1. CAELYX CLINICAL TRIALS Metastatic Breast Cancer (MBC)

2. Clinical Benefits of CAELYX in Breast Cancer
Anthracycline with cardiac sparing effect
Significantly reduced risk of cardiotoxicity
Preserves cardiac function for patients who can benefit from long-term anthracycline therapy
Comparable efficacy vs conventional doxorubicin
Clinical evidence demonstrates improved safety profile:
Lower incidence: Higher incidence:
Nausea/vomiting – Hand-foot syndrome
Alopecia (HFS)
Myelosuppression – Stomatitis
Cardiotoxicity
The rationale for CAELYX use in the treatment of breast cancer is based on the activity and safety demonstrated in clinical trials. The remainder of the presentation will highlight data from recently reported clinical trials demonstrating that:
Preclinical and clinical data continue to support that CAELYX therapy is associated with a significant reduction in risk of cardiotoxicity and preserves cardiac function, which is critical for patients who can benefit from long-term anthracycline therapy.
Comparable efficacy versus conventional doxorubicin for the first-line treatment of metastatic breast cancer (O’Brien 2004),
An improved safety profile with data supporting a significantly reduced risk of cardiotoxicity compared with conventional doxorubicin, a lower incidence of myelosuppression, nausea, vomiting, and alopecia than conventional doxorubicin (although an increase in the incidence of stomatitis and hand-foot syndrome [HFS] are often associated with CAELYX), and a lower incidence of myelosuppression compared with other salvage regimens (Keller 2004).

3. CAELYX – Current Indications
Monotherapy for MBC in patients who are at increased cardiac risk
Several studies demonstrating antitumor activity and acceptable tolerability in MBC and LABC
Advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen
AIDS-related KS in patients with low CD4 counts (<200 CD4 lymphocytes/mm3) and extensive mucocutaneous or visceral disease
CAELYX is indicated in the EU as monotherapy for the treatment of metastatic breast cancer in patients who are at an increased cardiac risk. This indication was based on studies demonstrating good antitumor activity as well as acceptable tolerability in MBC.
CAELYX is also indicated for use in advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen as well as in Kaposi’s sarcoma.

4. CAELYX in Breast Cancer: Target Populations
Rechallenge (eg, 1st-line treatment of MBC that responded to an anthracycline-containing regimen in adjuvant setting)
Combination therapy with trastuzumab
Patients with cardiovascular risk factors (eg, patients who present with hypertension, prior mediastinal irradiation, or a history of heart disease)
Elderly patients
Patients for whom the risk of specific toxicities are of significant concern (eg, alopecia, myelosuppression, N/V)
Studies of CAELYX in the metastatic setting suggest several target breast cancer populations may benefit from CAELYX therapy. These include
Rechallenge, for example, in the first-line treatment of metastatic disease in patients who responded to an anthracycline-containing regimen in the adjuvant setting (>12 months in remission),
Combination with trastuzumab therapy
Patients with cardiovascular risk factors (eg, patients with hypertension, prior mediastinal irradiation, or a history of heart disease)
Elderly patients, and
Patients for whom the risk of specific toxicities are of significant concern. CAELYX has a proven safety record with improved tolerability with respect to myelosuppression, alopecia, and N/V, making it an ideal treatment option.
All of these points provide a sound rationale for the use of CAELYX in the treatment of breast cancer

5. CAELYX Monotherapy
Sequential single-agent chemotherapy represents a reasonable option for patients with MBC
Monotherapy or sequential single-agent chemotherapy may be especially suitable for:
Elderly or patients with poorer performance status
Those unable to tolerate the toxicity of combination therapy
Patients with slowly growing tumors
As demonstrated by clinical trial findings, sequential single-agent chemotherapy represents a reasonable option for patients with MBC.
Furthermore, monotherapy or sequential single-agent chemotherapy may be especially suitable for:
Elderly or patients with poorer performance status
Patients unable to tolerate the toxicity of combination therapy
Patients with slowly growing tumors

6. Single-Agent CAELYX for MBC: Phase II Studies
Ranson
(JCO 1997)
Lyass
(Cancer 2000)
No. of patients 71 45
Pt. population
~ 40% previously-treated
100% pretreated;
69% ≥ 2 regimens; 71% previous anthracycline
CAEYLX regimen
45-50 mg/m2 q 3-4 wk x 6 cycles
35-70 mg/m2 q 3-6 wk
Efficacy – ORR
31%
33%
Safety
Gr 3/4 neutropenia
Gr 3/4 mucositis
HFS
27%
32%
5% of cycles
(45 mg/m2 Q 4 w)
Mild; dose-dependent
Dose-dependent
Schedule-dependent
The safety and efficacy of CAELYX as single-agent therapy for metastatic breast cancer have been evaluated in seven phase II trials. In six of the studies, patients who were previously-treated for metastatic disease were eligible. In one trial, CAELYX was administered as first-line treatment of MBC.
This slide summarizes results from two phase II trials in previously treated MBC. Favorable overall response rates of 31-33% were demonstrated. As the Lyass trial was a dose-finding trial, the toxicity associated with the drug was defined by dose as well as schedule, with neutropenia and mucositis occurring more frequently at higher doses. Palmar-plantar erythrodysethesia, or hand-foot syndrome (HFS), occurred at greater frequency in the every 3-week schedule and usually developed in patients after the 2nd cycle.

7. Single-Agent CAELYX for MBC: Phase II Studies
Coleman
(Proc. SABCS 2002)
No. of pts (evaluable)
106
Pt. population
Randomized; ≥ 65 yo or contraindication to standard anthra.; 33% pretreated
CAEYLX regimen
(A) 60 mg/m2 q 6 wk -or- (B) 50 mg/m2 q 4 wk
Efficacy – ORR
20-23%
Safety
Gr 3/4 neutropenia
Gr 3/4 mucositis
HFS NR
31% (A)/ 18% (B)
11% (B)
In a randomized phase II study, Coleman and colleagues looked at two different doses and schedules of CAELYX in MBC patients that were 65 years of age or older or who had refused or presented with a medical contraindication to standard anthracycline-based therapy. CAELYX was administered as 50 mg/m2 q 4 weeks or 60 mg/m2 every 6 weeks. Both regimens were tolerable; although an unexpected high incidence of mucositis was observed in arm A.

