1. NOT THE TAXANES Chemotherapy Joyce O’Shaughnessy, MD Baylor-Sammons Cancer Center US Oncology Dallas, TX

2. Do Patients Benefit from Salvage Chemotherapy?  No demonstrated survival improvement with salvage chemotherapy  No demonstrated superiority yet of one agent or regimen  No overall advantage of combination chemotherapy compared with sequential single agents  Several studies do show correlation between ORR and symtom control and QOL  Patient preferences and chemotherapy toxicity profile are important Cardoso F, et al Ann Oncol 13:197, 2002 McLachlan SA, et al Breast Cancer Res Treat 54:213, 1999

3. Not Anthracyclines and Taxanes Chemotherapies with Value  Capecitabine  Vinorelbine  Gemcitabine  Pegylated Liposomal Doxorubicin  Pemetrexed  Irinotecan  Epothilones, Nanoparticle Paclitaxel

4. Enzymatic activation of Capecitabine IntestineLiver Capecitabine 5'-DFCR 5'-DFUR CyD 5'-DFCR 5'-DFUR 5-FU Tumour Capecitabine Thymidine phosphorylase (TP) CyD CE 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase

5. Capecitabine in taxane-pretreated MBC  Capecitabine monotherapy has been evaluated in taxane-pretreated MBC in four separate trials in 500 patients –pivotal US trial (n=163) 1 –confirmatory US/French trial (n=75) 2 –German trial (n=136) 3 –French trial (n=126) 4 1 Blum JL et al. J Clin Oncol 1999;17:485–93 2 Blum JL et al. Cancer 2001;92:1759–68 3 Reichardt P et al. Eur J Cancer 2001;37(Suppl. 6):S191 (Abst 699) 4 Fumoleau P et al. Breast Cancer Res Treat 2001;69:285 (Abst 435)

6. Pivotal US trial in paclitaxel-pretreated MBC  Large, multicenter trial (n=163*)  Patients were pretreated with –prior paclitaxel100% –prior anthracyclines91% –prior 5-FU82% –prior agents (mean)4.7  Therapy –capecitabine 1,250mg/m 2 twice daily for 14 days, followed by a 7-day rest period Blum JL et al. J Clin Oncol 1999;17:485–93*One patient withdrew before receiving treatment

7. Pivotal US trial: capecitabine in paclitaxel-pretreated MBC  Rate of disease control: 63% –20% confirmed tumor response rate –43% stable disease (median 4 months)  Palliation: durable pain reduction in 47% of patients with considerable pain at baseline  Median TTP: 3.0 months  Median survival: 11.6 months 1 1 Survival updated in Blum JL et al. Eur J Cancer 2001;37(Suppl. 6):S190 (Abst 693)

8. Capecitabine: probability of survival with response or disease stabilization 0 4 8 12 16 20 24 28 32 36 Time (months) 1.0 0.8 0.6 0.4 0.2 0.0 5.3 Estimated probability 15.016.6 Responder Stable disease Progressive disease Blum JL et al. Eur J Cancer 2001;37(Suppl. 6):S190 (Abst 693)

9. Capecitabine in heavily pretreated MBC: prior chemotherapy *Some patients had previously received both paclitaxel and docetaxel

10. Capecitabine in taxane-pretreated MBC 1 Blum JL et al. Eur J Cancer 2001;37:S190 (Abst 693) 2 Blum JL et al. Cancer 2001;92:1759–68 3 Reichardt P et al. Eur J Cancer 2001;37(Suppl. 6):S191 (Abst 699) 4 Updated from Fumoleau P et al. Breast Cancer Res Treat 2001;69:285 (Abst 435) *Preliminary results

11. Capecitabine monotherapy safety profile  2% of patients experienced a grade 4 treatment-related adverse event  Most frequent grade 3/4 treatment-related adverse events were –hand-foot syndrome 15% –diarrhea 12% –stomatitis 5% –nausea 5%  No hair loss  No treatment-related deaths

12. capecitabine monotherapy: myelosuppression (n=498) Leukopenia Neutropenia Anemia Thrombo- cytopenia Grade 3 Grade 4 *Recorded as grade 3/4 laboratory adverse events

