MFOLFOX-bevacizumab or XELOX- bevacizumab then bevacizumab alone or with erlotinib in 1st line...

mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab alone or with erlotinib in 1st line treatment of patients with

metastatic colorectal cancer : Interim safety analysis of DREAM study.

C. Tournigand1, B. Samson2, W. Scheithauer3, C. Louvet1, T. Andre4, G. Lledo5, J. Latreille2, F. Viret6, B. Chibaudel7, A. de Gramont1;

1Hopital Saint Antoine, Paris, France; 2Hopital Charles Lemoyne, Greenfield Park, QC, Canada; 3University of Vienna, Vienna, Austria; 4Hopital Pitié-Salpetrière, Paris, France;

5Hopital Privé Jean Mermoz, Lyon, France; 6Institut Paoli Calmette, Marseille, France; 7Gercor, Paris, France

ABSTRACT

Background : Anti-VEGF or EGFR inhibitors demonstrated clinical activity in combination with chemotherapy (CT) in mCRC. The DREAM trial compares, after an induction CT of 6 cy of FOLFOX-Bev or XELOX-Bev, a maintenance with Bev +/- Erlotinib. We report here a pre-planned safety analysis of induction (I) and maintenance (M) phase for the first 200 patients.

Methods : Patients (pts) with untreated mCRC were randomly assigned to 2 arms (I): mFOLFOX+Bev (n=100), or mXELOX+Bev (n=100). mFOLFOX-Bev: LV 400 mg/m², Oxaliplatin (ox) 100 mg/m², B 5 mg/kg d1, 5FU ci 2.4g/m² 46h, q2w, mXELOX-Bev: Ox 100 mg/m² d1, capecitabine 2.5 g/m² d1-7, Bev 5mg/kg, q2w. To date, 117 pts with a disease control after 6 cy have had a 2nd randomisation (M): Bev alone (7.5 mg/kg q3w, n=56) or Bev+Erlotinib 150 mg/d (n=61) until PD.

Results : Pts characteristics were: sex: 124M/76F, median age: 62.4 years (26-80), primary tumors: colon 152, rectum 53, synchronous metastases: 150 pts, > 1 metastase site: 115, PS 0/1: 134/66, Alk. Ph.>UNL: 87 pts, and LDH>UNL: 88pts. For I, 92 pts in mFOLFOX-Bev and 93 in XELOX-Bev were evaluable for toxicity (tox). Tox (%) for mFOLFOX-Bev/XELOX-Bev were: any toxicity grade (gr) 3 or 4: 21/30; neutropenia gr 3 6/1, gr 4 0/2; febrile neutropenia gr 3 1/1, gr 4 0/1; thrombopenia gr 3 0/1, gr 4 0/2; anemia gr 2 8/15, gr 3 2/1; nausea gr 2 17/15, gr 3 4/6; vomiting gr 2 10/12, gr 3 2/5; mucositis gr 2 6/6, gr 3 0/4; diarrhea gr 2 8/12, gr 3 5/20, gr 4 0/1; neuropathy gr 2 23/17 gr 3 3/1; HFS gr 2 0/7, gr 3 0/2; hypertension gr 2 2/3, gr 3 1/0; proteinuria gr 2 1/5; SAEs 14/25.

For Maintenance, 56 pts in B and 61 pts in Bev+Erlotinib were evaluable. Tox (% Bev/Bev+Erlotinib) were: neutropenia gr 2 0/3; thrombopenia gr 2 2/0; nausea gr 2 2/2, gr 3 2/0; vomiting gr 3 2/0; mucositis gr 2 2/3; diarrhea gr 2 0/6, gr 3 2/6; skin tox gr 1 9/31, gr 2 0/38, gr 3 0/16, gr 4 0/2; proteinuria gr 2 5/5; hypertension gr 1 9/15, gr 2 3/8, gr 3 3/0. 

Conclusion : This interim safety analysis demonstrated that induction with mFOLFOX-Bev or XELOX-Bev as well as maintenance with Bev or Bev + Erlotinib appears to be well-tolerated, without unexpected side effects. The DREAM study is ongoing, with a prolonged induction phase of 6 months (3 mo with ox then 3 mo with fluoropyrimidines-B) before randomisation for maintenance therapy.

INTRODUCTIONOPTIMOX1 and 2 studies validated the "stop and go strategy" or stopping oxaliplatin after 6 cycles in metastatic colorectal cancer. (Tournigand et al. JCO 2006, Maindrault-Goebel, ASCO 2007)

Bevacizumab increases PFS in combination with first-line chemotherapy. (Saltz et al., JCO 2008)

A modified XELOX regimen (7 days on, 7 days off) demonstrated a good therapeutic ratio (Scheithauer et al., JCO 2003)

Erlotinib is an orally active, selective inhibitor of HER1/EGFR tyrosine-kinase. In preclinical models, administration of EGFR inhibitors in combination with antiangiogenic agents has shown additive cytotoxicity. (Ciardello et al. Clinical Cancer Res 2000, 2004)

mFOLFOX7 +bevacizumab

x6 cycles

mFOLFOX7 +bevacizumab

x6 cycles

mXELOX + bevacizumab

X6 cycles

mXELOX + bevacizumab

X6 cycles

N=640

RRAANNDDOOMMIISSAATTIIOONN

RRAANNDDOOMMIISSAATTIIOONN

bevacizumab bevacizumab + erlotinib+ erlotinibuntil PDuntil PD

bevacizumab bevacizumab + erlotinib+ erlotinibuntil PDuntil PD

DREAM study (Phase III)

bevacizumabbevacizumabuntil PDuntil PD

bevacizumabbevacizumabuntil PDuntil PD

RRAANNDDOOMMIISSAATTIIOONN

RRAANNDDOOMMIISSAATTIIOONN

PR PR or or SDSD

INDUCTION MAINTENANCE

LV 400 5-FU 2.4 g/m²mFolfox7oxali 100

D1 D1 D2 D2

Capecitabine 2500 mg/m²/dmXELOXoxali 100

D1 D1 D7 D7

bev. 5

bev. 5

erlotinib

Every 2 weeks

Every 2 weeks

CHEMOTHERAPYIN

DU

CT

ION

MA

INT

EN

AN

CE

bev. 7.5 Every 3 weeks

Erlotinib 150 mg/day, continuous

Inclusion criteriaHistologically proven adenocarcinoma of colon or rectum.

