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1、Drug Treatment of Metastatic Breast Cancer,FDA Approval Overview Patricia Cortazar, MD,微快车微信营销 ,Drugs approved for Metastatic Breast Cancer,Methotrexate1953 Cyclophosphamide1959 Thiotepa1959 Vinblastine1961 5-Fluorouracil1962 Doxorubicin1974,Paclitaxel1994 Docetaxel1996 Trastuzumab 1998 Capecitabine

2、1998 Capecitabine + Docetaxel2001 Abraxane2005 Lapatinib2006 Ixabepilone2007,Drugs approved in 2nd-3rd line Metastatic Breast Cancer,Paclitaxel,TAXOL is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvan

3、t chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated,Paclitaxel 135 mg/m2 3-hour infusion,TAXOL Study Design,Paclitaxel 175 mg/m23-hour infusion,471,Patients who failed one or two regimens of chemotherapy 67% previous anthracyclines,TAXOL Efficacy Res

4、ultsFull Approval,Docetaxel,TAXOTERE for Injection indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy,DocetaxelAccelerated Approval 1996,3 Phase II studies in total 134 patients Dose 100 mg/m2 q 3 weeks Endpoint: Overall RR 4

5、1% (95% CI: 33-49) PMC: Submit data from controlled clinical studies (TAX311, TAX304),Mytomicin 12 mg/m2 Q 6 weeks Vinblastine 6 mg/m2 Q 3 weeks,TAX304 Study Design,Docetaxel 100 mg/m2Q 3 weeks,392,Patients with Prior anthracycline regimens,TAX304 Efficacy ResultsFull Approval,Trastuzumab,Herceptin

6、is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.,Trastuzumab 4 mg/kg loading dose 2 mg/kg wkly maintenance,Herceptin MBC Study Design,222,Patients with

7、MBC HER2 overexpression 2+3+ 1 or 2 prior CT for MBC Anthracycline and Taxane,Herceptin monotherapy Full Approval,Capecitabine,Xeloda is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistan

8、t to paclitaxel and for whom further anthracycline therapy may be contraindicated, e.g., patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents.,Capecitabine monotherapy Accelerated Approval,Capecitabine,Xeloda is indicated in combination with Taxotere (do

9、cetaxel) for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.,Docetaxel 100 mg/m2 Q 3 weeks,Study Design,Capecitabine 1250 mg/m2 twice daily for 14 days Docetaxel 75 mg/m2 Q 3 weeks,511,metastatic breast cancer

10、resistant to Anthracycline 30% 1st line,Capecitabine Efficacy ResultsFull Approval,Overall Survival,median days Docetaxel - 352 Capecitabine + Doc - 442,Log rank p=0.0126,Lapatinib,TYKERB in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose t

11、umors over-express HER2 (ErbB2) who have received prior therapy including an anthracycline, a taxane and trastuzumab.,Capecitabine 2500 mg/m2 daily for 14 days,Study Design,Lapatinib 1250 mg/m2 continuously Capecitabine 2000 mg/m2 daily for 14 days,399,Locally advanced or metastatic breast cancer HE

12、R2+ prior anthracycline, Taxane and Herceptin.,Lapatinib Efficacy ResultsFull Approval,Efficacy of Combination Therapy:Kaplan-Meier Curves of TTP,Lapatinib + Capecitabine - Capecitabine -,p= 0.00013,Ixabepilone,Combination Therapy: Ixempra is indicated in combination with capecitabine for the treatm

13、ent of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant or for whom further anthracycline therapy is contraindicated.,Capecitabine 1250 mg/m2 BID Days 1 to 14 q 21 days,Study Design,Ixabepilone 4

14、0 mg/m2 Days 1 q 21 days Capecitabine1000 mg/m2 BID Days 1 to 14 q 21 days,752,Resistant to Taxane and anthracycline,Ixabepilone Efficacy ResultsFull Approval,Efficacy of Combination Therapy:Kaplan-Meier Curves of PFS,log rank p 0.0001,Ixabepilone,Monotherapy: Ixempra is indicated as monotherapy for

15、 the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.,Single-arm Monotherapy Studies (n=126),1st line Metastatic Breast Cancer,Drugs approved in 1st line Metastatic Breast Cancer,Herceptin + P

16、aclitaxel 1998 Gemcitabine + Paclitaxel 2004,Trastuzumab,Herceptin in combination with paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress HER2 protein and who have not received chemotherapy for their metastatic disease.,Chemotherapy Alone,Hercept

17、in 1st line MBC Study Design,Chemotherapy (AC or Paclitaxel) Herceptin loading: 4 mg/kg weekly: 2 mg/kg,469,Patients with untreated MBC HER2 overexpression 2+3+,Survival Time (months),Proportion Alive,0,5,10,15,20,25,30,0.0,0.2,0.4,0.6,0.8,1.0,Survival ALL Patients,Herceptin 79%,Control 68%,P 0.01,H

18、erceptin Full Approval Survival All Patients,Time to Progression (Months),Proportion Progression-Free,0,5,10,15,20,25,0.0,0.2,0.4,0.6,0.8,1.0,Time to Progression All Patients,Herceptin,Control,p 0.001,Gemcitabine,Gemzar in combination with paclitaxel is indicated for the first-line treatment of pati

19、ents with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.,Paclitaxel175 mg/m2 Days 1 and 8 q 21 days,Study Design,Gemcitabine 1250 mg/m2Days 1 and 8 q 21 days Paclitaxel175 mg/m2 Days 1 and 8 q 21

20、days,529,Unresectable, locally recurrent or metastatic breast cancer,Survival,Gemzar/Paclitaxel - 18.6 months Paclitaxel - 15.8 months,Log rank p=0.0489,SURVIVAL,Time to Progression,ENDPOINTS,Metastatic Breast Cancer,Survival: Basis of cytotoxic drug approval in 1st line MBC,Cytotoxic and biologic d

21、rugs are toxic Survival is both a safety and an efficacy parameter Deaths are caused by toxicity or progressive disease or both,Efficacy Reasons for using Survival as basis of approval in 1st line MBC,Effective drugs prolong life: Doxorubicin based regimens 6 months Herceptin 5 months Docetaxel 3 mo

22、nths Capecitabine + Docetaxel 3 months,Survival as a basis of approval: Examples,1st Line MBC: Herceptin + Paclitaxel Gemcitabine + Paclitaxel 2nd Line MBC Docetaxel monoterapy and Capecitabine + Docetaxel after failure of prior chemotherapy,Cross-over therapy confounds survival effect: truth or myt

23、h?,According to ODAC 6/99: No No literature to support this statement A drug used after tumor progression should have the same effect in both arms, and should not obscure the effect of the drug tested. Examples: Herceptin + chemo better than chemo, in spite of a 65% cross-over rate Camptosar + 5-FU/

24、leucovorin better than 5-FU/leucovorin, in spite of a 40% cross-over rate,SUMMARY,See ODAC transcript for Monday June 7, 1999, posted on the FDA website,TTP: Not acceptable for traditional approval in 1st line cytotoxic therapy for metastatic breast cancer,TTP as the basis of approval: Examples,2nd and 3rd Line MB