13. Rationale for capecitabine in combination: TP upregulation Paclitaxel100 Docetaxel15 Vinblastine3 Vindesine5 Mitomycin C5 Doxorubicin7.5 Cisplatin10 Cyclophosphamide200 Gemcitabine90 Vinorelbine12 012345678910 * * * * * * * † *p<0.05 † p value not available TP upregulation (x control activity) Ishitsuka H. Invest New Drugs 2000;18:343–54 Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388) (mg/kg)

14. Capecitabine TP upregulation 1 Bcl-2 downregulation 2 Docetaxel Potential mechanisms underlying Capecitabine plus Docetaxel synergy 1 Sawada N et al. Clin Cancer Res 1998;4:1013–9 2 Fujimoto-Ouchi K et al. Proc Am Assoc Cancer Res 2001 (Abst 463)

15. Capecitabine plus Docetaxel: overall survival* 11.514.5 Hazard ratio = 0.775 Log-rank p=0.0126 *Minimum follow-up of 15 months Capecitabine/docetaxel Docetaxel 1.0 0.8 0.6 0.4 0.2 0 Estimated probability 0246810121416182022242628 Time (months)

16. Post-study Therapies in the XT Study

17. Cytotoxic Agents Used in Post-Study Chemotheray

18. Impact of First-line Post-study Chemotherapy on Outcome in Patients in the Docetaxel Alone Arm  Capecitabine vs any other agents as 1st line post-study chemotherapy  Hazard ratio = 0.5 (p=0.0046): patients treated with capecitabine had a 50% decreased risk of dying  Median survival = 21 months for capecitabine-treated patients vs 12.3 months for other patients  Vinorelbine-containing regimen vs other agents as 1st line post-study chemotherapy (except for capecitabine)  Hazard ratio = 1 (p=0.94): simiar risk of dying  Median survival = 13.5 months for patients treated with vinorelbine-containing regimen vs other agents

19. Capecitabine plus Vinorelbine: feasible and active in a 21-day regimen 1 Ghosn M et al. Proc Am Soc Clin Oncol 2002;21:42b (Abst 1978) 2 Welt A et al. Proc Am Soc Clin Oncol 2001;20:58b (Abst 1979) 3 Ahn J-H et al. Proc Am Soc Clin Oncol 2002;21:55b (Abst 2030)  German regimen: randomized, phase III trial (vs XT) is under discussion  Safety profile: neutropenia and gastrointestinal side effects are dose limiting

20. Capecitabine plus bevacizamab: ongoing phase III trial  Bevacizumab is a recombinant, humanised monoclonal antibody to vascular endothelial growth factor (VEGF)  Active in patients with previously treated MBC 1  Recruitment (~400 patients) for a randomised, phase III trial in taxane-pretreated MBC is ongoing –capecitabine monotherapy versus capecitabine plus bevacizamab 2 1 Cobleigh MA et al. Breast Cancer Res Treat 2001;69:301 (Abst 520) 2 Details provided on US National Cancer Institute Clinical Trials Database (URL http://www.cancer.gov/clinical_trials/)

21. Ongoing phase I/II trials investigating capecitabine in all-oral combinations  capecitabine continuously + oral cyclophosphamide (New Zealand and Australia) 1 –MTD: capecitabine 666mg/m 2 twice daily, d1–28 + cyclophosphamide 125mg/m 2 d1–14, q28d –additional patients are being treated with capecitabine 666mg/m 2 + cyclophosphamide 100mg/m 2  capecitabine + oral idarubicin (Edinburgh, UK)  capecitabine + oral idarubicin/cyclophosphamide (China) 2  capecitabine + oral vinorelbine (Milan, Italy) 1 Findlay MP et al. Proc Am Soc Clin Oncol 2002;21:85b (Abst 2151) 2 Chan S-C et al. Proc Am Soc Clin Oncol 2002;21:53b (Abst 2023)

