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CAELYX CLINICAL TRIALS Metastatic Breast Cancer (MBC)

CAELYX CLINICAL TRIALS Metastatic Breast Cancer (MBC). 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

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CAELYX CLINICAL TRIALS Metastatic Breast Cancer (MBC)

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  1. CAELYXCLINICAL TRIALSMetastatic 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

  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

  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)

  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 ofcombination therapy • Patients with slowly growing tumors

  6. Single-Agent CAELYX for MBC: Phase II Studies

  7. Single-Agent CAELYX for MBC: Phase II Studies

  8. Single-Agent CAELYX for MBC: Phase II Studies *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 T R E A T M E N T Phase II N = 53 Previously treated MBC CAELYX 40 mg/m2 q 4 wk Compared results to 50 mg/m2 trial of similar design Al-Batran et al. Breast Cancer Res Treat. 2004; 88:S204. Abstract 5060. Updated based on poster.

  10. CAELYX 50 vs 40 mg/m2 in MBC: Outcomes Al-Batran et al. Breast Cancer Res Treat. 2004; 88:S204. Abstract 5060. 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 A T I O N C R O S S O V E R† CAELYX 40 mg/m2 q 4 wks* N = 36 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 *22 patients received drug on crossover; †18 patients received drug on crossover Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract 5057. Updated based on poster.

  13. CAELYX vs Docetaxel: Toxicity Yardley et al. Breast Cancer Res Treat. 2004;88:S203. Abstract 5057. Updated based on poster.

  14. CAELYX vs Conventional Doxorubicin in First-line Treatment of MBC: Phase III Trial Study Design • 1st-line MBC (Stages IIIB/IV) • Open-label, multicenter Stratification • Prior adjuvant anthracycline • Cardiac risk factor • Bone only mets • N = 509 • 68 international sites R A N D O M I Z A T I O N CAELYX 50 mg/m2 q 4 wks* 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;15:440-449.

  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 O’Brien et al. Ann Oncol. 2004;15:440-449.

  16. Baseline Patient Demographics O’Brien et al. Ann Oncol. 2004;15:440-449.

  17. Baseline Disease Characteristics O’Brien et al. Ann Oncol. 2004;15:440-449.

  18. Baseline DemographicsPrior Therapy *Chemotherapy or hormonal therapy. O’Brien et al. Ann Oncol. 2004;15:440-449.

  19. Baseline Cardiac Risk Factors O’Brien et al. Ann Oncol. 2004;15:440-449.

  20. Results: Treatment Summary *Including prior anthracycline therapy O’Brien et al. Ann Oncol. 2004;15:440-449.

  21. CAELYX vs Doxorubicin Response Rates* *Measurable disease (n=410); 25% in each group had no radiographic assessment of response. O’Brien et al. Ann Oncol. 2004;15:440-449.

  22. CAELYX vs Doxorubicin Progression-Free Survival (PFS) Intent-to-Treat Population 1.0 0.9 0.8 HR = 1.00 (95% CI: 0.82-1.22) 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 Months From Randomization O’Brien et al. Ann Oncol. 2004;15:440-449.

  23. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 CAELYX vs DoxorubicinOverall Survival (OS) Intent-to-Treat Population HR = 0.94 (95% CI: 0.74-1.19); P = .59 Probability Months From Randomization O’Brien et al. Ann Oncol. 2004;15:440-449.

  24. CAELYX vs Doxorubicin- Cardiac Events - O’Brien et al. Ann Oncol. 2004;15:440-449.

  25. 100 90 Conventional Doxorubicin 80 70 Kaplan-Meier Estimates of Cardiac Events 60 50 40 30 CAELYX 20 10 0 50 100 150 200 250 300 350 400 450 500 550 600 0 Cumulative Anthracycline Dose CAELYX vs DoxorubicinCardiac Events vs Cumulative Dose HR = 3.16 (95% CI: 1.58-6.31); P < .001 O’Brien et al. Ann Oncol. 2004;15:440-449.

  26. All < 300 ≥ 300 to < 450 ≥ 450 CAELYX vs DoxorubicinLVEF vs Cumulative Dose Cumulative Anthracycline Dose (mg/m2) 0 -2 n=54 n=62 n=152 -4 n=36 -6 n=58 -8 n=74 n=187 Median % Change From Baseline -10 -12 CAELYX -14 Conventional Doxorubicin -16 n=55 -18 O’Brien et al. Ann Oncol. 2004;15:440-449.

  27. CAELYX vs DoxorubicinCardiotoxicity in High-Risk Patients O’Brien et al. Ann Oncol. 2004;15:440-449.

  28. * Treatment-Related Adverse EventsAll Grades % Patients *Grade 2 alopecia = complete hair loss; grade 3-4 NA. O’Brien et al. Ann Oncol. 2004;15:440-449.

  29. Treatment-Related Adverse Events: Alopecia

  30. Treatment-Related Adverse EventsGrades 3/4* % Patients *Grade 3-4 alopecia NA ; grade 2 alopecia = complete hair loss; cardiotoxicity not included. O’Brien et al. Ann Oncol. 2004;15:440-449.

  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 O’Brien et al. Ann Oncol. 2004;15:440-449.

  32. CAELYX in MBC After Taxane Failure • 301 Patients • 52 International sites R A N D O M I Z A T I O N 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 - 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;22:3893-3901.

  33. CAELYX in MBC After Taxane FailureStudy Endpoints • Primary • Progression-free survival • Secondary • Overall survival • Overall response rate • Response duration • Event-free survival • Tolerability • QOL Keller et al. J Clin Oncol. 2004;22:3893-3901.

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

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

  36. Prior Therapy (cont.) Keller et al. J Clin Oncol. 2004;22:3893-3901.

  37. CAELYX in MBC After Taxane FailureResponse Rates Median Duration of Response 5.7 months 6.0 months Keller et al. J Clin Oncol. 2004;22:3893-3901.

  38. CAELYX in MBC After Taxane FailureProgression-Free Survival (PFS) 1.0 0.9 0.8 0.7 0.6 0.5 Progression-Free Survival HR = 1.26 (95% CI: 0.98-1.62) 0.4 0.3 0.2 0.1 0 0 3 6 9 12 Months Keller et al. J Clin Oncol. 2004;22:3893-3901.

  39. CAELYX in MBC After Taxane FailureOverall Survival (OS) HR = 1.05 (95% CI: 0.82-1.33) Overall Survival Months *Data updated in Keller et al. J Clin Oncol. 2004;22:3893-3901. 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) 0 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;22:3893-3901.

  41. Treatment-Related Adverse EventsAll Grades Percent of Patients Keller et al. J Clin Oncol. 2004;22:3893-3901.

  42. Treatment-Related Adverse EventsGrades 3/4 Percent of Patients Keller et al. J Clin Oncol. 2004;22:3893-3901.

  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

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

  45. CAELYX Combination Therapy for MBC

  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

  47. CAELYX CombinationsBreast Cancer

  48. CAELYX + Cyclophosphamide in BC

  49. CAELYX + Paclitaxel in MBC

  50. Neoadjuvant CAELYX + Paclitaxel in LABC T R E A T M E N T CAELYX 35 mg/m2 d 1 + Paclitaxel 175 mg/m2 d 1 q 3 wk Phase II N = 35 Newly diagnosed LABC RESULTS ORR 71% (CR 17%, PR 54%) pCR after 4-6 cycles 3 pts Grade 3 HFS 9% Grade 3/4 neutropenia 15% Alopecia 83% Gogas et al. Ann Oncol. 2002;13:1737-1742.

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