PLD in Metastatic Breast Cancer

8/10/2019 PLD in Metastatic Breast Cancer

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V1.0

Pegylated LiposomalDoxorubicin

and Breast Cancer


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V1.0

Reduced Cardiotoxicity andComparable Efficacy in a Phase III Trial

of Pegylated Liposomal Doxorubicin

Versus Conventional Doxorubicin forFirst-line Treatment of Metastatic

Breast Cancer

OBrien M et al. Ann Oncol 2004; 15: 440-449


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V1.0

OBrien Study Design

PLD 50 mg/m2

IV over 11.5 hours

Q4W

(n = 254)

Conventional

doxorubicin 60 mg/m2

IV over 1 hour Q3W

(n = 255)

1stline MBC, with

normal cardiac

function

Prior adjuvantanthracyclines

permitted

300 mg/m2

Randomized 1:1

N = 509

Progression-free survival and cardiotoxicityPrimary endpoints:

Phase III, randomized, multicenter, international, open-label trial


TR

E

A

T

T

O

P

R

O

G

R

E

SS

I

O

N


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V1.0

Baseline Patient Characteristics

*Cardiac risk factors: prior mediastinal irradiation, age >65 years, history of heart disease or had hypertension ordiabetes requiring medical treatment. OBrien M et al. Ann Oncol 2004; 15: 440-449

PLD

(n=254)

Conventional doxorubicin

(n=255)

Median age (years) 58 (2882) 57 (2582)

Race

Caucasian 77.1% 75.6%

Hispanic 19.6% 19.6%

Other 3% 4.6%

Menopausal status at diagnosis

Premenopausal 30.7% 35.2%

Post menopausal 68.8% 62.3%

Unknown 0.3% 2.3%

WHO Performance Status

0 53.9% 49%

1 37% 39.6%

2 9% 10.9%

Missing 0 0.3%

Cardiac risk factors 48% 47.4%


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V1.0

Cardiotoxicity


PLD

(n=254)

Conventional

doxorubicin

(n=255)

Patients who developed

cardiotoxicity (LVEF decrease)

4% 19%

Cardiotoxicity with signs and

symptoms of CHF0 4%

Cardiotoxicity without signs

and symptoms of CHF4% 15%

Signs and symptoms of CHF

alone


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V1.0

Efficacy Endpoints

*Overall response rate (n = 410); PLD n = 209; conventional doxorubicin n = 201


PLD

(n=254)

Conventional

doxorubicin

(n=255)

PFS 6.9 months 7.8 months

Overall Survival 21 months 22 months

Overall Response rate 33% 38%


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Cardiac Event Rates

100

90

80

70

60

50

40

30

20

10

0

0 50 100 150 200 300250 400 450 500 550 600350

Cumulative Anthracycline Dose (mg/m2)

Ka

plan-MeierEstimatesof

CardiacEvent

Rate

PLD

Conventionaldoxorubicin

Hazard ratio = 3.16 (95% CI: 1.58 - 6.31); P


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Incidence of Cardiotoxicity/

High-risk Patients


PLD Conventional

doxorubicin

HR

(95% CI)

Age 65 years 0 13.6% -

Cardiac risk factors 4.3% 21% 2.7(1.017.18)

Prior adjuvant

anthracycline

2.7% 38% 7.27

(0.9356.8)


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Non-hematologic Toxicities


PLD (n=254) Conventional doxorubicin (n=255)

All Grade 3-4 All Grade 3-4

Nausea 37% 3% 53% 5%

Alopecia 20% - 66% -

Vomiting 19%


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Hematologic Toxicities


PLD

(n=254)

Conventional

doxorubicin

(n=255)

All Grade 3-4 All Grade 3-4

Anemia 5% 1% 7% 2%

Leukopenia 2% 1% 11% 9%

Neutropenia 4% 2% 10% 8%

Thrombocytopenia 1% 0 1%


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Conclusions

PLD and conventional doxorubicin have comparable

efficacy (OS, PFS, and response rates)

PLD treated patients had a significantly lower

incidence of cardiotoxicity EMA/FDA approved license of PLD in metastatic breast

cancer based on these data

PLD treated patients had decreased alopecia,

myelosuppression, nausea, and vomiting, but morestomatitis, hand-foot syndrome, and infusion

reactions



12/36V1.0

Randomized Phase III Trial ofPegylated Liposomal Doxorubicin

(PLD) Versus Vinorelbine or

Mitomycin C Plus Vinblastine inWomen With Taxane-Refractory

Advanced Breast Cancer

Keller et al. J Clin Oncol 2004; 22: 3893-3901


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Study Design

Pegylated Liposomal

Doxorubicin (PLD) 50 mg/m2

IV over 1 hour Q4W

(n = 150)

Vinorelbine 30 mg/m2

(n = 129)

or

Mitomycin C 10 mg/m2

Vinblastine 5 mg/m2

(n = 22)

