Randomized phase III study of capecitabine, oxaliplatin and

bevacizumab with or without cetuximab in advanced colorectal cancer

CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG)

CJA Punt, J Tol, CJ Rodenburg, A Cats, GJ Creemers, JG Schrama, FLG Erdkamp, A Vos, L Mol, NF Antonini

Treatment of advanced colorectal cancer (CRC)

• Fluoropyrimidine-based chemotherapy plus the VEGF antibody bevacizumab is currently considered as the standard 1st line treatment

• Cetuximab is a chimaeric monoclonal antibody against the epidermal growth factor receptor (EGFR) which has shown efficacy as a single agent and in combination with chemotherapy

Background

• VEGF and EGFR share common downstream signaling pathways, and preclinical models have shown additive effects for VEGF and EGFR inhibition

• In irinotecan-resistant CRC the combination of irinotecan, cetuximab, and bevacizumab (BOND2 study)1 was feasible and suggested greater efficacy compared to irinotecan + cetuximab (BOND study)2

• Therefore, targeting both VEGF and EGFR in CRC appears a promising strategy and warrants evaluation in a prospective study

1 Saltz et al. J Clin Oncol 20072 Cunningham NEngl J Med 2004

Study design CAIRO2

Arm A Arm B

Randomization

CapecitabineOxaliplatin

Bevacizumab

CapecitabineOxaliplatin

BevacizumabCetuximab

Endpoints

• Primary endpoint

progression-free survival

• Secondary endpoints

overall survival, response rate, toxicity,

translational research

Statistical design

• Study was designed to detect a difference in median progression-free survival of 3 months (11m 14m) (HR 0.79), power 80%, =0.05, 2- tailed test

• Stratification parameters- prior adjuvant chemotherapy- serum LDH- number of affected organs- institution

• Histologically proven colorectal cancer

• Advanced disease not amenable to curative surgery

• Measurable disease parameters

• No previous systemic treatment for advanced disease

• Previous adjuvant chemotherapy should be completed 6 months prior to randomization

• Age 18 years

• WHO performance score 0-1

• Adequate hepatic, bone marrow, and renal function

• No therapeutic dose of anticoagulant drugs

• No significant cardiovascular or other disease

Main inclusion criteria

Dose and scheduleall cycles given 3-weekly

Arm ACycle 1-6:

• oxaliplatin 130 mg/m² day 1

• capecitabine 1000 mg/m² b.i.d. day 1-14

• bevacizumab 7.5 mg/kg day 1Cycle ≥ 7:

• capecitabine 1250 mg/m² b.i.d. day 1-14

• bevacizumab 7.5 mg/kg day 1

Arm B

• oxaliplatin, capecitabine, bevacizumab: as in arm A

• cetuximab weekly 250 mg/m² (400 mg/m² 1st dose)

Evaluation of response

• Evaluation of tumor response every 3 cycles (RECIST)

• Evaluation of toxicity prior to each cycle (NCI-CTC criteria, version 3.0)

• Central review was performed of all patient files when death occurred ≤ 30 days of the last administration of study drugs and which was accompanied by any other event than disease progression, irrespective of the causality reported for this event

• All serious adverse events and results of central review were submitted to the IDMC

Accrual

• Participation of 79 Dutch hospitals

• 755 patients were randomized between June 2005 and December 2006

• 736 patients were eligible

• 731 patients received ≥ 1 treatment cycle

• Median duration of follow-up 18.7 months

Arm A Arm B

n = 368 n = 368

Age, median (range) 62 (27-83) 62 (33-80)

Gender * male

female

56%

44%

64%

36%

Prior adjuvant treatment 15% 15%

Serum LDH normal

abnormal

57%

43%

56%

44%

Number of organs affected 1

> 1

45%

55%

44%

56%

WHO performance status 0 59% 66%

* p = 0.035

Baseline characteristics

Arm A Arm B p value

n = 368 n = 368

Median PFS (months)

(HR; 95% CI)

10.7

(9.7-12.5)

9.6

(8.5-10.7)

0.018

(1.21;1.03-1.45)

Median OS (months)

(HR; 95% CI)

20.4

(18.1-26.1)

20.3

(17.9-21.6)

0.21

(1.15;0.93-1.43)

