Randomized phase III study of capecitabine, oxaliplatin and bevacizumab with or without cetuximab in...

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