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1、Drug Treatment of Metastatic Breast CancerFDA Approval OverviewPatricia Cortazar, MD微快车微信营销 weikuaiche .Drugs approved for Metastatic Breast CancerMethotrexate1953Cyclophosphamide1959Thiotepa1959Vinblastine19615-Fluorouracil1962Doxorubicin1974.Paclitaxel1994Docetaxel1996Trastuzumab 1998Capecitabine1

2、998Capecitabine + Docetaxel2001Abraxane2005Lapatinib2006Ixabepilone2007Drugs approved in 2nd-3rd line Metastatic Breast Cancer.PaclitaxelTAXOL is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemo

3、therapy. Prior therapy should have included an anthracycline unless clinically contraindicated . Paclitaxel mg/m2 3-hour infusionTAXOL Study Design Paclitaxel 175 mg/m23-hour infusion 471Patients who failed one or two regimensof chemotherapy67% previous anthracyclines.TAXOL Efficacy ResultsFull Appr

4、ovalPaclitaxel 175235Paclitaxel 135236Response (months)28%22% P-value (log rank)p=0.135TTP median (months)4.23.0 P-value (log rank)p=0.027Survival (months)11.710.5 P-value (log rank)p=0.321.DocetaxelTAXOTERE for Injection indicated for the treatment of patients with locally advanced or metastatic br

5、east cancer after failure of prior chemotherapy.DocetaxelAccelerated Approval 19963 Phase II studies in total 134 patientsDose 100 mg/m2 q 3 weeksEndpoint: Overall RR 41% (95% CI: 33-49)PMC: Submit data from controlled clinical studies (TAX311, TAX304). Mytomicin 12 mg/m2 Q 6 weeks Vinblastine 6 mg/

6、m2 Q 3 weeksTAX304 Study Design Docetaxel 100 mg/m2Q 3 weeks 392Patients with Prior anthracyclineregimens.TAX304 Efficacy ResultsFull ApprovalDocetaxel203Myt +Vinblastine189TTP (months)4.32.5 Risk Ratio 95% CI (RR)0.750.61-0.94 P-value (log rank)p=0.01Survival (months)11.48.7 Risk Ratio* 95% CI (RR)

7、0.730.58-0.93 P-value (log rank)p=0.01.TrastuzumabHerceptin 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 dose2 mg/kg wk

8、ly maintenanceHerceptin MBC Study Design222Patients with MBCHER2 overexpression2+3+1 or 2 prior CT for MBCAnthracycline and Taxane.Herceptin monotherapy Full ApprovalResponse Rate14%CR2%PR12%Response Duration median (months)9Survival median (months)12.8.CapecitabineXeloda is indicated for the treatm

9、ent of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant 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

10、or doxorubicin equivalents.Capecitabine monotherapy Accelerated ApprovalPatients resistant to paclitaxel and anthracycline43CR0PR11Response Rate95% CI25.6%(13.5, 41.2)Response Duration median (days)Range154(63-233).CapecitabineXeloda is indicated in combinationwith Taxotere (docetaxel) for the treat

11、ment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.Docetaxel 100 mg/m2Q 3 weeksStudy Design Capecitabine 1250 mg/m2 twice daily for 14 days Docetaxel 75 mg/m2 Q 3 weeks511metastaticbreast cancer resistant to Anthracycline30

12、% 1st line.Capecitabine Efficacy ResultsFull ApprovalCapeciabine + DocetaxelDocetaxelTTP (median days)186128 95% CI(165-198)(105-136) Hazard Ratio0.643 P-value (log rank)p=0.01Survival (median days)442352 95% CI(375-497)(298-387) Hazard Ratio0.775 P-value (log rank)0.0126.Overall Survivalmedian days

13、Docetaxel - 352Capecitabine + Doc - 442 Log rank p=0.0126.LapatinibTYKERB in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express HER2 (ErbB2) who have received prior therapy including an anthracycline, a taxane and trastuzum

