© IEO 2009

Metronomic chemotherapy for breast cancer

M. Colleoni International Breast Cancer Study Group

(IBCSG), Division of Medical Senology,

European Institute of Oncology

© IEO 2009

Metronomic Scheduling and Inhibition of Tumor Growth: In Vivo Models

Cancer Res 2000, 60: 1878-86

© IEO 2009

Metronomic chemotherapy concept showing multiple mechanisms

3Nat Rev Clin Oncol 2015; 12: 631-44

© IEO 2009

Metronomic CT in breast cancer: number of published papers during

years

4

02468

1012141618

2002-20052006-20092010-20112012-2014

Cancer Treatment Reviews 40 (2014) 942–950

© IEO 2009

Neoadjuvant treatment for early breast cancer

© IEO 2009

Trials with metronomic chemotherapy in the neoadjuvant setting

6

Nat Rev Clin Oncol 2015; 12: 631-44

© IEO 2009

LET vs LET-CYC: Distribution of DiseaseResponse According to Treatment Arm

J Clin Oncol 2006; 24:3623-3628

© IEO 2009

Adjuvant treatment for early breast cancer

© IEO 2009

National Surgical Adjuvant Study for Breast Cancer 01 Trial

9 J Clin Oncol 27:1368-1374. 2009

© IEO 2009

Relapse-free survival, overall survival of the total patients treated with uracil and tegafur (UFT) or

cyclophosphamide, methotrexate, and fluorouracil

10J Clin Oncol 27:1368‐1374. 2009

Similar RFS and OS with oral UFT to those with classical CMF Higher QOL scores

IBCSG

CM Maintenance Chemotherapy (CMM)

IBCSG Trial 22-00 (CM Maintenance)

SURGERY

4-6 mos.

12 mos.

Stratify•Institution•Menopausal status

•Induction regimen

Induction Chemotherapy

4-6 mos.

*Any time from start of induction to within 8 weeks after first day of last course of induction

Observation (OBS)

1081 patients in ITT population; Median follow-up 6.9 years

Hormone receptor negative (< 10% positive cells by IHC) by locally-determined ER and PgR

Induction Chemotherapy

1086 patients enrolled Jan 2001 - Dec 2012RANDOMIZE*

IBCSG

Trial Treatment

• Low dose oral CM – C, cyclophosphamide 50 mg/day orally continuously– M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week

• CM Maintenance (CMM)– CM after induction chemotherapy for 12 months duration

• Cost of CMM: 10 €/month

IBCSG

Patient/Disease CharacteristicsCMM

(N=542)OBS

(N=539)Overall

(N=1081)

Median age (range) 52 (28, 79) 52 (23, 80) 52 (23, 80)

Premenopausal 44% 46% 45%

Tumor > 2 cm 57% 52% 54%

Grade 3 84% 85% 84%

Lymph Node +ve 43% 42% 42%

HER2+ve* 19% 19% 19%

Triple Negative 75% 75% 75%

*6% unknown local HER2

IBCSG

Disease-Free Survival

IBCSG

Disease-Free SurvivalTriple Negative Node Positive and Triple Negative

Adherence with CMM and Disease-Free Survival

Landmark: patients alive and disease-free approximately 1 year from cessation of induction chemotherapy, when CMM would be finished.

All Patients Triple Negative

IBCSG

Select AEs Grade 3 Grade 4Leukopenia 8 1Neutropenia 2 4Elevated SGPT 9 -Elevated SGOT 32 1Nausea 4 -Vomiting 3 -Dysuria 2 -Infection 4 -Pain 3 -Cardiovascular 3 -Neurologic 3 -Ocular/Visual - 1

Adverse Events CMM (N=473*)

64 patients (14%) experienced at least one grade 3 or 4 AE attributable to CMM; no grade 5

*Safety Population:Received some CMM:471 assigned CMM2 assigned OBS

Possibly, probably, definitely due to CMM

© IEO 2009

Treatment of advanced breast cancer

© IEO 2009

ESO-ESMO 2nd international consensus guidelines for advanced breast cancer

(ABC2)

Advanced breast cancer (ABC) is a treatable but still generally incurable disease. The goals of care are to optimize both length and quality of life

Annals of Oncology Ann Oncol 2014; 25: 1871–1888 The Breast 2014, http://dx.doi.org/10.1016/j.breast.2014.08.009

© IEO 2009

Strenghts and weakeness of oral CT

• Surveys have shown that most patients prefer oral to i.v.

