Pegylated Liposomal Doxorubicin

and Breast Cancer

V1.0

Reduced Cardiotoxicity and

Comparable Efficacy in a Phase III Trial
of Pegylated Liposomal Doxorubicin
Versus Conventional Doxorubicin for
First-line Treatment of Metastatic
Breast Cancer
OBrien M et al. Ann Oncol 2004; 15: 440-449

V1.0

OBrien Study Design

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

1st line MBC, with

normal cardiac
function
Prior adjuvant
anthracyclines
permitted
300 mg/m2
Randomized 1:1
N = 509

Primary endpoints:

V1.0

T
R
E
A
T

PLD 50 mg/m2
IV over 11.5 hours
Q4W
(n = 254)

T
O

Conventional
doxorubicin 60 mg/m2
IV over 1 hour Q3W
(n = 255)

P
R
O
G
R
E
S
S
I
O
N

Progression-free survival and cardiotoxicity

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

Baseline Patient Characteristics

PLD
(n=254)

Conventional doxorubicin
(n=255)

58 (2882)

57 (2582)

Caucasian

77.1%

75.6%

Hispanic

19.6%

19.6%

3%

4.6%

Premenopausal

30.7%

35.2%

Post menopausal

68.8%

62.3%

Unknown

0.3%

2.3%

53.9%

49%

37%

39.6%

9%

10.9%

Missing

0.3%

Cardiac risk factors

48%

47.4%

Median age (years)

Race

Other
Menopausal status at diagnosis

WHO Performance Status

*Cardiac risk factors: prior mediastinal irradiation, age >65 years, history of heart disease or had hypertension or
diabetes requiring medical treatment.
OBrien M et al. Ann Oncol 2004; 15: 440-449
V1.0

Cardiotoxicity
PLD
(n=254)

Conventional
doxorubicin
(n=255)

4%

19%

Cardiotoxicity with signs and

symptoms of CHF

4%

Cardiotoxicity without signs

and symptoms of CHF

4%

15%

Signs and symptoms of CHF

alone

<1%

<1%

Patients who developed

cardiotoxicity (LVEF decrease)

V1.0

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

Efficacy Endpoints
PLD
(n=254)

Conventional
doxorubicin
(n=255)

PFS

6.9 months

7.8 months

Overall Survival

21 months

22 months

33%

38%

Overall Response rate

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

V1.0

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

Kaplan-Meier Estimates of
Cardiac Event Rate

Cardiac Event Rates

100
90
80
70
60
50
40
30
20
10
0

Hazard ratio = 3.16 (95% CI: 1.58 - 6.31); P<0.001

Conventional
doxorubicin

PLD

0 50 100 150 200 250 300 350 400 450 500 550 600
Cumulative Anthracycline Dose (mg/m2)
V1.0

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

Incidence of Cardiotoxicity/
High-risk Patients
PLD

Conventional
doxorubicin

HR
(95% CI)

13.6%

Cardiac risk factors

4.3%

21%

2.7
(1.01 7.18)

Prior adjuvant
anthracycline

2.7%

38%

7.27
(0.93 56.8)

Age 65 years

V1.0

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

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%

<1%

31%

4%

Hand-foot syndrome

48%

17%

2%

Stomatitis

22%

5%

15%

2%

Mucositis

23%

4%

13%

2%

Fatigue

12%

<1%

16%

2%

Anorexia

11%

1%

10%

<1%

Asthenia

10%

1%

13%

1%

Rash

10%

2%

2%

Abdominal pain

8%

1%

4%

1%

Constipation

8%

<1%

9%

<1%

Pigmentation abnormal

8%

<1%

2%

<1%

Fever

8%

7%

<1%

Diarrhoea

7%

1%

8%

<1%

Erythema

7%

<1%

1%

Weakness

6%

<1%

8%

2%

Mouth ulceration

5%

<1%

V1.0

0 15: 440-449
OBrien M4%
et al. Ann Oncol 2004;

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%

1%

<1%

V1.0

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

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

V1.0

PLD treated patients had decreased alopecia,

myelosuppression, nausea, and vomiting, but more
stomatitis, hand-foot syndrome, and infusion
reactions

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

Randomized Phase III Trial of

Pegylated Liposomal Doxorubicin
(PLD) Versus Vinorelbine or
Mitomycin C Plus Vinblastine in
Women With Taxane-Refractory
Advanced Breast Cancer
Keller et al. J Clin Oncol 2004; 22: 3893-3901

V1.0

Study Design

Taxane-refractory,
MBC with normal
cardiac function
< 2 prior
chemotherapies,
excluding adjuvant
therapy
Prior adjuvant
anthracycline
permitted 450 mg/m2
N = 301

Primary endpoint:
V1.0

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)

T
R
E
A
T

T
O
P
R
O
G
R
E
S
S
I
O
N

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

Baseline Demographics
PLD (n=150)

Comparator (n=151)

56 (3387)

56 (3083)

60-70

19%

17%

>70

81%

83%

Premenopausal

40%

35%

Perimenopausal

6%

8%

Post menopausal

54%

56%

<1%

IIIB

2%

7%

IV

98%

93%

1%

35%

33%

39%

31%

26%

34%

Median age (years)

Karnofsky performance score

Menopausal status at diagnosis

Unknown

Disease Stage

Number of Metastatic sites

V1.0

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

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%

5.7 months

6.0 months

Median DOR

V1.0

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

PFS

V1.0

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

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

OS

OS was comparable for PLD vs. comparator

All 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 (HR
0.94; 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 (HR
1.05; 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)

