CHIMIOTHÉRAPIE ORALE MÉTRONOMIQUE

PERSPECTIVES

EC ANTOINE

ISHH, PARIS

MONACO VENDREDI 5 FÉVRIER 2016

Metronomic chemotherapy is an reasonable treatment option, for patients not requiring rapid tumor response.

LoE: 1 B 88,3%

The better studied regimen is CM (low dose oral

cyclophosphamide and methotrexate); other regimens are being evaluated (including capecitabine and vinorelbine).

Randomized trials are needed to accurately compare

metronomic CT with standard dosing regimens.

chimiothérapie en Phase métastatique

Proposition Statut Niveau de

preuve Votes (#1 - n = 43)

(#2 - n = 44)

Oui Non Abst.

La chimiothérapie métronomique est une option thérapeutique raisonnable chez les patientes ne nécessitant pas une réponse tumorale rapide.

Nouveau 1B 88,4 % 7,0 % 4,6 %

Même prescrites en adjuvant, si la dose cumulée n’a pas été atteinte et en l’absence de contre-indications cardiaques, les anthracyclines peuvent être réutilisées en situation métastatique, surtout si l’intervalle libre est d’au moins 1 an.

Nouveau 1C 93,2 % 2,3 % 4,5 %

Les chimiothérapies métronomiques en clinique (ex du cancer du sein)

Romiti A et al. Cancer Chemother Pharmacol 2013;72:13–33

Metronomic protocol Study design Patients (N) ORR (%) Clinical benefit (%) Median TTP (months) Median OS (months)

mCTX + mMTX Phase II 64 19 32 3

mCTX + mMTX versus

mCTX + mMTX-Thalidomide Phase III

86

85

21

12

41

41

4

4

18

17

mCTX + mMTX-Dalteparin-Prednisone

Phase I/II 41 17 24 2 12

mCTX + mMTX-CXB Phase II 67 0 31 2 8

mCTX + mMTX-Trastuzumab Phase II 22 18 46 6

mCTX-Pegylated Doxorubicin Phase II 29 62 96

mCTX + CAP Phase II 66 30 53 5 17

mCTX + CAP Phase II 45 44 58 12* Not reached

mCAP Phase II 60 24 62 7 17

m5FU-Eniluracil Phase II 33 48 78 7

mCAP-mTXT-CXB Phase II 38 34 42 4 10

mVRL Phase II 34 elderly 38 70 8 16

m5FU-Megestrol acetate Phase II 29 31 41 7 13

mCTX-Letrozole versus Letrozole

Phase II R 57 57

88 72

97 95

mCAP-mCTX-Bev Phase II 46 48 68 10

mCAP-mCTX-Bev-Erlotinib Phase II 24 62 75 11 25

mCAP-mMTX-Bev Phase II 24 32 64 7* 14

mVRL-Bev Phase II 13 8 54 4*

Vinorelbine orale vs Intra-veineuse: Une « Bioéquivalence » validée.

1

10

100

1000

10000

0 12 24 36

Time (h)

Blo

od

Co

nc

(ng

/ml)

25 mg/m² I.V.

versus

60 mg/m² Oral

Equivalent AUCs : I.V. Oral

30 mg/m² 80 mg/m²

25 mg/m² 60 mg/m²

30 mg/m² I.V.

versus

80 mg/m² Oral

1

10

100

1000

10000

0 12 24 36

Time (h)

Blo

od

Co

nc

(ng

/ml)

Marty, Ann. Oncol. 2001

Vinorelbine orale en monothérapie, Schéma Conventionnel. Etude Freyer

– Etude de phase II multicentrique en 1ère ligne de CSM (n=64)

– Schéma thérapeutique: NAVELBINE Oral 60 mg/m2/semaine pendant les 3 premières semaines, puis 60 mg/m2/semaine selon la toxicité

– Taux de RO: 31% (Obj principal)

– PFS: 4,3 mois

– OS de 23,9 mois

Enregistrement

Freyer, JCO 2003;

– Tolérance

Clin Cancer Res 2009;15:6454-6461

3 responders received nonstop treatment for over 3 years without over toxicity.

Metronomic administration of oral vinorelbine is

feasible at doses up to 50 mg thrice a week

Phase I trial of metronomic oral vinorelbine in patients with advanced cancer

Lakshmi Rajdev, Abdissa Negassa, Qun Dai, Gary Goldberg, Kathy Miller, Joseph A. Sparano

Cancer Chemother Pharmacol (2011) 68:1119–1124

Oral vinorelbine may be given using a metronomic schedule, 50 mg thrice weekly for three of 4 weeks,

with minimal toxicity in patients with advanced cancer.

10

Vinorelbine orale en schéma métronomique Etude Briasoulis (dose optimale)

Briasoulis E et al. BMC Cancer 2013;13:263

5

0

2 4 6 8 12 20 36 10 16 30

Steady state VRL levels over time (all patients)

30 mg 40 mg 50 mg

0

10

–5

VR

L co

nce

ntr

atio

n (

ng/

mL)

Metronomic oral vinorelbine monotherapy has clinical activity as first-line therapy in Breast Cancer Patients.