• A minority prefer i.v. due to possible less effectiveness of oral therapies (last resort)

• Robust data are required to convince the full benefit of ora chemotherapy

J Clin Oncol 1997; 15: 110–115Ann Oncol 2006; 17: 205–210Breast Cancer Res Treat 2005; 92: 265–272

© IEO 2009

Metronomic chemotherapy

• Attractive to consider a therapeutic strategy with good toxicity profile

• Good tumor control

• Not expensive for the health system

© IEO 2009

Trials with metronomic chemotherapy in metastatic breast cancer

22

© IEO 2009

Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line Chemotherapy for Advanced Breast Cancer

J Clin Oncol 29:4498-4504

© IEO 2009

Capecitabine Versus Classical Cyclophosphamide, Methotrexate, and Fluorouracil As First-Line Chemotherapy for Advanced Breast Cancer:

PFS and OS

J Clin Oncol 29:4498-4504

The average duration of chemotherapy was longer in those assignedcapecitabine than in those assigned CMF

© IEO 2009

Trials with metronomic chemotherapy + biological agents in metastatic breast cancer

25Nat Rev Clin Oncol 2015; 12: 631-44

© IEO 2009Clinical benefit (31-41%)

FIRST STUDYDrug Dose Day

1 2 3 4 5 6 7MTX 2,5 mg x 2 oral

CTX 50 mg oral

SECOND STUDYDrug Dose Day

1 2 3 4 5 6 7MTX 2,5 mg x 2 oral

CTX 50 mg oral

Ann Oncol. 2002 ;13(1):73-80.

Metronomic Cyclophosphamide + Methotrexate

Ann Oncol. 2006;17(2):232-8.

© IEO 2009

PCB = no disease progression (CRs, PRs, or SDs) for ≥ 12 months

24/153 pts with PBC (15.7%)

Median duration of response: 20.7 months (range, 1.5-44.6)

Prolonged clinical benefit (PCB) with metronomic chemotherapy (CM) in MBC

Anticancer Drugs. 2006;17:961-7.

© IEO 2009

Delivery of a multitargeted antiangiogenic regimen with significant anticancer activity without the side effects typically associated with chemotherapy

Rationale of treating patients using combinations of metronomic chemotherapy plus targeted therapeutics, such as:

- Targeted antiangiogenic agents

- HER-2/HER-1 inhibitors

New strategies: metronomic CT + targeted therapeutics

© IEO 2009

Combinations of metronomic chemotherapy, bevacizumab and trastuzumab (or cetuximab)

Clin Cancer Res, 2006 12; 904

© IEO 2009

Bevacizumab 10 mg/kg iv every 2 weeks

Cyclophosphamide 50 mg/day orally at 9 a.m. (Endoxan®)Capecitabine 500 mg x 3/day orally after

meals(Xeloda®)

Metronomic Chemotherapy + Bevacizumab(BEX):

Treatment Schedule

J Clin Oncol 2008; 26 :4899-905

© IEO 2009

N %

Assessable patients 46CR 1 3PR 18 45SD24 weeks 8 20SD<24 weeks 8 20PD 5 13

Overall response (CR+PR) 19 48%Clinical benefit (CR+PR+SD24 weeks) 27 68%

J Clin Oncol 2008; 26 :4899‐905

Metronomic Chemotherapy + Bevacizumab (BEX):

Results

© IEO 2009

All Grades ≥ Grade 3

Mucositis 36 ‐Leucopenia 25 2Asthenia 25 ‐Nausea 24 1HFS 24 ‐Hypertension 22 8Neurology (paresthesias) 20 ‐Neutropenia 15 2Constipation 17 ‐Transaminitis 17 2Headache 16 ‐Diarrhea 16 ‐Proteinuria 15 1Vomiting 8 1Cystitis 7 ‐

J Clin Oncol 2008; 26 :4899‐905

Metronomic Chemotherapy + Bevacizumab (BEX):

Main Side Effects

© IEO 2009Name _ Datum33

SAKK 24‐09: Study Design

Randomiza-tion Bevacizumab

Cyclophos.Capecitabine(74 patients)

BevacizumabPaclitaxel

(73 patients)Arm A

Arm B

until PD, unacc.

toxicity or withdrawal

Follow up

ASCO,2014

© IEO 2009Name _ Datum34

Toxicities defining primary endpoint

Arm A (n=71) Arm B (n=68)Grade 3 Grade 4 Grade 3 Grade 4

Arthralgia 2 - 2 -Headache - - 2 -Infection 5 - 4 -Neuropathy 7 - - -Thromboembolic 2 1 4 -Nausea 1 - 3 -Mucositis - - 1 -Total 17 1 16 -