Response rate

(CR + PR)44% 44% 0.88

Disease control rate

(CR + PR + SD)83% 81% 0.39

Efficacy results

Results were confirmed in the subgroup of patients with EGFR+ tumors

0 6 12 18 24 30Months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n f

ree

surv

ival

pro

bab

ility

Arm A (without cetuximab)

Arm B (with cetuximab)

Arm A (without cetuximab) 10.7 months (9.7-12.5) Arm B (with cetuximab) 9.6 months (8.5-10.7)

Progression-free survival

Hazard ratio for progression 1.21

p value 0.018

0 6 12 18 24 30Months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Ove

rall

surv

ival

pro

bab

ility

Arm A (without cetuximab)

Arm B (with cetuximab)

Overall survival

Arm A (without cetuximab) 20.4 months (18.1-26.1) Arm B (with cetuximab) 20.3 months (17.9-21.6)

Hazard ratio for survival 1.15

p value 0.21

Arm A

n = 366

Arm B

n = 365

p value

All grade 3-4 72% 82% 0.0013

Skin toxicity excluded

(except HFS)72% 75% 0.37

Hematological toxicity 2% 2% 0.99

Diarrhea 19% 26% 0.026

Vomiting 9% 6% 0.20

Hand-foot syndrome 19% 19% 0.98

Neurotoxicity 10% 8% 0.37

GI perforation 0.3% 1.4% 0.10

Venous thromboembolic events

7% 8% 0.66

Toxicity (grade 3-4)

Arm A

n = 366

Arm B

n = 365

All grade acneiform skin reactions 4% 84%*

Grade 3 acneiform skin reactions 0.5% 25%*

All grade nail changes 13% 32%*

Grade 3 nail changes 0.3% 4%*

* p<0.001

Skin toxicity associated with cetuximab

Arm A

n = 368

Arm B

n = 368

Deaths ≤ 30 days of last treatment (any cause)

18 (5%) 18 (5%)

Treatment related 4 (1%) 2 (0.5%)

- GI perforation 3 1

- respiratory insufficiency 1

- neutropenic fever 1

60-day mortality 7 (1.9%) 9 (2.4%)

Mortality

Arm A

n = 366

Arm B

n = 365p value

Number of cycles (range) median 10 (1-39) 9 (1-40) 0.02

mean

12.0 10.6

Reasons for treatment discontinuation

- disease progression including death 53% 50% 0.32

- toxicity 27% 32% 0.22

- secondary metastasectomy 5% 5%

- patient refusal 7% 6%

- other 8% 7%

Treatment characteristics

Arm B (with cetuximab): skin grade 3 (n=104)

Arm B (with cetuximab): skin grade 0-1 (n=109)Arm B (with cetuximab): skin grade 2 (n=152)

PFS according to skin toxicity

Arm B grade 0-1 vs 2 vs 3: p ≤ 0.01

0 6 12 18 24 30months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

pro

gre

ss

ion

su

rviv

al

pro

ba

bil

ity

Arm B (with cetuximab): skin grade 0-1 (N=111)Arm B (with cetuximab): skin grade 2 (n=152)

Arm B (with cetuximab): skin grade 3 (N=102)

Arm A (without cetuximab): overall (N=366)

Arm B (with cetuximab): skin grade 0-1 (n=109)Arm B (with cetuximab): skin grade 2 (n=152)Arm B (with cetuximab): skin grade 3 (n=104)

Arm A (without cetuximab): overall (n=366)

PFS according to skin toxicity

Arm A vs arm B grade 0-1: p < 0.0001

Wildtype

n = 305 (61%)

Mutation

n = 196 (39%)

Arm A 152 (50%) 103 (53%)

Arm B 153 (50%) 93 (47%)

Genotyping by Q-PCR - based assay

No difference in baseline characteristics between patients with KRAS wildtype and mutation (except higher serum LDH in wildtype)

No correlation between KRAS status and cetuximab-related skin toxicity

KRAS genotyping (n=501)

Wildtype

n = 305 (61%)

Mutation

n = 196 (39%)p value

Arm A 152 (50%) 103 (53%)

Arm B 153 (50%) 93 (47%)

Median PFS (months)

Arm A 10.7 12.5 0.92

Arm B 10.5 8.6 0.47

p value 0.10 0.043

KRAS genotyping (n=501)

0 6 12 18 24 30months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Pro

gre

ssio

n f

ree

surv

ival

pro

bab

ility

KRAS and PFS

Arm A (without cetuximab); KRAS mutantArm B (with cetuximab); KRAS mutantArm A (without cetuximab); KRAS wildtypeArm B (with cetuximab); KRAS wildtype

