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CAELYX CLINICAL TRIALS Metastatic Breast Cancer (MBC)

CAELYX CLINICAL TRIALS Metastatic Breast Cancer (MBC)

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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.