8. Single-Agent CAELYX for MBC: Phase II Studies
Schmid
(Proc. SABCS 2004)
Mlineritsch
(Onkologie 2004)
No. of patients (evaluable)
24 (19) 30
Pt. population
Heavily pretreated (med. prior regimens, 4); 88% prior anthra.; 83% prior taxane; cum. dox < 400 mg/m2 at entry
Failure of prior chemo for MBC (10% prior adjuvant anthra)
CAEYLX regimen
25 mg/m2 q 2 wk
45 mg/m2 q 4 wk
Efficacy – ORR
5% (CB* = 21%)
31%
Safety
Gr 3/4 neutropenia
Gr 3/4 mucositis
HFS
13% (no grade 4)
3% FN
30% (all ≤ grade 2)
This slide summarizes results from two phase II trials in previously treated MBC.
Schmid and colleagues evaluated the efficacy, tolerability, and pharmacokinetic profile of a biweekly schedule of CAELYX in 24 heavily pretreated patients with MBC. The rationale for the biweekly schedule was to provide more constant drug levels and to obtain a more flexible regimen. Treatment was generally well tolerated, with no grade 3 or 4 leukopenia, neutropenia, or thrombocytopenia. Three patients reported HFS. Of 19 patients assessable for response, 1 had a PR and 3 SD (clinical benefit rate [CB] = 21%). Overall, this study established that biweekly CAELYX is an easily manageable schedule with a favorable toxicity profile.
Austrian investigators evaluated the clinical benefit and toxicity of CAELYX 45 mg/m2 every 4 weeks in 30 patients with MBC who failed a prior chemotherapy regimen for MBC. Nine patients (31%) had a PR and 16 SD for a CB rate of 86%. The median time to progression was 4 months, median duration of response 7 months, and median survival 12 months. Skin toxicity was the most common adverse event (30%), but none were grade 3 or 4 events. Findings of this trial demonstrate a well-tolerated regimen with high rate of clinical benefit.
With a respectable objective response rate and tolerability demonstrated for CAELYX in this previously treated MBC population, trials in the first-line setting were warranted.
*Clinical Benefit =PR + SD > 6 mo.; 3 of 4 received prior anthra.

9. CAELYX 50 vs 40 mg/m2 in MBC: A Phase II Trial
Previously treated MBC
CAELYX 40 mg/m2 q 4 wk
A recently reported phase II trial evaluated a dose modification of CAELYX (40 mg/m2 every 4 weeks) in heavily pretreated patients with MBC. The results of this study were compared to those of a previous multicenter study of similar design evaluating CAELYX 50 mg/m2 every 4 weeks (n=46) in order to assess differences in toxicity.
Al-Batran et al. Breast Cancer Res Treat. 2004; 88:S204. Abstract Updated based on poster.
Compared results to 50 mg/m2 trial of similar design
Al-Batran et al. Breast Cancer Res Treat. 2004; 88:S204. Abstract Updated based on poster.

10. CAELYX 50 vs 40 mg/m2 in MBC: Outcomes
Efficacy
ORR
PFS, median
OS, median
17%
4.6 mo
13.8 mo
13%
3.3 mo
9.8 mo
Safety
Dose reduction, % pts
Median no. of cycles
Toxicity
Grade 3/4 HFS
Grade 3/4 Stomatitis
Grade 3/4 Neutropenia
28% 5 7%
16% 4 0% 2% 9%
Of the 53 patients enrolled, 45 patients treated with the lower CAELYX dose were evaluable for toxicity and tumor response and this was compared to 46 patients treated with 50 mg/m2.
Monthly CAELYX demonstrated ORRs ranging from 13-18% and clinical benefit rates of 51-53%. Notably, the lower dose of CAELYX was associated with less grade 3 or 4 HFS, grade 3 or 4 neutropenia, dose reductions, and treatment shifts due to nonhematologic toxicity. A trend toward improved PFS and OS were demonstrated with the higher dose level.
Al-Batran et al. Breast Cancer Res Treat. 2004; 88:S204. Abstract Updated based on poster.
Al-Batran et al. Breast Cancer Res Treat. 2004; 88:S204. Abstract Updated based on poster.

11. CAELYX vs Docetaxel in MBC: A Randomized Phase II Trial
Study Design
1st-line MBC
Open-label, crossover
Phase II
Eligibility
Prior adjuvant anthracycline or taxane if ≥ 6 mo
≤ 300 mg/m2 of prior doxorubicin
Normal LVEF
N = 73 R A N D O M I Z T C R O S V E R†
CAELYX 40 mg/m2 q 4 wks*
N = 36
Investigators at the Sarah Cannon Cancer Center and the Minnie Pearl Cancer Research Network are conducting an open-label, crossover, randomized phase II trial to compare the outcomes between CAELYX and weekly docetaxel as first-line treatment of women with MBC.
Though patient accrual is continuing for a planned total of 120 evaluable patients, interim results of the first 73 patients were reported at the 2004 San Antonio Breast Cancer Symposium.
Patients with MBC who were 6 months or longer from completion of adjuvant therapy and had received cumulative doxorubicin doses < 360 mg/m2 were eligible.
Patients were randomly assigned to receive either:
CAELYX 40 mg/m2 every 4 weeks for a maximum of 8 cycles prior to crossover or
Docetaxel 36 mg/m2 weekly x 3 every 4 weeks for a maximum of 8 cycles prior to crossover.
Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract 5057.
Docetaxel 36 mg/m2 d 1, 8, 15 q 4 wks*
N = 37
*Max. 8 cycles prior to crossover
†At time of progression
Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract 5057.

12. CAELYX vs Docetaxel: Interim Results
Median no. of cycles
2.5 4
Response rate (initial regimen)
17%
22%
Progression-free survival
6.9 mo
5.4 mo
Overall survival
15.8 mo
13.6 mo
With median number of cycles received of 2.5 and 4, respectively, CAELYX and docetaxel demonstrated similar response rates (17% vs 22%) as first-line treatment of MBC.
At this interim analysis, both progression-free and overall survival rates favor first-line treatment with CAELYX, although it is not yet statistically significant.
Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract 5057.
*22 patients received drug on crossover; †18 patients received drug on crossover
Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract Updated based on poster.

13. CAELYX vs Docetaxel: Toxicity
% of Pts
Grade 3 and 4 Toxicity
CAELYX
(n=36)
Docetaxel
(n=37)
Neutropenia 14
Anemia 3 5
Transfusions 6 11
Fatigue 30
Arthralgia
Nausea 16
HFS
Stomatitis
Hospitalization 17 35
Grade 3 or 4 hematologic toxicity did not differ between the treatment arms, though patients who received docetaxel required more transfusions and hospitalizations.
Grade 3 or 4 nonhematologic toxicities were increased 2-fold with weekly docetaxel, and were most notable for fatigue, arthralgias, and hospitalizations.
Grade 3 and 4 HFS and stomatitis were uncommon, occurring slightly more frequently in patients treated with CAELYX.
Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract Updated based on poster.