© IEO 2009Name _ Datum35

Progression free survival stratified by treatment arm

months

estim

ated

sur

viva

l pro

babi

lity /

/ / //////////

/

///

/

//

//

/ /

//

///

/ // / /

// /

/ / /

/ / /

/

0 4 8 12 16 20 24 28 32 360

0.2

0.4

0.6

0.8

1

# at riskPBCCB

73 64 38 16 7 4 3 2 0 074 46 33 20 14 8 3 3 1 0

Control: PBTreatment: CCB

© IEO 2009Name _ Datum36

Less hair loss in arm B was the onlyclinically relevant and statistically significant difference in QoL

Objective response rates:

• 58% (42/73; 95% CI 0.46–0.69)• 50% (37/74; 95% CI 0.39–0.61)

Activity and tolerability

© IEO 2009

Vinorelbine 40 mg day 1, 3, 5

Cyclophosphamide 50 mg/day orally at 9 a.m. (Endoxan®)Capecitabine 500 mg x 3/day orally after meals(Xeloda®)

Metronomic Chemotherapy (VEX):Treatment Schedule

© IEO 2009

Metronomic Chemotherapy (VEX):Patients’ features at baseline

Pretreated Number(46)

Metastatic siteNot visceralVisceralMultiple

17326

N° of sites34

133

Previous lineChemotherapyETBoth

23014

Untreated Number(42)

Metastatic siteNot visceralVisceralMultiple

19320

N° of sites34

103

Previous Adj(neo)therapyAnthraTaxane

188

ECCO 2015

© IEO 2009

Metronomic Chemotherapy (VEX):Median Time to progression

Untreated Pretreated

Median TTP 26.5 mo 9.6 mo

1-yr PFS 73% 38%

2-yr PFS 52% 28%

Response Rate (PR+CR) 35% 30%

ECCO 2015

© IEO 2009

Metronomic Chemotherapy (VEX):Side Effects (untreated)

G1 N° pts

Nausea 21

Diarrhea 19

HFS 5

Leucopenia 2

Transaminitis 9

G2 N° pts

Leucopenia 16

HFS 6

Transaminitis 6

Alopecia none

G3:2 neutropenia,1 anemia, 1 diarrhea, 2 HFS, 2 Transaminitis

© IEO 2009

Metronomic Chemotherapy (VEX):Side effects (pretreated)

G1 N° pts

Leucopenia 8

Transaminitis 17

Nausea 8

Diarrhea 14

Astenia 14

G2 N° pts

Transaminitis 2

HFS 5

Leucopenia 6

Alopecia none

G3:1 leucopenia, 1 neutropenia, 1 nausea, 1 mucositis, 2 HFS

© IEO 2009

VICTOR 2Multicenter Phase II

(end of enrollment April 2015)

Combination

ABC3 Lisbona; EBCC 2016 Amsterdam.

L M M G V S D

Capecitabine 500 x3 mg/daily

Oral VNR 40 mg TD D1,3,5 weekly

Schedule

Primary objective: - CB ≥24 weeks

Secondary objective:- Outcome (PFS, OS)- Tolerability- QoL- Compliance

Patients’ characteristicsN 85 (100%)Median age 65 (38-85)Receptor status

Luminal A 81 (95%)Visceralinvolvement

55 (65%)

I° line treatment 23 (27.1%)

© IEO 2009

SAFETY and EFFICACYCombination

85 pts enrolled

Toxicity G3/4 (%)Neutropenia 1.2%Thrombocytopenia 0.2%Diarrhoea 0.5%Mucositis 0.3%

669 cycles evaluable for toxicity

ACTIVITY %

Clinical Benefit(CR+PR+SD≧24 weeks) 80%

ABC3 Lisbona; EBCC 2016 Amsterdam.

© IEO 2009

CONCLUSIONS Metronomic chemotherapy demonstrated activity

in BC

Provided disease control for a significant proportion of patients with MBC

The low burden of personal costs to the patient and the possibility to continue the treatment for several months support the use of metronomic CT as an additional therapeutic tool

Metronomic combinations in early stages key for future trials

Trend toward a benefit as maintenance in high risk triple negative breast cancer

© IEO 2009

CONCLUSIONS

• Despite the published literature, metronomic chemotherapy approaches are currently not widely used in everyday practice

• This emphasizes the need for new large studies comparing this approach with more conventional therapies

45