22. Single-Agent Vinorelbine: Salvage Therapy in Anthracycline or Taxane Resistant MBC

23. Vinorelbine versus Melphalan in Anthracycline-Pretreated MBC  Vinorelbine 30 mg/m2 weekly versus Melphalan 25 mg/m2 every 4 weeks  183 pts 2:1 randomization  Measurable or evaluable allowed  Objective response or SD: 46% versus 28%  TTP: 12 versus 8 weeks; p<.001  OS: 35 versus 31 weeks; p=0.034  No difference QOL, cancer-related symptoms Jones SE, et al J Clin Oncol 13:2567, 1995

24. Gemcitabine: Phase II Studies 25%20250 mg/m2 over 6 hours – D1, 8, 15Schmid, 99 42%191250 mg/m2 – D1, 8, 15 q28Gerson, 00 13%241250 mg/m2 – D1, 8, 15 q28Brodowicz, 98 28%431200 mg/m2 – D1, 8, 15 q28Spielmann, 97 37%351200 mg/m2 – D1, 8, 15 q28Blockstein, 96 30%141000 mg/m2 – D1, 8, 15 q28Akrivakis, 95 14%421000 mg/m2 – D1, 8, 15 q28Possinger, 99 25%40800 mg/m2 – D1, 8, 15 q28Carmichael, 95 Overall RRNo. PtsDoseStudy

25. Dose/Schedule in MBC with Gemcitabine and Vinorelbine Study Dose (mg/m 2 ) Previous Chemotherapy Gokmen G1200 days 1, 8 7 pt (32%) third line V30 days 1,8 13 pt (59%) second line q21d Gokmen E. PASCO 2000.a427 Haider G 1 000 days 1,15, 21 45 pt untreated for MBC V40 days 1, 21 15 pt had one prior regimen G-CSF 5mcg/kg/d Haider K, Breast Cancer Research and Treatment 1999;55:203-211 Moser G1200 days 1, 8 25 pt first line V25 days 1, 8 13 pt second line q21d 11 pt second line with taxane Moser PASCO 2001.a1973

26. Efficacy in MBC with Gemcitabine and Vinorelbine PatientsORRMedianMedian (eval.) (%) TTPDSurvival(mos) Gokmen 2000 22 ‡ 45% 5.5 NR Haider 1999 45* 56%9.5>14 15** 40%7.0 12 Moser 200130 30% NR NR ‡ 77% previously treated * untreated ** previously treated

27. Biweekly Gemcitabine and Vinorelbine  50 pts MBC s/p anthracyclines and 50% with prior taxane  GEM 1000 and VRL 25 mg/m2 every 2 wks  ORR 54% (8% CRs), mainly soft tissue/lung  Duration response/SD 4 to 9+ mos  No pt required dose reduction  Grade 1/2 neutropenia, asthenia  Biweekly GEM/VRL active in pretreated MBC  Stathopoulas GP, et al. JCO 20:37, 2001

28. Dose/Schedule in MBC with Gemcitabine and Cisplatin 31 heavily pretreated (>2 regimens) 24 minimally pretreated (0-1regimens) G1000 days 2, 8 C25 days 1-4 q21d Doroshow Doroshow PASCO 2000 all pt failed anthracyclines all pt failed taxanes G1000 days 1, 8,15 C25 days 1, 8,15 q28d Chaudhry Chaudhry PASCO 2000 Most heavily pretreated Dose dependent on prior regimen ( >2 regimen received G 600mg) (1st 12pt treated on q28d schedule) G750 days 1, 8 C30 days 1, 8 q21d Nagourney Nagourney et al, JCO 2000 Previous ChemotherapyDose (mg/m 2) Study

29. Efficacy in MBC with Gemcitabine and Cisplatin Patients ORRMedian Median (eval.) (%) TTPD Survival Nagourney 30 53 23.5 wks 46 wks Chaudhry 28 39 NR NR Doroshow 23* 26 NR Not yet reached 21** 43 * Heavily Pretreated ** Minimally Pretreated NR = Not Reported