Unresectable metastatic disease, i.e. non suitable for complete carcinological surgical resection.

No previous chemotherapy and/or immunotherapy for metastatic disease.

In case of previous adjuvant chemotherapy, progression-free interval from end of previous adjuvant chemotherapy > 6 months (2 years if oxaliplatin or CPT11 received as adjuvant therapy)

Measurable lesion or non measurable lesions

Age 18 years - 80 years.

WHO (ECOG) performance status 0-2 .

Hematological status:

Neutrophils 1,5 109/L

Platelets 100 109/L

Haemoglobin > 9 g/dL (may be transfused to maintain or exceed this level)

International Normalized Ratio (INR) 1.5; APPT <1.5 x UNL

Adequate renal function, No proteinuria at baseline.

Hepatic function: Total bilirubin < 1.5 x upper normal limit (UNL), ALP :< 3 x ULN

Neurologic status: no peripheral sensory neuropathy (NCI grade 0).

Patients Characteristicsn=200

Sex ratio 124 M / 76 F

Median Age 62.4 years (26-80yrs)

WHO PS 0 vs 1 134 vs 66 pts

Colon vs rectum 152 vs 53 pts

Synchronous mets150 pts

>1 metastatic site 115 pts

Alk Phosphatase >UNL 87 pts

LDH>UNL 88 pts

INDUCTION CHEMOTHERAPY Hematologic toxicity (grade 3-4)

FOLFOX-BevacizumabN=92

%

XELOX-BevacizumabN=93

%

Neutropenia grade 3 grade 4

60

12

Thrombocytopenia grade 3 grade 4

00

12

Anemia grade 3 grade 2

28

115

Febrile neutropenia 1 2

INDUCTION CHEMOTHERAPY Non-Hematologic toxicity

FOLFOX-Bevacizumab N=92

%

XELOX-BevacizumabN=93

%

Nausea grade 3 grade 2

4 17

615

Vomiting grade 3 grade 2

210

512

Mucositis grade 3 grade 2

06

46

Diarrhea grade 3-4 grade 2

58

2112

Neuropathy grade 3 grade 2

323

117

Hand-Foot syndrome grade 3 grade 2

00

27

FOLFOX-Bevacizumab

N=92%

XELOX-Bevacizumab

N=93%

HTA grade 3 grade 2

12

03

Proteinuria grade 3 grade 2

01

05

INDUCTION CHEMOTHERAPY Bevacizumab-related toxicity

BevacizumabN=56

%

Bevacizumab – ErlotinibN=61

%

Nausea grade 3 grade 2

22

02

Vomiting grade 3 2 0

Mucositis grade 2 2 3

Diarrhea grade 3 grade 2

02

66

Neutropenia grade 2 0 3

Thrombocytopenia grade 2 2 0

MAINTENANCE : toxicity

MAINTENANCE toxicity

Bevacizumab N=56

%

Bevacizumab – ErlotinibN=61

%

Cutaneous toxicity Grade 1 Grade 2 Grade 3 Grade 4

9000

3138162

HTA Grade 1 Grade 2 Grade 3

933

1580

Proteinuria Grade 2 5 5

Conclusion

Acknowledgement : Roche for financial support of the DREAM study

Both mFOLFOX7-bevacizumab and mXELOX-bevacizumab are well tolerated as first-line therapy in metastatic colorectal cancer

As expected, the main toxicity of the association of bevacizumab and erlotinib is cutaneous (18% grade 3-4)

Considering the recent results of OPTIMOX2, a prolongation of the maintenance phase from 3 months to 6 months before maintenance therapy has been adopted in the study

KRAS status will be available for all patients

18%verif

mFOLFOX7 +bevacizumab

X6 cycles

mFOLFOX7 +bevacizumab

X6 cycles

mXELOX + bevacizumab

x6 cycles

mXELOX + bevacizumab

x6 cycles

bevacizumab bevacizumab + erlotinib+ erlotinibuntil PDuntil PD

bevacizumab bevacizumab + erlotinib+ erlotinibuntil PDuntil PD

DREAM study (Phase III)DREAM study (Phase III)New designNew design

bevacizumabbevacizumabuntil PDuntil PD

bevacizumabbevacizumabuntil PDuntil PD

RANDOMISATION

RANDOMISATION

CR2 or

PR or SD

mLV5FU2 +bevacizumab

3 months

mLV5FU2 +bevacizumab

3 months

FOLFIRI – bevacizumab 6 monthsFOLFIRI – bevacizumab 6 months

Or1

1 investigator’s choice

Or1

2without surgery

REGISTRATION

REGISTRATION

• Inclusion criteria :– IP 0 – 2– Alk Ph < 5xN

capecitabine +bevacizumab

3 months

capecitabine +bevacizumab

3 months