14. Conventional doxorubicin 60 mg/m2 q 3 wks†
CAELYX vs Conventional Doxorubicin in First-line Treatment of MBC: Phase III Trial
N = 509
68 international sites
Study Design
1st-line MBC (Stages IIIB/IV)
Open-label, multicenter
Stratification
Prior adjuvant anthracycline
Cardiac risk factor
Bone only mets R A N D O M I Z T
CAELYX 50 mg/m2 q 4 wks*
In a open-label, multicenter trial, 509 women with previously untreated MBC (stage IIIB/IV), from 68 international sites, were randomized to receive either CAELYX 50 mg/m2 IV every 4 weeks or conventional doxorubicin 60 mg/m2 IV every 3 weeks.
Prior hormonal or adjuvant anthracycline therapy was permitted, as long as the cumulative doxorubicin dose (or doxorubicin-equivalent dose) was ≤ 300 mg/m2, and the adjuvant chemotherapy-free interval of >12 months.
Normal LVEF was required.
Patients were prospectively stratified based on three criteria:
prior adjuvant anthracycline exposure;
presence of bone metastases as only site of metastatic disease; and the
presence of at least one cardiac risk factor. Cardiac risk factors were defined as prior mediastinal irradiation, age ≥ 65 years, history of heart disease or hypertension, or diabetes requiring medical attention.
Treatment was continued until disease progression, unacceptable toxicity, or in the conventional doxorubicin arm, until a cumulative doxorubicin dose of 550 mg/m2 was reached.
Conventional doxorubicin 60 mg/m2 q 3 wks†
*Until PD or unacceptable toxicity.
†Until PD or cumulative anthracycline dose of 550 mg/m2.
O’Brien et al. Ann Oncol. 2004;15:

15. CAELYX vs Doxorubicin Study Endpoints
Primary
Progression-free survival (non-inferiority)
Cardiotoxicity:
Cardiac event as defined by:
LVEF decrease of ≥ 20% from baseline if resting LVEF remained in normal range
LVEF decrease of ≥ 10% if resting LVEF became abnormal
Patients also assessed for clinical signs/symptoms of CHF
Secondary
Overall survival
Overall response rate
Tolerability
The endpoints of the trial are summarized on this slide.
Primary: To test whether efficacy (progression-free survival [PFS]) of CAELYX was statistically noninferior to conventional doxorubicin and whether significantly less cardiotoxicity was observed with CAELYX. A protocol-specified cardiac event was defined as a LVEF decrease of ≥ 20% from baseline if resting LVEF remained in normal range, or a LVEF decrease of ≥ 10% if LVEF became abnormal (defined by institution‘s normal values). Patients were also assessed for clinical signs/symptoms of congestive heart failure.
Secondary: To compare treatment effects on overall survival (OS), overall response rate, tolerability, and health care resource utilization (use of growth factors, transfusions, antiemetics, etc.).
O’Brien et al. Ann Oncol. 2004;15:

16. Baseline Patient Demographics
CAELYX
(N=254)
Conventional Doxorubicin
(N=255)
Median age, years 59 58
Menopausal status, %
Premenopausal
Postmenopausal 31 69 35 62
Estrogen receptor status, %
ER +
ER - 21 40 23
WHO performance status, % 1 2 54 37 9 49 11
From June 1998 to August 2000, 509 women were enrolled, 254 in the CAELYX group and 255 in the conventional doxorubicin group. Both groups were comparable with respect to demographic and disease characteristics, including:
Age (median 58 to 59 years);
Menopausal status;
Estrogen receptor status; and
WHO performance status.
O’Brien et al. Ann Oncol. 2004;15:

17. Baseline Disease Characteristics
CAELYX
(N=254)
Conventional Doxorubicin
(N=255)
No. of metastatic sites, % 1 2
≥ 3 37 33 30 41 31 28
Metastatic site classification, %
Visceral
Nonvisceral
Bone metastases only 59 32 9 56 34 10
Patients in both arms of the study were well matched for the number and the sites of metastatic disease, with 30% in both treatment arms having 3 or more metastatic sites. Approximately 60% of patients had visceral disease and 10% had bone only disease.
O’Brien et al. Ann Oncol. 2004;15:

18. Baseline Demographics Prior Therapy
CAELYX
(N=254)
Conventional Doxorubicin
(N=255)
Prior therapy*, %
Adjuvant only
Advanced disease only
Adjuvant and advanced disease 65 52 5 8 62 42 7 12
Prior conventional anthracycline, % 15 16
Baseline cum. anthracycline (mg/m2), %
< 150
> 300 2
< 1 13 1
Previous radiation therapy, % 47 49
Two-thirds of the patients in each group had received prior therapy; approximately one-half of the patients received prior chemotherapy of hormonal therapy in the adjuvant setting. One patient in the CAELYX group received chemotherapy only for advanced disease and two patients in the conventional doxorubicin group received both chemotherapy and hormonal therapy for advanced disease; all three of these patients were in violation of the protocol.
Fifteen percent of the CAELYX-treated patients and 16% of the conventional doxorubicin-treated patients had received prior adjuvant anthracyclines with an even distribution or prior baseline cumulative anthracycline between the two groups.
Approximately one-half of the patients received prior XRT.
*Chemotherapy or hormonal therapy.
O’Brien et al. Ann Oncol. 2004;15:

19. Baseline Cardiac Risk Factors
CAELYX
(N=254)
Conventional Doxorubicin
(N=255)
No cardiac risk factors, % 52 53
Prior cardiac risk factors, %
Prior mediastinal irradiation
History of heart disease
History of hypertension
Age ≥ 65
≥ 2 risk factors 48 4
0.4 12 15 17 47 3 13
Approximately one-half of the patients in each group presented with at least one cardiac risk factor. Risk factors were defined as prior mediastinal irradiation, history of heart disease, history of hypertension, and 65 years of age or older. Approximately 15% in each group presented with at least 2 cardiac risk factors.
O’Brien et al. Ann Oncol. 2004;15:

20. Results: Treatment Summary
CAELYX
(N=254)
Conventional Doxorubicin
(N=255)
Median duration of therapy, wks (cycles)
21 (5.3)
19 (6.3)
Mean dose per cycle, mg/m2 48 58
Mean cycle length, days
29.6
22.3
Median cum. anthracycline exposure*, mg/m2
293
361
Drug discontinuation, % 24
Patients in the CAELYX group received a median of 5.3 cycles of treatment, whereas patients in the conventional doxorubicin group received a median of 6.3 cycles. Corresponding mean cycle lengths were 29.6 and 22.3 days, respectively.
The mean dose per cycle was 48 mg/m2 for CAELYX and 58 mg/m2 for conventional doxorubicin.
Twenty-four percent (24%) of patients in each group discontinued treatment.
Patients in the CAELYX group received a median of 5.3 cycles of treatment, whereas patients in the conventional doxorubicin group received a median of 6.3 cycles. Corresponding mean cycle lengths were 29.6 and 22.3 days, respectively.
The mean dose per cycle was as follows: 48 mg/m2 for CAELYX and 58 mg/m2 for conventional doxorubicin.
More patients in the CAELYX group discontinued treatment for an adverse drug reaction (22% vs 9%), whereas more patients in the conventional doxorubicin group discontinued treatment for cardiotoxicity (14% vs 2%).
*Including prior anthracycline therapy
O’Brien et al. Ann Oncol. 2004;15:

21. CAELYX vs Doxorubicin Response Rates*
Conventional Doxorubicin
(N=201)
Overall response rate (CR + PR)
33%
38%
Complete response (CR) 3% 4%
Partial response (PR)
29%
34%
Stable disease (SD)
25%
Progressive disease (PD)
18%
11%
Median duration of response
7.3 mo
7.1 mo
Of the 509 patients entered into the study, 410 patients were assessable for disease response.
The overall response rate was similar between CAELYX and conventional doxorubicin, 33% vs 38%, repectively.
Twenty-five percent of assessable patients in each group had stable disease.
The median duration of response was 7.3 months in the CAELYX group vs 7.1 months in the conventional doxorubicin group.
*Measurable disease (n=410); 25% in each group had no radiographic assessment of response.
O’Brien et al. Ann Oncol. 2004;15:

22. CAELYX vs Doxorubicin Progression-Free Survival (PFS)
Intent-to-Treat Population
CAELYX
Conventional doxorubicin
Median PFS, mo.
6.9
7.8
1.0
0.9
0.8
HR = 1.00 (95% CI: )
0.7
0.6
Probability
0.5
0.4
Of the 509 patients, 81% (410/509) progressed at a median of 6.9 months in the CAELYX arm and 7.8 months in the conventional doxorubicin arm.
The hazard ratio (HR) for PFS was 1.00 (95% confidence interval [CI] for HR = ); consistent with non-inferiority of CAELYX compared with conventional doxorubicin.
0.3
0.2
0.1 5 10 15 20 25 30 35
Months From Randomization
O’Brien et al. Ann Oncol. 2004;15:

23. CAELYX vs Doxorubicin Overall Survival (OS)
Intent-to-Treat Population
CAELYX
Conventional doxorubicin
Median OS, mo. 21 22
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
HR = 0.94 (95% CI: ); P = .59
Probability
Overall survival (OS) was also comparable between both treatment groups (median OS of 21 months for CAELYX versus 22 months for conventional doxorubicin; HR = 0.94; 95% CI: ).
At the time of the analysis, approximately 56% of patients in each arm had died.
When adjusted for potential imbalances in prognostic variables using the Cox regression analysis, the HR was 0.94 (95% CI: ), again consistent with the unadjusted treatment HR. 5 10 15 20 25 30 35
Months From Randomization
O’Brien et al. Ann Oncol. 2004;15:

24. CAELYX vs Doxorubicin - Cardiac Events -
Conventional Doxorubicin
(N=255)
LVEF decrease
LVEF decrease +
signs/symptoms of CHF
LVEF decrease alone 10 48 38
Signs and symptoms of CHF without LVEF decrease 2
Patients who stopped therapy due to cardiac event 6 36
The effect of either drug on LVEF is listed on this slide. Compliance with performing MUGA evaluations was high. Overall, 339 patients had serial MUGA scan data for evaluation; in addition, all patients were followed clinically for signs and symptoms of CHF.
Fifty-eight patients met the protocol-defined LVEF criteria for cardiotoxicity (a decrease of ≥ 20% from baseline if resting LVEF remained in the normal range, or a decrease of ≥ 10% if the LVEF became abnormal), 10 CAELYX-treated patients compared with 48 conventional doxorubicin-treated patients. None of the 10 CAELYX-treated patients developed clinical signs and symptoms of CHF, whereas 10 of the 48 doxorubicin-treated who had cardiotoxicity by LVEF criteria developed signs or symptoms of CHF. Two patients in each group developed clinical CHF but did not have a corresponding LVEF decrease.
Among the CAELYX-treated patients, 6 or 2% discontinued therapy due to cardiac toxicity versus 36 patients, or 14% in the conventional doxorubicin arm.
O’Brien et al. Ann Oncol. 2004;15:

25. CAELYX vs Doxorubicin Cardiac Events vs Cumulative Dose
100 90 80 70 60 50 40 30 20 10
150
200
300
250
400
450
500
550
600
350
Cumulative Anthracycline Dose
Kaplan-Meier Estimates of Cardiac Events
CAELYX
Conventional Doxorubicin
HR = 3.16 (95% CI: ); P < .001
This graph depicts the rate of cardiac events versus cumulative anthracycline dose. The risk of developing cardiotoxicity was significantly higher for patients receiving doxorubicin than for those receiving CAELYX, with a HR = 3.16 (for comparison of cumulative anthracycline dose at the first protocol-specified cardiac event).
At cumulative doses > 500 mg/m2, there was a 40% risk of developing a cardiac event with doxorubicin compared with only an 11% risk with CAELYX.
Important to note, at all cumulative doses above 450 mg/m2, the risk for patients treated with CAELYX did not increase.
O’Brien et al. Ann Oncol. 2004;15:

26. CAELYX vs Doxorubicin LVEF vs Cumulative Dose
Cumulative Anthracycline Dose (mg/m2)
All
< 300
≥ 300 to < 450
≥ 450 -2
n=62
n=54 -4
n=152
n=36 -6
n=58 -8
n=74
n=187
Median % Change From Baseline
As expected with conventional doxorubicin, the mean percentage change from baseline in LVEF was positively correlated with increasing cumulative dose.
The bar graphs reflects cumulative dose at which the MUGA scan was performed.
With CAELYX, left ventricular function remained relatively constant with increasing cumulative dose.
With conventional doxorubicin, decreases in ventricular function were considerably higher than with CAELYX, and increased as cumulative dose increased. At cumulative doses at or above 450 mg/m2, a seven-fold greater mean percentage decrease in LVEF was observed with conventional doxorubicin (-17.2% versus -2.3%; mean percentage change from baseline in LVEF in doxorubicin-treated and CAELYX-treated patients, respectively).
-10
-12
CAELYX
-14
Conventional Doxorubicin
-16
n=55
-18
O’Brien et al. Ann Oncol. 2004;15:

27. CAELYX vs Doxorubicin Cardiotoxicity in High-Risk Patients
Events HR
95% CI
≥ 65 years of age
CAELYX
Doxorubicin
Prior adjuvant anthracycline
Cardiac Risk factor 78 66 38 40
122
121 9 1 11 5 21
N/A
7.27
2.7
In all subgroups analyzed, including patients at high risk for developing CHF and those that received prior adjuvant anthracycline therapy, there was an increased risk of developing cardiotoxicity if receiving doxorubicin versus CAELYX.
In the subgroup that received prior adjuvant anthracycline therapy, the risk of developing cardiotoxicity was 7-fold higher with conventional doxorubicin than with CAELYX.
O’Brien et al. Ann Oncol. 2004;15:

28. Treatment-Related Adverse Events All Grades*
% Patients
Hand-foot syndrome (HFS) was the most common adverse event associated with CAELYX, occurring in 48% of patients; HFS was seen in 5 (2%) of the conventional doxorubicin patients.
Nausea and vomiting of any severity were less often associated with CAELYX (37% and 19%, respectively) than with conventional doxorubicin treatment (53% and 31%, respectively). Grade 3 vomiting was reported in 2 patients treated with CAELYX versus 11 patients treated with conventional doxorubicin.
Mucositis and stomatitis were more commonly associated with CAELYX (23% and 22%, respectively) than with conventional doxorubicin (13% and 15%, respectively).
However, alopecia was markedly less frequent with CAELYX (20%) than with conventional doxorubicin (66%).
*Grade 2 alopecia = complete hair loss; grade 3-4 NA.
O’Brien et al. Ann Oncol. 2004;15:

29. Treatment-Related Adverse Events: Alopecia
CAELYX
(N=254)
Conventional Doxorubicin
(N=255)
Overall incidence
20%
66%
Pronounced or total hair loss 7%
54%
The overall incidence of alopecia was markedly lower with CAELYX (20%) than with conventional doxorubicin (66%).
Pronounced or total hair loss was reported in only 7% of CAELYX-treated patients compared with 54% of conventional doxorubicin patients.