30. Pegylated Liposomal Doxorubicin  509 pts PLDox 50 mg/m2 every 4 weeks versus Doxorubicin 60 mg/m2 every 3 weeks  OS similar; 2 pts CHF with PLDox vs 12 with Dox  31% ORR in 64 pts with 45-60 mg/m2 every 3 to 4 weeks (anthracycline-naïve)  Phase I: PLDox 24 mg/m2 and Gemcitabine 800 mg/m2 D1, 8 q 21 days; 9/27 objective responses  Phase I: PLDox 40 mg/m2 and Vinorelbine 30 mg/m2 day 1, 15

31. Pegylated Liposomal Doxorubicin vs. Standard Salvage Regimen for Taxane-Pretreated Patients PLDox 50 mg/m 2 q 4wks vs. Vinorelbine 20 mg/m 2 q wk or Mitomycin C 20 mg/m 2 d1 IV, q 6wks Vinblastine 5 mg/m 2 d1,21 IV, q 6wks 301 patients evaluable for safety and efficacy  85% chose Vinorelbine PLDox 50 mg/m 2 q 4wks vs. Vinorelbine 20 mg/m 2 q wk or Mitomycin C 20 mg/m 2 d1 IV, q 6wks Vinblastine 5 mg/m 2 d1,21 IV, q 6wks 301 patients evaluable for safety and efficacy  85% chose Vinorelbine

32. Pegylated Liposomal Doxorubicin in Taxane-Pretreated Patients Prior treatment with an anthracycline Prior treatment with an anthracycline – 84% as adjuvant or for advanced disease – 37% “anthracycline resistant” (Progression on or within 6 months of anthracycline) 37% progressed within 8 weeks of study entry Prior treatment with an anthracycline Prior treatment with an anthracycline – 84% as adjuvant or for advanced disease – 37% “anthracycline resistant” (Progression on or within 6 months of anthracycline) 37% progressed within 8 weeks of study entry Actual Patients Eligible Patients – Measurable disease – Progressed on prior taxane-containing regimen – Karnofsky Performance > 60%; LVEF > 50% – Measurable disease – Progressed on prior taxane-containing regimen – Karnofsky Performance > 60%; LVEF > 50%

33. PLDox in Taxane-Pretreated Patients Response Rates

34. PLDox vs a Standard Salvage Regimen After Taxane Failure 369120 PLDox Comparator Progression-Free Survival 0.0 0.3 0.4 0.6 0.8 1.0 Months from Start of Treatment % Progression-Free Survival Hazard Ratio 1.26 p = 0.11 Hazard Ratio 1.26 p = 0.11

35. PLDox vs. a Standard Salvage Regimen After Taxane Failure Overall Survival PLDox Comparator 0.0 0.2 0.4 0.6 0.8. 1.0 369120 1518 Months from Start of Treatment % Overall Survival

36. The Non-Taxanes  Capecitabine, Gemcitabine, Vinorelbine and Pegylated Liposomal Doxorubicin are active and generally well tolerated cytotoxics that DON’T CAUSE ALOPECIA  They are highly active in combination with the taxanes or with each other  We need comparative trials of non-taxane doublets with taxane-based doublets

37. Pemetrexed N-[4-[2-(2-amino-3,4-dihydro-4- oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid Pemetrexed Taylor EC, et al. J Med Chem 35:4450-4454, 1992 

38. Pemetrexed Key Intracellular Folate Enzyme Targets Pemetrexed (multitargeted antifolate) Pemetrexed dUMPdTMP 10-CHO-THF DHF THF GAR fGAR PRPP AMP, GMP DNA, RNA DNA NADPH NADP+ TS: thymidylate synthase DHFR: dihydrofolate reductase GARFT: glycinamide ribonucleotide formyltransferase 5,10-CH2-THF TSTS GARFTGARFT DHFRDHFR

39. Spielmann, Martin et al: Subset of patients with prior anthracycline and taxanes, n=31. Patient Characteristics Pemetrexed 600 mg/m2 q3w (no vitamins suppl.) Median Age 55 (30-75) PS 0-1 99% Sites of disease 90% visceral disease (lung and/or liver) 6% with bone metastasis Spielmann, Martin et al. Clin Breast Ca 2:47-51, 2001