Wildtype

n = 305 (61%)

Mutation

n = 196 (39%)p value

Arm A 152 (50%) 103 (53%)

Arm B 153 (50%) 93 (47%)

Median OS (months)

Arm A 23.0 24.9 0.90

Arm B 22.2 19.1 0.52

p value 0.49 0.35

KRAS genotyping (n=501)

Conclusions - I

• The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab results in a significantly decreased progression-free survival, without affecting overall survival

• The addition of cetuximab to chemotherapy and bevacizumab results in a significant increase of skin toxicity and diarrhea, however the toxicity is acceptable in both treatment arms

• The grade of cetuximab-related skin toxicity significantly correlates with PFS

• The results of cetuximab are not significantly influenced by KRAS status

• In patients with KRAS mutation the addition of cetuximab to chemotherapy and bevacizumab results in a significant decrease in PFS

• Toxicity as a reason for discontinuation of treatment does not significantly differ between treatment arms, therefore a negative interaction between anti-VEGF and anti-EGFR antibodies cannot be excluded

Conclusions - II

DCCG CAIRO2 study - acknowledgementsInvestigators: C. Smorenburg, Alkmaar; R.Hoekstra, Almelo; C.Rodenburg, Amersfoort; J.van der Hoeven, Amstelveen; A.Cats, M.Geenen, C. van Groeningen, D.Richel, B.de Valk, N.Weijl, Amsterdam; J.Douma, Arnhem; P.Nieboer,Assen; F.Valster, Bergen op Zoom; R.Rietbroek, Beverwijk; A.Ten Tije, Blaricum; O.Loosveld, Breda; D.Kehrer, Capelle a/d IJssel; M.Bos, Delft; Z.Erjavec,Delfzijl; H.Sinnige, C.Knibbeler, Den Bosch; W.Van Deijk, F.Jeurissen, H.Sleeboom Den Haag; H.de Jong, Den Helder; A.Imholz, Deventer; E.Muller, Doetinchem; J. vanden Bosch,Dordrecht; S.Hovenga, Drachten; E.Balk, Ede; G.Creemers, M.Dercksen, Eindhoven; M.Legdeur, Enschede; A.Smals, Geldrop; H.van Halteren, Goes; M. van Hennik, Gorinchem; A.van der Torren, Gouda; G.Hospers, R.de Jong, Groningen; G.de Klerk, Haarlem; P.Zoon, Harderwijk; J.Wals, Heerlen; V.Derleyn, Helmond; H.Dankbaar, Hengelo; S.Luyckx, Hilversum; C. de Swart, Hoofddorp; J.Haasjes, Hoogeveen; W.Meijer, Hoorn; M.Polee, Leeuwarden;M.Tesselaar, Leiden; H.Oosterkamp,Leidschendam; J.Bollen, Lelystad; R.Jansen, Maastricht; P. van der Velden, Middelharnis; P.Slee, Nieuwegein; C.Punt, C.Mandigers, Nijmegen; A.Vos, Oss; M.den Boer, Roermond; D. de Gooyer, Roosendaal; A.Planting, A.vander Gaast, J.Pegels, T.Kok, F.de Jongh, Rotterdam; J.Braun, Schiedam; F.Erdkamp, Sittard; G.Veldhuis, Sneek; A.van Reisen, Terneuzen; C.Kruijtzer, Tiel; H.Roerdink, J. van Riel, Tilburg; D.ten Bokkel Huinink, E.Voest, Utrecht; M. van Diemen, Veghel; G.Vreugdenhil, Veldhoven; M.Werter, Venlo; L.Kerkhofs, Vlissingen; P.Schiphorst, Winterswijk; A.van Bochove, Zaandam; A.Ogilvie, Zoetermeer; A.Honkoop, Zwolle Pathology: J.van Krieken, J.Dijkstra, E.Börger, NijmegenStatisticians: N.Antonini, O.Dalesio, Amsterdam Central Datamanagement: L.Mol, F.van Leeuwen, IKO Nijmegen, Independent Data Monitoring Committee: P. De Mulder †, D.Sleijfer, G.Stoter, Supported by Dutch Cancer Foundation, and unrestricted scientific grants from Merck Serono, Roche, Sanofi-Aventis