30. Treatment-Related Adverse Events Grades 3/4*
% Patients
The incidence of grade 3 and 4 toxicity was low for both groups.
The most commonly reported grade 3/4 toxicity was HFS for the CAELYX-treated patients. The incidence of grade 3 HFS was 17%; there was no grade 4 (life-threatening) HFS. Skin toxicity resulted in treatment discontinuation in 7% of CAELYX-treated patients.
*Grade 3-4 alopecia NA ; grade 2 alopecia = complete hair loss; cardiotoxicity not included.
O’Brien et al. Ann Oncol. 2004;15:

31. Study Conclusions
CAELYX provides comparable efficacy to conventional doxorubicin
CAELYX has significantly less cardiotoxicity than conventional doxorubicin
7-fold reduction in risk of cardiotoxicity with CAELYX in pts previously treated with anthracyclines
CAELYX has a distinct side effect profile
Significantly less alopecia, N/V, myelosuppression
Manageable HFS
CAELYX has an improved risk-benefit profile
In this large randomized phase III trial, CAELYX demonstrated comparable efficacy to conventional doxorubicin, in terms of both progression-free and overall survival, in the first-line treatment of women with metastatic breast cancer.
The results of this trial clearly demonstrated that CAELYX is less cardiotoxic than conventional doxorubicin in all subgroups analyzed and results in significantly fewer clinical cardiac events. In women who had received prior anthracycline therapy, the risk of developing cardiotoxicity was 7 times higher with conventional doxorubicin than with CAELYX.
CAELYX has a distinct side effect profile relative to conventional doxorubicin with improved cardiac safety, and with less alopecia, N/V, and myelosuppression. There was a higher incidence of skin toxicity (HFS) associated with CAELYX therapy. The HFS, however, is reversible and easily managed with appropriate supportive care measures.
Based on the safety and efficacy data, CAELYX has an improved risk-to-benefit profile, offering a therapeutic alternative to conventional doxorubicin for the first-line treatment of women with metastatic breast cancer.
O’Brien et al. Ann Oncol. 2004;15:

32. CAELYX in MBC After Taxane Failure
301 Patients
52 International sites R A N D O M I Z T
Study Design
MBC after taxane failure (Stage IIIB/IV)
Open-label, multicenter
Phase III
Stratification
Number of prior regimens (1 or 2)
Presence of bone metastases only (yes/no)
CAELYX 50 mg/m2 q 4 weeks
N = 150
Vinorelbine 30 mg/m2 weekly
- OR -
In a randomized, open-label, multicenter phase III trial of CAELYX in taxane-refractory metastatic breast cancer, 301 women from 52 international sites, were randomized to receive either CAELYX, 50 mg/m2 IV every 4 weeks, or to standard salvage chemotherapy (SSC), investigator-determined at site, to be either:
vinorelbine 30 mg/m2 IV weekly –OR–
mitomycin C 10 mg/m2 IV on Days 1 and 28 and vinblastine 5 mg/m2 IV on Days 1, 14, 28 and 42 for 2 cycles (Days 1 to 56); subsequent cycles: mitomycin C 10 mg/m2 IV on Day 1 and vinblastine at 5 mg/m2 IV on Days 1 and 21. Mitomycin C was administered at 6- to 8-week intervals after adequate hematologic recovery.
Women with advanced breast cancer that had failed a prior taxane-containing regimen, defined as having progressed during or within 6 months of the last dose of taxane-based therapy for advanced disease, were eligible.
Patients could have received 1, but no more than 2, prior chemotherapy regimens for advanced disease; last regimen must have included a taxane.
Patients that had received a prior cumulative doxorubicin-equivalent dose > 450 mg/m2, or a cumulative epirubicin dose > 840 mg/m2 were excluded.
Patients were stratified based on number of prior regimens (1 or 2), and presence of bone metastases only (yes or no).
N = 129
Mitomycin C 10 mg/m2 d 1, 28
Vinblastine 5 mg/m2 d 1, 14, 28, 42*
N = 22
*Days 1-56 for 2 cycles; subsequent cycles: Mitomycin C on d 1 and vinblastine D1, 21; Mitomycin C dosed every 6 to 8 wks.
Keller et al. J Clin Oncol. 2004;22:

33. CAELYX in MBC After Taxane Failure Study Endpoints
Primary
Progression-free survival
Secondary
Overall survival
Overall response rate
Response duration
Event-free survival
Tolerability
QOL
The endpoints of the trial are summarized on this slide.
Primary: Progression-free survival (PFS).
Secondary: Overall survival (OS), overall response rate, response duration, event-free survival, tolerability, health-related quality of life, and clinical benefit response.
Keller et al. J Clin Oncol. 2004;22:

34. Baseline Characteristics
CAELYX
(N=150)
Comparator
(N=151)
Age, years 56
Postmenopausal, % 54
Estrogen Receptor Status, %
Positive
Negative 47 33 48 32
Sites of Metastasis, %
Visceral
Bone only 63 10 66
Previous Chemotherapy Regimens, n 1 2
1 only bone mets
2 only bone mets 22 23 3
Baseline disease characteristics were representative of patients with advanced breast cancer and comparable between treatment groups.
The majority of patients (63% to 66%) had visceral disease.
The groups were comparable with regard to patient stratification based on number of previous chemotherapy regimens for metastatic disease and presence of bone metastases.
PLD = pegylated liposomal doxorubicin hydrochloride.
Keller et al. J Clin Oncol. 2004;22:

35. Prior Therapy CAELYX (N=150) Comparator (N=151) Adjuvant therapy, % 7873
Hormonal therapy, % 65 59
Chemotherapy, %
Adjuvant only
Advanced disease only
Adjuvant plus advanced disease 4 22 74 27 69
Prior therapy is summarized on the following 2 slides.
Approximately three-quarters of the patients in each treatment arm received prior adjuvant therapy. The majority of the patients received chemotherapy in both the adjuvant and advanced setting.
PLD = pegylated liposomal doxorubicin hydrochloride.
Keller et al. J Clin Oncol. 2004;22:

36. Prior Therapy (cont.) CAELYX (N=150) Comparator (N=151)
Regimens for advanced dz, % 1 2 56 35 52 36
Anthracycline exposure, % 83 84
Cumulative prior anthracycline dose (mg/m2), %
0-300
>
>450 61 17 5 26 3
Primary anthracycline resistance, % 39
Radiation therapy, % 77 71
Half of the patients received 1 prior regimen for advanced disease, while one-third of the patients had received 2 prior regimens.
Eighty-three percent of patients received prior anthracycline therapy; 35% to 39% were deemed primary anthracycline-resistant, defined by the protocol as having disease progression during anthracycline therapy for MBC or within 6 months of receiving an anthracycline-containing regimen in the adjuvant or metastatic setting.
Of those who have received prior adjuvant anthracyclines, most received less than or equal to 300 mg/m2 cumulative dose.
The majority of the patients had received prior radiation therapy.
PLD = pegylated liposomal doxorubicin hydrochloride.
Keller et al. J Clin Oncol. 2004;22:

37. CAELYX in MBC After Taxane Failure Response Rates
Comparator
(N=117)
Overall Response (CR + PR)
Complete Response (CR)
Partial Response (PR)
Stable Disease (SD)
Progressive Disease (PD)
10% 2% 8%
28%
32%
12%
Median Duration of Response months months
For protocol-eligible patients, the overall response rate, stable disease rate, as well as the median duration of response, were comparable between the two treatment groups.
[Need to clarify #s on this slide, including protocol ineligible group; numbers in journal article table do not add up to sample size quoted in table…n=80 and 85 for the respective treatment arms]
Keller et al. J Clin Oncol. 2004;22:

38. CAELYX in MBC After Taxane Failure Progression-Free Survival (PFS)
Comparator
Median PFS, mo.
2.9
2.5
1.0
0.9
0.8
0.7
0.6
Progression-Free Survival
0.5
0.4
HR = 1.26 (95% CI: )
0.3
0.2
0.1
Median progression-free survival (PFS) was similar for CAELYX and comparator, 2.9 months vs 2.5 months, respectively, with a trend in favor of CAELYX (HR = 1.26, 95% CI: , P = .11). The progression-free survival data were mature, with 246 events representing 82% of the total study population.
Within 2 months of study initiation, 33% of the patients in the CAELYX group and 41% of the patients in the comparator group had progressed.
At the time of the clinical cutoff, the survival data were relatively immature, with 172 deaths representing 56% of the total study population. 3 6 9 12
Months
Keller et al. J Clin Oncol. 2004;22:

39. CAELYX in MBC After Taxane Failure Overall Survival (OS)
Comparator
Median OS*, mo. 11 9
HR = 1.05 (95% CI: )
Overall Survival
Overall survival was similar between treatment groups (CAELYX-treated group median 11 months vs 9 months for comparator); his difference was not statistically significant (HR = 1.05, 95% CI: , P = .71).
Approximately one-third of the patients in each group died within 6 months of study initiation.
Months
*Data updated in Keller et al. J Clin Oncol. 2004;22:
Data on file Schering-Plough.

40. Progression-Free Survival by Subgroup
CAELYX is effective independent of patient subsets
Patient Population/Subgroups
Protocol Evaluable (115/117)
Age < 55 (49/55)
Age ≥ 55 (66/62)
Performance ≥ 80% (93/99)
Performance < 70% (22/18)
Bone Only (11/11)
Not Bone Only (104/106)
With Any Anthracycline Exposure (92/96)
With No Anthracycline Exposure (23/21)
With Anthracycline Resistance (46/34)
With No Anthracycline Resistance (69/80)
Estrogen Recept: Negative (41/40)
Estrogen Recept: Positive (54/56)
Number of Chemo Regimens < 2 (72/72)
Number of Chemo Regimens ≥ 2 (43/45)
Disease-Free Interval ≤ 24 (52/65)
Disease-Free Interval > 24 (63/52)
Specific subgroups of protocol-eligible patients (those patients that received treatment and met all eligibility criteria), were analyzed retrospectively.
The trend for PFS or OS in favor of CAELYX was maintained in most subgroups analyzed.
0.8 1 2 3
Hazard Ratio with a 95% C.I.
Subgroups analyzed retrospectively based on protocol-eligible patients.
Keller et al. J Clin Oncol. 2004;22:

41. Treatment-Related Adverse Events All Grades
Percent of Patients
The safety data included all randomized patients: CAELYX, n = 150; Vinorelbine, n = 129; Mitomycin C + Vinblastine, n = 22
Eighty-three percent of CAELYX cycles, 56% of vinorelbine cycles, and 83% of mitomycin C plus vinblastine cycles were administered at >80% of the dose.
The most frequently reported adverse events, occurring at similar rates in all 3 treatment groups, were nausea, vomiting, and fatigue.
While neutropenia, neuropathy, and asthenia were uncommon in the CAELYX-treated group and occurred less frequently compared to the comparators, PPE and stomatitis occurred more frequently. Because patients had been previously treated with a taxane, the incidence of alopecia was low, occurring in 5% of patients overall.
Keller et al. J Clin Oncol. 2004;22:

42. Treatment-Related Adverse Events Grades 3/4
Percent of Patients
As highlighted in this slide, the regimens were well tolerated, with minimal grade 3 or 4 toxicity reported.
The incidence of grade 3 hand-foot syndrome (HFS) was 18%, with only 1 case of grade 4 HFS. The discontinuation rate due to HFS was 8%.
Grade 3/4 neutropenia occurred in 8% of patients receiving vinorelbine.
Keller et al. J Clin Oncol. 2004;22:

43. Cardiac Toxicity
Defined per protocol as a decrease in LVEF of ≥ 15 points from baseline or a ≥ 5-point decrease from baseline if level is below LLN for the institution
LVEF changes assessed only in patients receiving CAELYX
22 patients had LVEF changes consistent with protocol-defined cardiac toxicity
No correlation with cumulative anthracycline dose
4 patients dc’d drug due to LVEF decrease
No patient developed clinical CHF
Cardiac toxicity was defined per the protocol as a decrease in LVEF of ≥ 15 points from baseline or a ≥ 5-point decrease from baseline if level is below the lower limits of normal (LLN) for the institution. LVEF changes were assessed only in the patients receiving CAELYX; of those, 22 patients had changes consistent with protocol-defined cardiac toxicity. There was no correlation between the development of cardiac toxicity and cumulative anthracycline dose. Four patients discontinued the drug due to the LVEF change. No patients developed clinical congestive heart failure.

44. Study Conclusions
CAELYX demonstrates activity in MBC after taxane failure:
PFS: 2.9 months (vs 2.5 months comparator)
OS: 11.0 months (vs 9.0 months comparator)
CAELYX has comparable efficacy to vinorelbine/mitomycin for MBC refractory to taxane-based therapies
q 4 wk CAELYX = q wk vinorelbine administration
CAELYX represents a therapeutic option for pts with heavily pretreated, taxane-refractory MBC
This phase III trial represents the first prospective, randomized, controlled study of CAELYX in advanced breast cancer after taxane failure.
CAELYX demonstrated activity as denoted by both the PFS and OS compared to common salvage regimens. It is also important to note that in the anthracycline-resistant subgroup, patients in the CAELYX group derived as much benefit from retreatment with CAELYX as the patients who received standard salvage therapy. It was thought that these patients would be unlikely to respond to retreatment or rechallenge of an anthracycline; nonetheless, CAELYX demonstrated activity in this heavily pretreated patient population.
The efficacy of CAELYX was comparable to common salvage regimens used in the treatment of women with taxane-refractory MBC, and was accomplished in the absence of significant myelosuppression and neuropathy.
As such, CAELYX represents a therapeutic option for the treatment of women with heavily pretreated, taxane-refractory MBC.
Keller et al. J Clin Oncol. 2004;22:

45. CAELYX Combination Therapy for MBC
A number of phase II studies utlizing CAELYX combinations have also been undertaken.