40. Spielmann, Martin et al: Efficacy Results 1 CR, 7 PR 26% 6 SD > 4 months 19% Median duration of response 5.4 months Median survival 12.8 months Spielmann, Martin et al. Clin Breast Ca 2:47-51, 2001

41. Spielmann, Martin et al : Hematologic and Lab Toxicity (CTC Grade, % patients, n= 31) Spielmann, Martin et al. Clin Breast Ca 2:47-51, 2001

42. Spielmann, Martin et al : Non-lab Toxicity (CTC Grade, % patients, n= 31) Spielmann, Martin et al. Clin Breast Ca 2:47-51, 2001

43. Llombart et al: Patient Characteristics, n=45 N=45 (32 evaluable, 7 too early, 6 ineligible) Pemetrexed 500 mg/m2 q3w (no vitamins suppl.) Median Age 56 (31-72) Median PS0 (0-2) Median # sites of disease 2 (1-6) 79% visceral disease (lung and/or liver) Prior # chemotherapy 2 (1-4) Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000 (Poster)

44. Llombart et al : Efficacy Results N=32 evaluable 0 CR, 6 PR 19% 17 SD 53% Median survival NA Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000 (Poster)

45. Llombart et al : Hematologic and Lab Toxicity (CTC Grade, % patients, n= 45) Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000 (Poster)

46. Llombart et al : Non-lab Toxicity (CTC Grade, % patients, n= 45) Llombart et al. Breast Cancer Res Treatment 58(1): A526, 2000 (Poster)

47. Pemetrexed Combinations in MBC  Pemetrexed - Taxane  Pemetrexed - Doxorubicin  Pemetrexed - Gemcitabine  Pemetrexed - Cyclophosphamide

48. DOWN WITH ALOPECIA !!! Can we create a highly effective combination chemotherapy regimen that does NOT cause ALOPECIA?

49. Non-Alopecia Chemotherapy Agents  Capecitabine  Vinorelbine  Gemcitabine  Pegylated Liposomal Doxorubicin  Pemetrexed  Weekly Lower Dose Cisplatin  Methotrexate  5-Fluorouracil  ? Lower Dose Weekly Docetaxel or Paclitaxel

50. Plea to the BCIRG Demonstrate that a non-alopecia combination chemotherapy regimen is as effective (or more) as AC/FAC/FEC for metastatic breast cancer and TAKE IT INTO EARLY STAGE BREAST CANCER

51. THANK YOU

52.  Topics –Preclinical rationale for epothilone –Initial Phase 2 results (ASCO 2002) Epothilone BMS-247550 HN O O OH OH S N O BMS-247550

53. O HO OH O O O S N O H 3 C O CH 3 OH H 3 C CH 3 3 3 3 OH CH 3 O H 2 NO Epothilone Eleutherobin Discodermolide Me O OMe O O OH OAc N N O O Me sidechain core sugar Taxane mimetics: A second generation of tubulin polymerizing agents Polymerization of tubulin Optical Density (350 mm) Discodermolide Epothilone B Eleutherobin Paclitaxel No Compound Control Lindel et al ‘97Ter Harr et al ‘96Bollag et al ‘95 sec

54. Epothilone: Distinct binding to tubulin Computer model of beta-tubulin mutations Taxane Epothilone Giannakakou et al. Proc. Natl. Acad. Sci. USA 2000, 97, 2904

55. Novel epothilone BMS-247550 overcomes taxane resistance  Known mechanisms of taxane resistance –Increase drug efflux MDR MRP –Tubulin alteration Mutation Increasing resistance 150 137 9.7 450 18 7.4 12.3 6.9 16 7.3 0100200300400500 Pat-7 (Clinical) A2780Tax (Tubulin Mutation ) A2780 HCTVM46(MDR) HCT116 Cytotoxicity (IC 90 or IC 50, nM) BMS-247550 Paclitaxel

56. F Taxane resistant Pat-21 breast cancer Novel epothilone BMS-247550: Activity against clinical taxane resistance Years 00.20.40.60.811.21.41.61.82 Pat-21 (Breast) Biopsied ADR + CMF (10 cycles) TAXOL + Dexverapamil (4 cycles)