V1.0

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

Progression-free Survival
PLD

Comparator

HR
(95% CI)

Prior Anthracycline Exposure

Any (n)

2.4 months
(92)

2.7 months
(96)

0.96
(0.70-1.32)

None (n)

5.8 months*
(23)

2.1 months
(21)

2.40
(1.16-4.95)

Anthracycline Resistant (progression on or within 6 months)

Yes (n)

2.6 months
(46)

2.6 months
(34)

1.14
(0.70-1.83)

No (n)

3.7 months
(69)

2.6 months
(80)

1.26
(0.87-1.82)

*P =0.015 for the subgroup of patients with no prior anthracycline exposure

V1.0

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

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)

V1.0

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)

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

Selected AEs of Interest

PLD (n=150)

V1.0

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%

Vomiting

20%

4%

17%

3%

18%

Asthenia

9%

1%

15%

4%

32%

Stomatitis

22%

5%

4%

Neutropenia

3%

2%

14%

8%

5%

Mucositis NOS

14%

3%

0.8%

5%

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

Conclusions

PLD has comparable efficacy to standard salvage

regimens used in taxane-refractory patients
Activity seen with PLD in anthracycline- and taxane-refractory
patients

V1.0

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 pretreated, taxane-refractory advanced breast cancer

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

A randomized phase III study

evaluating pegylated liposomal
doxorubicin (PLD) versus capecitabine
as first-line therapy for metastatic
breast cancer (MBC): Results of the
PELICAN study
Jger E et al. J Clin Oncol 2010; 28(15s): Abstract 1022

V1.0

Study Design

Metastatic breast
cancer patients
N = 210
(randomized 1:1)
Stratified by age
and prior adjuvant
anthracycline
therapy

Primary endpoint:

V1.0

Pegylated Liposomal
Doxorubicin (PLD) 50 mg/m2
Q28D

Capecitabine
1,250 mg/m2 BID x 14 days
Q21D

D
i
s
e
a
s
e
P
r
o
g
r
e
s
s
i
o
n

Time to disease progression (TTP)

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

Efficacy Results
PLD
(n=105)

Capecitabine
(n=105)

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%

Median number of cycles

Median TTP

V1.0

Prior adjuvant anthracycline treatment had a negative impact on TTP

in the capecitabine group (4.8 months vs. 9.0 months (p=0.0098)
Jger E et al. J Clin Oncol 2010; 28(15s): Abstract 1022.

Adverse Events
PLD
(n=105)

Capecitabine
(n=105)

P Value

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

Diarrhoea (grade 3/4)

V1.0

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

Conclusions

V1.0

PLD and capecitabine demonstrated similar

effectiveness with regard to TTP
PLD arm showed a better tolerability profile
compared to capecitabine

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

The clinical benefit of pegylated

liposomal doxorubicin in patients
with metastatic breast cancer
previously treated with conventional
anthracyclines: a multicentre phase II
trial
Al-Batran S et al. Br J Cancer 2006; 94(11): 1615-1620

V1.0

Study Design

Metastatic breast
cancer patients
At least one prior
chemotherapy for
metastatic disease
Previously treated
with anthracyclines
N = 79

Pegylated Liposomal
Doxorubicin (PLD) 50 mg/m2
every 4 weeks

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

Primary endpoint:

V1.0

D
i
s
e
a
s
e
P
r
o
g
r
e
s
s
i
o
n

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

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

Patient Demographics
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%

31.6%

35.4%

ER+ and PgR+

HER2+

86%
5.1%*

Site of disease

Bone only

6.3%

Non-visceral soft tissue only

11.1%

Visceral

82.6%

* n=3 by histochemistry or amplification by FISH

V1.0

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

Treatment History
PLD (n=79)

Previous chemotherapy for MBC

1 regimen

37.9%

2 regimens

29.1%

3 regimens

32.9%

Prior anthracycline-base therapy

100%

Adjuvant only

22.8%

Metastatic only

68.4%

Both settings

8.9%

Anthracycline free interval

V1.0

0-12 months

41.8%

>12 months

58.2%

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

Efficacy Results
PLD (n=79)
ORR (CR+PR)
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 months

Median OS

V1.0

12.7%

12.3 months

Anthracycline resistant

9.0 months

Non-anthracycline resistant

12.5 months

Anthracycline resistant defined as having disease progression on anthracyclinebased therapy for MBC or within 6 months of adjuvant anthracycline-based therapy
Al-Batran S et al. Br J Cancer 2006; 94(11): 1615-1620

OS and PFS

V1.0

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

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 Interval

V1.0

0-12 months (n=29)

24.1%

>12 months (n=32)

25%

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

Safety Results
Non-Hematological (n=79)

All Grades

Grade 1-2

Grade 3-4

Alopecia

53.8%

53.8%*

Nausea

47.4%

42.3%

5.1%

Diarrhoea

15.3%

15.3%

Vomiting

34.6%

32.0%

2.5%

Constipation

34.6%

30.7%

3.8%

Fever

19.2%

19.2%

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%

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%

Haematological (n=76)

*20 Grade 1,22 grade 2; most events were considered not related to PLD but to prior therapies by the investigator
V1.0

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

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

V1.0

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

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)

V1.0

In general, no overlapping toxicity so readily able to

combine with other agents such as taxanes and
gemcitabine