46. Rationale for CAELYX Combinations
Preclinical synergy
Non-overlapping mechanisms/toxicities
Polychemotherapy, in particular with taxane-anthracycline-based regimens, is especially suitable for patients with:
Life-threatening disease
Symptomatic visceral metastatic disease
Quickly growing tumors
Ability to tolerate the toxicity of combination therapy
The rationale for combining CAELYX with other chemotherapeutic agents includes but is not limited to:
The preclinical synergy observed between doxorubicin and a number of chemotherapeutic agents;
Non-overlapping mechanisms and toxicity profiles that make combination therapy attractive;
And that polychemotherapy, in particular with taxane-anthracycline-based regimens, is especially suitable for patients with life-threatening disease, symptomatic visceral metastatic disease, quickly growing tumors, and those with the ability to tolerate the toxicity of combination therapy.

47. CAELYX Combinations Breast Cancer
Investigators
Combination
Response
Overmoyer 1998; Silverman 1999; Srimuninnimit 2002
PLD + cyclophosphamide
41%-68%
Jones 2000; Gogas 2002; Rigatos 2003; Vorobiof 2004; Fulfaro 2004
PLD + paclitaxel
56%-75%
Sparano 2001; Holmes 2003; Alexopoulos 2004; Morabito 2004
PLD + docetaxel
32%-64%
Martin 2002; Gebbia 2002; Ardavanis 2003
PLD + vinorelbine
36%-68%
Rivera 2003; Fabi 2004
PLD + gemcitabine
48%-52%
Guastalla 2003
PLD + cyclophosphamide + 5-fluorouracil
Several phase I-II studies have examined the utility of CAELYX in combination with other agents or modalities in order to improve the efficacy and reduce the toxicity of treatment for metastatic breast cancer. Some of these combinations are listed here. Most of these studies involve populations of women with metastatic breast cancer, but a few include patients with locally advanced disease.
These combinations have achieved promising overall response rates, ranging from 32% to 75%. Numerous additional investigator-sponsored trials evaluating CAELYX alone or in combination with other agents are currently underway.

48. CAELYX + Cyclophosphamide in BC
Silverman
(Proc. ASCO 1999)
Srimuninnimit
(Proc. ASCO 2002)
No. of patients / med. cycles
20 / NR
30 / NR
Pt. population
Untreated (n=6) or previously treated MBC; prior adjuvant anthra. (n=3)
LABC: T3 (n=7); T4 (n=23)
Regimen
CAELYX
Cyclophosphamide
Q 3 wk
30 mg/m2 d 1
600 mg/m2 d 1
Q 3 wk x 3
35 mg/m2 d 1
Efficacy – ORR*
60%
73%
Safety
G 3/4 neutropenia FN
G 3/4 HFS
Cardiac
Moderate 25% NR
Mild 15%
37% 3%
The CAELYX-cyclophosphamide combination has been studied in at least two phase II trials. The combination provides high response rates (60-73%), which are similar to the standard AC combination, but without the cardiotoxic potential and with low hematologic toxicities.

49. CAELYX + Paclitaxel in MBC
Vorobiof
(Breast 2004)
Rigatos
(Oncol Rep 2003)
No. of patients
No. of cycles, median 34 6 24
Not reported
Pt. population
1st line for MBC; 41% received adjuvant chemo- or chemoendocrine therapy (anthra.: 2 pts)
1st line for MBC; all evaluable pts received prior adjuvant chemotherapy
Regimen
CAELYX
Paclitaxel
Q 3 wk
30 mg/m2
175 mg/m2
Efficacy – ORR
73%
70% (23 evaluable)
Safety per patient
G 3/4 neutropenia FN
G 3/4 HFS
Cardiac
2 toxic deaths
21% 6%
29%
1 pt LVEF ↓ > 20%
22%
48%
1-arrhythmia
1-LVEF ↓ (not defined)
Doxorubicin and paclitaxel are two of the most active agents in the treatment of breast cancer. Two recently reported phase II studies have investigated the feasibility of the combination of CAELYX and paclitaxel and are outlined on this slide.
The patient eligibility and treatment regimens were similar for both studies.
Consistent response rates in the range of 70% were achieved.
Toxicity was similar for the two studies. The combination proved to be well tolerated, with approximately 20% of patients in each study developing grade 3 or 4 neutropenia. As demonstrated in both studies, the combination seemed to be essentially devoid of any grade 3 or 4 nausea, vomiting, and mucositis. There were differences in the incidence of PPE and neuropathy. Although the studies were similar, all of the patients in the Rigatos study received prior adjuvant chemotherapy (versus only 41% in the Vorobiof study) and 26% of the patients had a performance status of 2 (versus no patient with a PF of 2 in Vorobiof study). One patient in each study had a documented decrease in LVEF compared to baseline.

50. Neoadjuvant CAELYX + Paclitaxel in LABCR E A M N
CAELYX 35 mg/m2 d 1 +
Paclitaxel 175 mg/m2 d 1
q 3 wk
Phase II
N = 35
Newly diagnosed LABC
RESULTS
ORR % (CR 17%, PR 54%)
pCR after 4-6 cycles 3 pts
Grade 3 HFS 9%
Grade 3/4 neutropenia 15%
Alopecia 83%
The CAELYX-paclitaxel combination has also been evaluated in the neoadjuvant setting.
In this phase II study, 35 patients with newly diagnosed locally advanced breast cancer (T3N1, T0-3N2-3, T4a-cN0-3, T4d) received CAELYX, 35 mg/m2 IV on day 1, followed by paclitaxel, 175 mg/m2 also on day 1, every 3 weeks for 4 cycles. Responding patients continued treatment and received a total of 6 cycles. At that time, a modified radical mastectomy was performed.
Following surgery, patients who had unfavorable tumor characteristics (LN+, ER-, or high nuclear grade) were treated with 6 cycles of CMF.
Overall, 71% of patients responded to the neoadjuvant therapy. Of the 6 patients that achieved a clinical complete response, 3 patients had a confirmed pathological complete response at the time of surgery.
Toxicity was manageable. Fifteen percent of the patients experienced grade 3 or 4 neutropenia and 3 patients, or 9%, developed grade 3 PPE. Six patients required dose reduction due to PPE. Alopecia occurred in 83% of the patients and was attributed to paclitaxel.
Gogas et al. Ann Oncol. 2002;13:

51. CAELYX + Docetaxel in MBC
Alexopoulos
(Ann Oncol 2004)
Holmes
(Proc. SABCS 2003)
No. of patients / med. cycles
44 / 6
48 / 4
Pt. population
1st line for MBC; 46% received prior adjuvant chemotherapy; 23% anthra.-based
1st line for MBC; 48% received prior adjuvant chemotherapy
Regimen
CAELYX
Docetaxel
Q 3 wk
30 mg/m2
75 mg/m2
Q wk x 3; Q 28 d
10 mg/m2
25 mg/m2
Efficacy – ORR*
64%
32%
Safety
G 3/4 neutropenia FN
G 3/4 HFS
Cardiac
18% 9% 2%
Anthra-pretx: mean Δ in LVEF of 4% 4% 6% NR
Phase II combinations with docetaxel have also established activity in the treatment of MBC. Both of the studies listed on this slide investigated the combination in the first-line treatment of MBC, and allowed for prior adjuvant anthracycline use.
The Alexopoulos study evaluated an every 3-week combination of CAELYX and docetaxel, whereas Holmes, evaluated a weekly schedule of the combination.
Both studies demonstrated activity, albeit to a lesser extent with the weekly regimen.
The regimens were tolerable, as noted by the lack of substantial grade 3/4 toxicities. The weekly regimen was associated with less toxicity overall, and in particular, less myelosuppression.
*Assessable pts

