

• Grade 4: 20%

– Nail Changes• Grade 3: 27%

• Grade 4: 4%



• Conclusions:– Toxicity was acceptable in both arms– Except for skin toxicity, no difference in the incidence of other

grade 3/4 toxicities were observed between the two treatment arms

– Study is ongoing


Combination vs. Sequential Chemotherapy


Sequential Compared to Combination Chemotherapy with Capecitabine, Irinotecan,

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

Phase III Study

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

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)

Koopman M, et al. ECCO 14. Abstract O#3015.

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 is 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


Novel Chemotherapy Regimens


Capecitabine (C), in Combination with Irinotecan (I) and Oxaliplatin (O) (XELOXIRI)

as First-Line Treatment of Metastatic Colorectal Cancer (MCRC): Results of a Pilot Study by the Gruppo Oncologico Nord-Ovest

(G.O.N.O.) S. Bursi, G. Masi, F. Loupakis, A. Antonuzzo, S. Chiara, E. Pfanner,

I. Petrini, M. T. Barletta, G.G. Baldi, A. Falcone

XELOXIRI Study Design

• Phase I – Dose of C in combination with I and O (q 2wk regimen)

• Irinotecan: 165mg/m2 d1

• Oxaliplatin 85 mg/m2 d1

• Capecitabine 2,500 mg/m2/die d1-7; then, increase to 3,000 mg/m2/die or decrease to 2,000 mg/m2/die based on DLT

– Recommended dose of C was 2,000 mg/m2

• DLT: diarrhea

• Phase II– 36 patients– Endpoints: RR and toxicities

Bursi S, et al. ECCO 14. Abstract P#3063.

XELOXIRI Study Patient Characteristics


Patients N = 36 100%

Age, median (range) 65 (42-73)

Sex (M/F) 28/8 78%/22%

ECOG PS 0/1-2 32/4 89%/11%

Primary colon/rectum 26/10 72%/28%

Previous adjuvant CT 9 25%

Multiple sites of disease 18 50%

Liver involvement = 25% 16 44%

XELOXIRI Study Toxicity per Patient

Adverse Event Grade 1-2 Grade 3-4

Nausea 72% 3%

Diarrhea 53% 30%

Neutropenia 39% 28%*

Thrombocytopenia 31% 8%

Neurotoxicity 56% 6%

* Febrile neutropenia: 8% • 3 patients were hospitalized for febrile neutropenia and diarrhea and 1 died from sepsis


XELOXIRI Study Toxicity per Cycle

Adverse Event Grade 1-2 Grade 3-4

Nausea 29% --

Diarrhea 28% 5%

Neutropenia 26% 4%*

Thrombocytopenia 11% 1%

Neurotoxicity 32% 1%

* Febrile neutropenia: 1% • Dose reduction (% of cycles): capecitabine 30%; oxaliplatin 14%; irinotecan 37%


XELOXIRI Study Efficacy


N (35) %

Complete response 2 6%

Partial response 23 65%

Stable disease 8 23%

Progression 2 6%

• PFS: 13.9 mos. (12 events)

• OS: Not reached (10 events)

71%

XELOXIRI Study Conclusions

• XELOXIRI is feasible with grade 3/4 being the DLT• Recommended dose (q 2-weeks):

– Capecitabine 2,000 mg/m2/die d1-7– Irinotecan: 165mg/m2 d1– Oxaliplatin 85 mg/m2 d1

• At this dose, XELOXIRI is feasible with manageable toxicities but requires administration of a reduced dose intensity of capecitabine compared to XELOX or XELIRI

• Preliminary response rate is promising (RR: 71%)• This study is ongoing to better determine activity and

safety profile of the combination at the recommended dose


Capecitabine in Second-Line Metastatic CRC


Capecitabine + Oxaliplatin (XELOX) vs. 5-FU/LV + Oxaliplatin (FOLFOX4) as

Second-Line Treatment for Patients with Metastatic Colorectal Cancer (MCRC):

Phase III Trial Results

D. Cunningham, M. Rothenberg, M. Navarro, C. Butts, Y. Bang, J. Cox, R. Goel, S. Gollins, L. Siu

XELOX vs. FOLFOX4 Study Design

• Primary Endpoint: TTP, PFS, OS

XELOXCapecitabine 1,000 mg/m2 twice daily, d 1-14 +

Oxaliplatin 130 mg/m2 d1 q 3-weeks

FOLFOX4Oxaliplatin 85 mg/m2 d1 + LV 200 mg/m2

followed by 5-FU 400 mg/m2 bolus and 600 mg/m2 22-h infusion d 1-2

q 2-weeks

mCRC(N = 627)

Cunningham D, et al. ECCO 14. Abstract O#3012.

XELOX vs. FOLFOX4 Results

XELOX FOLFOX4 HR [95% CI]

PFS (PPP), mos. 5.1 5.5 1.03 [0.87-1.24]

PFS (ITT), mos. 4.7 4.8 0.97 [0.83-1.14]

OS (PPP), mos. 12.7 13.2 1.07 [0.88-1.31]

OS (ITT), mos. 11.9 12.6 1.03 [0.87-1.23]

Response rate 23% 20%

Response rate (independent review)

18% 14%

Grade 3/4 toxicity 60% 72%


XELOX vs. FOLFOX4 Conclusions

• Second-line treatment of mCRC with XELOX is non-inferior to FOLFOX4 in terms of PFS, OS, and RR

• Safety profile is similar between the two regimens with no unexpected toxicities– Grade 3/4 toxicities: 60% XELOX vs. 72% FOLFOX4– Consistent with previous studies


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?

Capecitabine in the Treatment of Colorectal Cancer

Closing Comments

John L. Marshall, MD

A Report from ECCO 14 Oral Chemotherapy in Colorectal Cancer John L. Marshall, MD Chief, Division of...

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