Progression-Free SurvivalPrimary endpoint:

Taxane-refractory,

MBC with normal

cardiac function

< 2 prior

chemotherapies,excluding adjuvant

therapy

Prior adjuvant

anthracycline

permitted 450 mg/m2

N = 301

T

R

E

A

T

T

O

P

R

O

G

R

E

S

SI

O

N



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Baseline Demographics

PLD (n=150) Comparator (n=151)

Median age (years) 56 (3387) 56 (3083)

Karnofsky performance score

60-70 19% 17%

>70 81% 83%

Menopausal status at diagnosis

Premenopausal 40% 35%

Perimenopausal 6% 8%

Post menopausal 54% 56%

Unknown 0


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Response Rates

PLD (n=115) Comparator (n=117)

ORR (CR+PR) 10% 12%

CR 2% 2%

PR 8% 10%

SD 28% 28%

PD 32% 32%

Median DOR 5.7 months 6.0 months



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PFS


PFS was similar for PLD vs. comparator (2.9 months vs.2.5 months; P=0.11)


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OS

OS was comparable for PLD vs. comparatorAll randomised patients - median OS, 10.4 months vs. 9.0

months (HR 1.07; 95% CI, 0.79 to 1.45; P=0.57).

Protocol-eligible patients - median OS was consistent with

the results of the analysis for the entire study population (HR0.94; 95% CI, 0.68 to 1.33)

Updated survival analysis (October 2001) was

consistent with the original analysis

All randomized patients - median OS 11.0 vs. 9.0 months (HR1.05; 95% CI, 0.82 to 1.33; P=0.71)

Protocol-eligible patients - median OS 11.0 vs. 9.7 months

(HR 1.01; 95% CI, 0.77 to 1.33; P=0.93)



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Overall Survival

PLD Comparator HR

(95% CI)

Prior Anthracycline Exposure

Any (n) 9.2 months

(92)

9.5 months

(96)

0.86

(0.58-1.26)

None (n) 10.4 months

(23)

10.4 months

(21)

1.51

(0.65-3.52)

Anthracycline Resistant (progression on or within 6 months)

Yes (n) 8 months(46)

6.1 months(34)

1.05(0.61-1.83)

No (n) 11.2 months

(69)

10.4 months

(80)

1.03

(0.65-1.60)



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Selected AEs of Interest

PLD (n=150) Vinorelbine

(n=129)

Mitomycin C +

Vinblastine (n=22)

All Grade 3-4 All Grade 3-4 All Grade 3-4

Nausea 31% 3% 27% 7% 23% 5%

Fatigue 20% 4% 21% 2% 9% 5%

HFS 37% 19% 0.8% 0 0 0

Vomiting 20% 4% 17% 3% 18% 0

Asthenia 9% 1% 15% 4% 32% 0

Stomatitis 22% 5% 4% 0 0 0Neutropenia 3% 2% 14% 8% 5% 0

Mucositis NOS 14% 3% 0.8% 0 5% 0



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Conclusions

PLD has comparable efficacy to standard salvage

regimens used in taxane-refractory patientsActivity seen with PLD in anthracycline- and taxane-refractory

patients

PLD treated patients experienced more HFS and

stomatitis

Comparator-treated patients experienced more

neuropathy, constipation and neutropenia

PLD is a useful regimen in women with heavily pre-

treated, taxane-refractory advanced breast cancer



22/36V1.0

A randomized phase III studyevaluating pegylated liposomal

doxorubicin (PLD) versus capecitabine

as first-line therapy for metastaticbreast cancer (MBC): Results of the

PELICAN study

Jger E et al. J Clin Oncol 2010; 28(15s): Abstract 1022


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V1.0

Capecitabine

1,250 mg/m2BID x 14 days

Q21D

Pegylated Liposomal

Doxorubicin (PLD) 50 mg/m2

Q28D

Study Design

Time to disease progression (TTP)Primary endpoint:

Metastatic breast

cancer patients

N = 210

(randomized 1:1)

Stratified by age

and prior adjuvant

anthracycline

therapy

D

i

s

e

a

s

e

P

r

o

g

r

e

ss

i

o

n

Jger E et al. J Clin Oncol 2010; 28(15s): Abstract 1022.