52. CAELYX + Docetaxel in MBC
Morabito (Breast Caner Res Treat 2004)
No. of patients / med. cycles
33/4
Pt. population
1st line for MBC; LABC pts included and evaluated separately
Regimen
CAELYX
Docetaxel
Q 3 wk
35 mg/m2
35 mg/m2 d 2, 9
Efficacy – ORR*
64%
Safety
G 3/4 neutropenia FN
G 3/4 HFS
Cardiac
9% 0% 14% NR
In a recently reported study, women with locally advanced or MBC received CAELYX, 35 mg/m2 IV on day 1, in combination with weekly docetaxel, 35 mg/m2 IV on days 2 and 9, every 3 weeks. This dosing regimen was established in the phase I portion of this study.
Forty-two consecutively recruited patients were included in the phase II portion. Thirty-nine patients were assessable for response, 33 patients with metastatic disease, and 6 patients with locally advanced disease.
Previous adjuvant therapy with anthracyclines was allowed up to a total dose of doxorubicin ≤ 300 mg/m2 or epirubicin ≤ 450 mg/m2.
The overall response rate for the 39 assessable patients was 64% (ITT analysis of all 42 patients was 59.5%); 58% of the patients with metastatic disease and 100% of the patients with locally advanced disease responded to therapy.
Toxicity was manageable, with moderate rates of both hematologic and nonhematologic toxicities reported.
Morabito et al. Breast Cancer Res Treat. 2004;86:
*Assessable pts

53. CAELYX + Vinorelbine in MBC
Martin
(Clin Breast Ca 2004)
Gebbia
(Oncology 2002)
Ardavanis
(ASCO 2003)
No. of patients / med. cycles
35 / 6
30 (18 / 6†)
32 / 3
Pt. population
Prior anthra. therapy in adjuvant or metastatic setting
100% received prior adjuvant chemotherapy; no pt had prior chemo for MBC
Taxane- or anthra.-pretx’d
Regimen
CAELYX
Vinorelbine
Q 4 wk
35 mg/m2 d 1
30 mg/m2 d 1
Q 15 d
20 mg/m2
30 mg/m2
40 mg/m2 d 1
25 mg/m2 d 1, 15
Efficacy – ORR*
35%
68% (63%†)
41%
Safety
G 3/4 neutropenia FN
G 3/4 HFS
Cardiac
44% (G 4) 9% 6%
3 pt had LVEF ↓ (not defined)
39%†
--†
1 pt had 15% ↓ in LVEF†
53% -- NR
Combination studies with vinorelbine have also shown consistent findings in both previously treated and untreated patients. Response rates ranging from 35-41% in patients previously treated with an anthracycline and/or taxane, to 68% in patients that had not received previous treatment for their metastatic disease. All studies listed allowed prior adjuvant anthracycline use.
Toxicity was somewhat consistent with previous studies of CAELYX combinations, although a greater frequency of myelosuppression was reported with the vinorelbine combinations.
*Assessable pts
†Phase II portion

54. CAELYX + Gemcitabine in MBC
Rivera
(JCO 2003)
Fabi
(ASCO 2004)
No. of patients / med. cycles
49 / 6
28 / 5
Pt. Population
Previously untreated; 57% received prior adjuvant chemo; 39% prior adjuvant anthra.
Untreated (n=15) or previously treated MBC (1 or 2 prior regimen); 39% received prior anthra.
Regimen
CAELYX
Gemcitabine
Q 3 wk
24 mg/m2 d 1
800 mg/m2 d 1, 8
25 mg/m2 d 1
Efficacy – ORR*
ORR anthra. pretx’d
52%
58%
48%
36%
Safety
G 3/4 neutropenia FN
G 3/4 HFS
Cardiac
74% 2% 6%
1 pt LVEF ↓ of 21% (had prior med. XRT)
39%
3.5% --
Two recently reported phase II studies evaluating the activity and safety of the combination of gemcitabine and CAELYX are listed on this slide.
The Rivera study evaluated the combination in previously untreated MBC patients, whereas the Fabi study included both untreated and previously treated patients. A little over one-third of the patients in both studies had received prior anthracycline therapy, either in the adjuvant or metastatic settings.
The combination of CAELYX and gemcitabine is active with response rates of 50%. Both studies provided response data for anthracycline-pretreated patients, which were consistent with previously reported studies suggesting a significant benefit in the retreatment/rechallenge of patients with previous anthracycline exposure.
The most common grade 3 or 4 toxicities noted were hematologic in nature.
*Assessable pts

55. CAELYX Combinations Conclusions
Phase II studies of CAELYX combinations demonstrate considerable activity in the treatment of MBC
Most combinations utilize a CAELYX dosage of mg/m2 on a Q 3 wk schedule
Regimens have been generally well tolerated
CAELYX is a rational substitute for conventional anthracyclines in combination therapy for MBC
Phase II studies of CAELYX combinations demonstrate considerable activity in the treatment of MBC.
Most combinations utilize a CAELYX dosage of mg/m2 on a Q 3 wk schedule.
Regimens have been generally well tolerated.
CAELYX is a rational substitute for conventional anthracyclines in combination therapy for MBC.

56. CAELYX in Breast Cancer: Conclusions
CAELYX is a novel anthracycline with established efficacy in MBC
CAELYX is associated with a distinct safety profile
Reduced rates of alopecia, nausea/vomiting, and myelosuppression; manageable hand-foot syndrome; and, preservation of cardiac function
CAELYX offers a convenient regimen for various subgroups of MBC patients, including in the setting of anthracycline rechallenge
Phase II studies of CAELYX combinations demonstrate considerable activity and tolerability
CAELYX is a rational substitute for conventional doxorubicin in combination therapy for MBC
To conclude, the data presented demonstrates that CAELYX is a novel anthracycline with an increasing role in the treatment of breast cancer.
As demonstrated by clinical studies, CAELYX is associated with a distinct safety profile, with reduced rates of alopecia, N/V, and myelosuppression; the main side effect is manageable hand-foot syndrome.
Preclinical and clinical data continue to support that CAELYX therapy preserves cardiac function, which is critical for patients who can benefit from long-term anthracycline therapy.
In the metastatic setting, randomized studies demonstrated that CAELYX provides comparable efficacy to conventional doxorubicin as first-line treatment and to commonly used salvage regimens in patients whose tumors had become taxane-refractory. Data also support the activity of rechallenge in patients previously treated with an anthracycline.
Clinical trials in breast cancer, in both the locally advanced and metastatic settings, demonstrate CAELYX combinations are both active and tolerable.
Data demonstrate that CAELYX provides a rational substitute for conventional doxorubicin both as a single agent and in combination therapy for the treatment of MBC.