• Dosing: 70 mg/m2 split in 3 doses / week

• Schedule: days 1, 3, and 5; 3 weeks on/ 1 week off (maximum 12 cycles)

• Duration: maximum 12 cycles

• Age > 70 years

Addeo R, Sgambato A, Cennamo G et al. Clin Breast Cancer 2010;10:301–6

Response measure Number of patients (%)

Complete response 2 (6)

Partial response 11 (32)

Overall response rate 13 (38)

No change 11 (32)

Disease control rate 23 (68)

Progressive disease 10 (29)

Total 34 (100)

PFS (median value) = 7.7 months (95% CI: 6.9–9.1) Median: 15.9 months (95% CI: 13.1–15.9 months)

100

80

60

40

0

Surv

ival

(%

)

5 10 15 20 25 Time (months)

Overall survival

20

100

80

60

40

0

Pro

gres

sio

n-f

ree

surv

ival

(%

)

5 10 15 20 25 Months after treatment

PFS according to Karnofsky performance status (KPS)

20

>80 KPS ≤80 KPS P=0.03

9,8

6,14

7,98

8,05

8,7

8,8

6,7

11,8

6,1

7

3,98

8

5,2

5,9

4,2

0 2 4 6 8 10 12

Anthra adjuvants 30- 55%

Anthra adjuvants 100%

Docetaxel

Paclitaxel

Paclitaxel

Docetaxel

Paclitaxel

Docetaxel

Docetaxel & capecitabine

Paclitaxel & bévacizumab

Paclitaxel & lapatinib

Docetaxel & bevacizumab*

Paclitaxel & bevacizumab

Docetaxel & gemcitabine

Docetaxel & capecitabine

Paclitaxel & gemcitabine

Docetaxel caelyx

O’Shaugnessy 2002

Miller 2007

Dileo 2008

Miles 2008

Albain 2009

Sparano 2009

O’Shaugnessy 2002

Miller 2007

Dileo 2008

Miles 2008

Miles 2008

Chan 2009

Chan 2009

Albain 2008

Sparano 2009

Anthra adjuvants 100%

Anthra adjuvants 70%

Anthra adjuvants 30- 55%

Survie sans progression : principaux protocoles de première ligne

Albain KS, JCO 26:3950–3957 2008 | DiLeo A, JCO 26:5544–5552, 2008 | O'Shaughnessy J, JCO 20:2812–2823 2002 | Miller K, NEJM 357:2666–2676, 2007 | Miles, Abstract LBA1011 ASCO 2008 | Sparano J, Abstract SABCs 2008 | Chan S, J Clin Oncol 1753–

1760 2009

4,2

5,9

5,2

8

3,9

7

6,1

6,7

8,8

8,7

8,0

7,9

11,9

6,1

9,8

* Hors AMM

Metronomic oral vinorelbine monotherapy is well tolerated as first-line therapy

• Dosing: 70 mg/m2

• Schedule: Days 1, 3, and 5; 3 weeks on/1 week off (maximum 12 cycles) • Duration: maximum 12 cycles • Age > 70 years

Addeo R, Sgambato A, Cennamo G et al. Clin Breast Cancer 2010;10:301–6

Adverse event

By patient (n=34) (%) By cycle (n=186) (%)

Grades 1–2 Grade 3 Grade 4 Overall Grades 1–2 Grade 3 Grade 4 Overall

Haematological

Neutropenia 16 (47) 3 (9) 0 19 (57) 27 (15) 8 (4) 0 35 (19)

Anaemia 7 (29) 3 (9) 0 9 (26) 22 (12) 7 (4) 0 60 (16)

Thrombocytopenia 4 (12) 1 (3) 0 5 (15) 16 (9) 3 (2) 0 19 (10)

Febrile neutropenia – 1 (3) 0 1 (3) 7 (4) 2 (1) 0 9 (5)

Non-haematological

Febrile infection 7 (21) 2 (6) 0 9 (26) 7 (4) 6 (3) 0 13 (7)

Diarrhoea 6 (18) 1 (3) 0 7 (21) 7 (4) 1 (5) 0 8 (4)

Nausea 14 (41) 1 (3) 0 15 (44) 24 (13) 5 (3) 0 29 (16)

Vomiting 6 (17) 1 (3) 0 7 (21) 15 (8) 3 (2) 0 18 (10)

Stomatitis 4 (12) 1 (3) 0 5 (15) 9 (5) 0 0 9 (5)

Fatigue 4 (12) 0 0 4 (12) 7 (4) 0 0 7 (4)

Constipation 4 (12) 0 0 4 (12) 7 (4) 0 0 7 (4)

Neuromotor/sensory 2 (6) 0 0 2 (6) 3 (2) 0 0 3 (2)

Alopecia 27 (79) 0 0 27 (79) NA 0 0 NA

3-week cycles

Tempo-Breast1 randomized phase II trial ( first-line MBC chemo )

MBC ER-positive and HER2-negative Pretreated by hormone therapy

Treatment until disease progression

RA

ND

OM

ISAT

ION

“ weekly schedule “

Oral Vinorelbine 80 mg/m² weekly (first cycle at 60)

“ metronomic schedule “

Oral Vinorelbine 50 mg total dose 3 times per week continuously