57. Initial Phase 2 results using 50 mg/m 2 over 1 hour (ASCO 2002) Phase I/II responses also observed in aggressive NHL, colorectal, gastric, ovary, prostate, head and neck, cervical cancer, GIST and melanoma * Phase I results, doses 35-40 mg/m 2

58. –Microtubule stabilization is a clinically validated biological target –Epothilone (BMS-247550) is active in vitro and in vivo against taxane-resistant tumor models –Activity demonstrated in taxane-refractory patients in Phase I and II –Phase 2 studies are in progress, in a broad program via BMS and NCI Novel epothilone BMS-247550: Summary HN O O OH OH S N O BMS-247550

59. Enhanced Tumor Penetration of Paclitaxel by a Novel Biological Nanotransporter Mechanism ABI-007: Nanoparticle Paclitaxel

60. Overall Response Patients, n (%) ABI-007 175 mg/m 2 ABI-007 300 mg/m 2 ParameterN = 43 N = 63 No. evaluable41 59 Overall response21 (51%) 36 (61%) 95% CI[36 %– 67%] [49 %– 73%] Complete response3 (7%) 4 (7%) Partial response18 (44%) 32 (54%) Stable disease15 (37%) 11 (19%) Progressive disease5 (12%) 12 (20%)

61. Response by Prior Therapy Patients, N/N (%) ABI-007 ABI-007 Parameter 175 mg/m 2 300 mg/m 2 P value Anthracycline-naïve9/21 (43)19/28 (68).08 95% CI[22 – 64][51 – 85] Anthracycline-exposed12/20 (60)17/31 (55)NS 95% CI[39 – 81][37 – 72] Adjuvant only anthracycline7/11 (64)11/13 (85).24 95% CI[35 – 92][65 – 104] Metastatic anthracycline5/9 (56)6/18 (33)NS 95% CI[23 – 88][12 – 55]

62. ABI-007 Activity in Patients Previously Exposed to Taxol Patients, n (%) ABI-007 ABI-007 Parameter 175 mg/m 2 300 mg/m 2 Prior taxane exposure211 Patients evaluable29 Overall response rate02 (22) Complete response (CR)01 (11)* Partial response (PR)01 (11) § Stable disease (SD)2 (100)4 (44) CR + PR + SD2 (100)6 (67) *Patient achieving a complete response was heavily pretreated with FAC, radiotherapy, Taxol 225 mg/m 2 (second-line with Taxol resistance), doxil, and gemcitabine. §Patient achieving a partial response was previously treated with Taxol 250 mg/m 2 in the adjuvant setting.

63. Capecitabine plus Trastuzumab: at least additive activity in a BC xenograft model Fujimoto-Ouchi KF et al. Cancer Chemother Pharmacol 2002;49:211–16 1,000 800 600 400 200 100 2025303540455055 * * * Tumour volume (mm 3 ) Control capecitabine trastuzumab capecitabine + trastuzumab Days after inoculation *p<0.05 BT474 xenograft

64. Capecitabine plus Trastuzumab is a feasible combination: the German experience  18 patients with anthracycline- and taxane-pretreated HER2+ MBC received 21-day cycles of –standard-dose trastuzumab, weekly –capecitabine 1,125mg/m 2 twice daily, days 1–14  62% ORR in 13 patients  Minimal side effects  Additional phase II investigation is ongoing Bangemann N et al. Ann Oncol 2000;11(Suppl. 4):143 (Abst 653P)

65. Summary of Single-Agent Vinorelbine in MBC

66. Irinotecan in Metastatic Breast Cancer  Randomized Phase II 100 mg/m2 weekly 4 on/2 off (A) versus 240 mg/m2 q 3 weeks (B)  102 pts; 75% prior anthracyclines; 80% prior taxane  29% ORR (6/21)  Grade 3/4 diarrhea 8 pts (A) and 5 pts (B)  Grade 3/4 vomiting 2 pts (A) and 8 pts (B)  Grade 4 neutropenia 6 pts (A) and 10 pts (B) Perez EA, et al Proc ASCO 21, A206, 2002