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Efficacy Results

Prior adjuvant anthracycline treatment had a negative impact on TTP

in the capecitabine group (4.8 months vs. 9.0 months (p=0.0098)

PLD

(n=105)

Capecitabine

(n=105)

Median number of cycles 5 5

Median TTP 6.7 months 7.1 months

Prior anthracycline therapy 5.9 months 4.8 months

No prior anthracycline therapy 6.9 months 9.0 months

1-year overall survival 82% 75%

Overall response rate 24% 26%



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Adverse Events

PLD

(n=105)

Capecitabine

(n=105)

P Value

Diarrhoea (grade 3/4) 0 12% 0.0002

Thromboembolic events

(grade 3/4) 2% 10% 0.033

Hand-foot syndrome 36% 25% 0.1352

Cardiac events 9% 12% 0.4999



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V1.0

Conclusions

PLD and capecitabine demonstrated similar

effectiveness with regard to TTP

PLD arm showed a better tolerability profile

compared to capecitabine



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V1.0

Pegylated Liposomal

Doxorubicin (PLD) 50 mg/m2every 4 weeks

Study Design

Clinical benefit of PLD (CR+PR+SD 6 months duration)Primary endpoint:

Metastatic breast

cancer patients

At least one prior

chemotherapy formetastatic disease

Previously treated

with anthracyclines

N = 79

Di

s

e

a

s

e

P

r

o

g

r

e

s

si

o

n

Al-Batran S et al. Br J Cancer 2006; 94(11): 1615-1620

All patients received vitamin B6 (Pyridoxine) 300 mg orally once daily to prevent PPE


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V1.0

Patient Demographics

* n=3 by histochemistry or amplification by FISH

PLD (n=79)

Median age (years) 58

Karnofsky performance score

100 22.7%

90 34.1%

80 43.2%

Number of metastastic sites

1 32.9%

2 31.6%

3 35.4%

ER+ and PgR+ 86%

HER2+ 5.1%*

Site of disease

Bone only 6.3%

Non-visceral soft tissue only 11.1%

Visceral 82.6%



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V1.0

Treatment History

PLD (n=79)

Previous chemotherapy for MBC

1 regimen 37.9%

2 regimens 29.1%

3regimens 32.9%Prior anthracycline-base therapy 100%

Adjuvant only 22.8%

Metastatic only 68.4%

Both settings 8.9%

Anthracycline free interval

0-12 months 41.8%

>12 months 58.2%



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V1.0

PLD (n=79)

ORR (CR+PR) 12.7%

CR 1.3%

PR 11.4%

SD 27.8%

Median DOR 12 months

Median PFS 3.6 months

Stable disease (any) 9.5 months

Anthracycline resistant 2.8 months

Non-anthracycline resistant 3.7 monthsMedian OS 12.3 months

Anthracycline resistant 9.0 months

Non-anthracycline resistant 12.5 months

Efficacy Results

Anthracycline resistant defined as having disease progression on anthracycline-

based therapy for MBC or within 6 months of adjuvant anthracycline-based therapyAl-Batran S et al. Br J Cancer 2006; 94(11): 1615-1620


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OS and PFS



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Efficacy Results

Clinical Benefit 6 Months

All patients (N=79) 24%

1 regimen (n=30) 30%

2 regimens (n=23) 21.7%

3 regimens (n=26) 19.2%

Prior chemotherapy

Anthracycline resistant (n=31) 16.1%

Non-anthracycline resistant (n=48) 29.1%

Anthracycline Free Interval0-12 months (n=29) 24.1%

>12 months (n=32) 25%



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V1.0

Safety Results

*20 Grade 1,22 grade 2; most events were considered not related to PLD but to prior therapies by the investigator

Non-Hematological (n=79) All Grades Grade 1-2 Grade 3-4

Alopecia 53.8% 53.8%* 0

Nausea 47.4% 42.3% 5.1%

Diarrhoea 15.3% 15.3% 0

Vomiting 34.6% 32.0% 2.5%

Constipation 34.6% 30.7% 3.8%

Fever 19.2% 19.2% 0

Infection 28.2% 20.5% 7.6%

Neuropathy 32.0% 29.4% 2.5%

Hand-foot syndrome 46.1% 39.7% 6.4%

Mucositis 43.5% 33.3% 10.2%

Haematological (n=76) All Grades Grade 1-2 Grade 3-4

Neutropenia 50.0% 32.8% 17.1%

Leukopenia 72.3% 57.8% 14.4%

Anemia 88.1% 78.9% 9.2%

Thrombocytopenia 34.2% 30.2% 3.9%



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V1.0

Conclusions

Overall clinical benefit rate was 24% 16.1% in patients with anthracycline resistance vs. 29% in

patients classified as having non-anthracycline-resistant

disease

Median PFS and OS were 3.6 and 12.3 months,respectively

PLD was generally well tolerated

No cardiac toxicities were seen and no significant

changes in electrocardiograms or echocardiograms

were observed during the study

PLD was associated with an clinical benefit in

anthracycline pre-treated patients with MBCAl-Batran S et al. Br J Cancer 2006; 94(11): 1615-1620


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PLD in MBC - Conclusion

PLD and conventional doxorubicin have similar

efficacy, however PLD has: significantly lower risk of cardiac toxicity

improved convenience

differing tolerability profiles (less alopecia, nausea and

vomiting, myelosuppression but more HFS and stomatitis)

In general, no overlapping toxicity so readily able to

combine with other agents such as taxanes and

gemcitabine

Documents

PLD in Metastatic Breast Cancer