14、ab. Capecitabine 2500 mg/m2 daily for 14 days Study DesignLapatinib 1250 mg/m2 continuouslyCapecitabine 2000 mg/m2 daily for 14 days 399Locally advancedor metastaticbreast cancerHER2+ prior anthracycline,Taxane andHerceptin.Lapatinib Efficacy ResultsFull ApprovalIndependent radiology ReviewInvestiga

15、torLap +CapCapLap +CapCapTTP # events82102121126Median (weeks)27.118.623.918.3Hazard ratio 95% CI0.57(0.43, 0.77)0.72(0.56, 0.92)P-value0.000130.00762ORR %23.713.931.817.4.Efficacy of Combination Therapy:Kaplan-Meier Curves of TTPLapatinib + Capecitabine -Capecitabine -p= 0.00013.IxabepiloneCombinat

16、ion Therapy:Ixempra is indicated in combination with capecitabine for the treatment 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 contraindicate

17、d. . Capecitabine 1250 mg/m2 BID Days 1 to 14 q 21 daysStudy Design Ixabepilone 40 mg/m2 Days 1 q 21 days Capecitabine1000 mg/m2 BID Days 1 to 14 q 21 days752Resistant to Taxane andanthracycline.Ixabepilone Efficacy ResultsFull ApprovalIxa + Cape375Capecitabine377PFS (months)5.74.1 Hazard Ratio 95%

18、CI 0.690.58-0.83 P-value (log rank)p 0.0001.Efficacy of Combination Therapy:Kaplan-Meier Curves of PFSlog rank p 0.0001.IxabepiloneMonotherapy:Ixempra is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to

19、 anthracyclines, taxanes, and capecitabine. Single-arm Monotherapy Studies (n=126)Independent radiology ReviewInvestigatorORR (%)12.418.3 95% CI6.9, 19.911.9, 26.1Response DurationMedian (months)6.0 95% CI5.0, 7.6.1st line Metastatic Breast Cancer.Drugs approved in 1st line Metastatic Breast CancerH

20、erceptin + Paclitaxel 1998Gemcitabine + Paclitaxel 2004.TrastuzumabHerceptin 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 Al

21、oneHerceptin 1st line MBC Study Design Chemotherapy (AC or Paclitaxel) Herceptin loading: 4 mg/kg weekly: 2 mg/kg469Patients with untreated MBCHER2 overexpression2+3+.Survival Time (months)Proportion Alive0510152025300.00.20.40.60.81.0Survival ALL PatientsHerceptin 79%Control 68%P 0.01.Herceptin Ful

22、l ApprovalSurvival All Patients.Time to Progression (Months)Proportion Progression-Free05101520250.00.20.40.60.81.0Time to Progression All PatientsHerceptinControlp 0.001.GemcitabineGemzar in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast can

23、cer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.Paclitaxel175 mg/m2 Days 1 and 8 q 21 daysStudy Design Gemcitabine 1250 mg/m2Days 1 and 8 q 21 days Paclitaxel175 mg/m2Days 1 and 8 q 21 days529Unresectable,locally recurr

24、entor metastaticbreast cancer.SurvivalGemzar/Paclitaxel - 18.6 monthsPaclitaxel - 15.8 monthsLog rank p=0.0489 SURVIVAL.Time to Progression.ENDPOINTS Metastatic Breast Cancer.Survival: Basis of cytotoxic drug approval in 1st line MBCCytotoxic and biologic drugs are toxicSurvival is both a safety and

25、 an efficacy parameterDeaths are caused by toxicity orprogressive disease or both.Efficacy Reasons for using Survival as basis of approval in 1st line MBCEffective drugs prolong life:Doxorubicin based regimens 6 monthsHerceptin 5 monthsDocetaxel 3 months Capecitabine + Docetaxel 3 months .Survival a

26、s a basis of approval: Examples1st Line MBC:Herceptin + PaclitaxelGemcitabine + Paclitaxel2nd Line MBCDocetaxel monoterapy andCapecitabine + Docetaxel after failure of prior chemotherapy.Cross-over therapy confounds survival effect: truth or myth?According to ODAC 6/99: NoNo literature to support th

27、is statementA 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 rateCamptosar + 5-FU/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 websiteTTP: Not acceptable for traditional ap