Presentation on theme: "Drug Treatment of Metastatic Breast Cancer"— Presentation transcript:
1 Drug Treatment of Metastatic Breast Cancer FDA Approval OverviewPatricia Cortazar, MD
2 Drugs approved for Metastatic Breast Cancer MethotrexateCyclophosphamide 1959ThiotepaVinblastine5-Fluorouracil 1962Doxorubicin
3 Drugs approved in 2nd-3rd line Metastatic Breast Cancer PaclitaxelDocetaxelTrastuzumabCapecitabineCapecitabine + Docetaxel 2001AbraxaneLapatinibIxabepilone
4 PaclitaxelTAXOL® is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated
5 Paclitaxel 135 mg/m2 3-hour infusion TAXOL Study DesignPaclitaxel mg/m2 3-hour infusion471Patients who failedone or two regimensof chemotherapy67% previousanthracyclinesPaclitaxel mg/m hour infusion
6 TAXOL Efficacy Results Full Approval Paclitaxel 175235Paclitaxel 135236Response (months)28%22%P-value (log rank)p=0.135TTP median (months)4.23.0p=0.027Survival (months)11.710.5p=0.321
7 DocetaxelTAXOTERE® for Injection indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy
8 Docetaxel Accelerated Approval 1996 3 Phase II studies in total 134 patientsDose 100 mg/m2 q 3 weeksEndpoint: Overall RR41% (95% CI: 33-49)PMC: Submit data from controlled clinical studies (TAX311, TAX304)
10 TAX304 Efficacy Results Full Approval Docetaxel203Myt +Vinblastine189TTP (months)4.32.5Risk Ratio95% CI (RR)0.75P-value (log rank)p=0.01Survival (months)11.48.7Risk Ratio*0.73
11 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.
12 Herceptin MBC Study Design Trastuzumab 4 mg/kg loading dose2 mg/kg wkly maintenance222Patients with MBCHER2 overexpression2+3+1 or 2 prior CT for MBCAnthracycline and Taxane
13 Herceptin monotherapy Full Approval Response Rate14%CR2%PR12%Response Duration median (months)9Survival median (months)12.8
14 CapecitabineXeloda® is indicated for the treatment 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 or doxorubicin equivalents.
15 Capecitabine monotherapy Accelerated Approval Patients resistant to paclitaxel and anthracycline43CRPR11Response Rate95% CI25.6%(13.5, 41.2)Response Duration median (days)Range154(63-233)
16 Capecitabine Xeloda® is indicated in combination with Taxotere (docetaxel) for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.
17 Study Design 511 Capecitabine 1250 mg/m2 twice daily for 14 days Docetaxel mg/m2Q 3 weeks511metastaticbreast cancerresistant toAnthracycline30% 1st lineDocetaxel mg/m2Q 3 weeks
19 Overall Survival median days Docetaxel ---- 352 Capecitabine + DocLog rank p=0.0126
20 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 trastuzumab.
21 Study Design 399 Lapatinib 1250 mg/m2 continuously Capecitabine mg/m daily for 14 days399Locally advancedor metastaticbreast cancerHER2+ prioranthracycline,Taxane andHerceptin.Capecitabine mg/m daily for 14 days
23 Efficacy of Combination Therapy: Kaplan-Meier Curves of TTP Lapatinib + CapecitabineCapecitabinep=
24 Ixabepilone Combination 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 contraindicated.
25 Capecitabine 1250 mg/m2 BID Days 1 to 14 q 21 days Study DesignIxabepilone 40 mg/m2 Days 1 q 21 daysCapecitabine 1000 mg/m2BID Days 1 to 14 q 21 days752Resistant toTaxane andanthracyclineCapecitabine mg/m BID Days 1 to 14 q 21 days
27 Efficacy of Combination Therapy: Kaplan-Meier Curves of PFS log rank p<
28 Ixabepilone Monotherapy: Ixempra is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.
31 Drugs approved in 1st line Metastatic Breast Cancer Herceptin + PaclitaxelGemcitabine + Paclitaxel
32 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.
33 Herceptin 1st line MBC Study Design Chemotherapy (AC or Paclitaxel)Herceptin loading: 4 mg/kgweekly: 2 mg/kg469Patients with untreatedMBCHER2 overexpression2+3+Chemotherapy Alone
34 Survival Time (months) Survival ALL Patients1.00.80.6Proportion Alive0.4Herceptin 79%Control 68%0.2P < 0.010.051015202530Survival Time (months)
36 Time to Progression All Patients Time to Progression (Months) 1.00.8p < 0.001HerceptinProportion Progression-Free0.6Control0.40.20.0510152025Time to Progression (Months)
37 GemcitabineGemzar in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.
38 Study Design 529 Gemcitabine 1250 mg/m2 Days 1 and 8 q 21 days Paclitaxel 175 mg/m2Days 1 and 8 q 21 days529Unresectable,locally recurrentor metastaticbreast cancerPaclitaxel 175 mg/m2Days 1 and 8 q 21 days
41 Metastatic Breast Cancer ENDPOINTSMetastatic Breast Cancer
42 Survival: Basis of cytotoxic drug approval in 1st line MBC Cytotoxic and biologic drugs are toxicSurvival is both a safety and an efficacy parameterDeaths are caused by toxicity orprogressive disease or both
43 Efficacy Reasons for using Survival as basis of approval in 1st line MBC Effective drugs prolong life:Doxorubicin based regimens→ 6 monthsHerceptin → 5 monthsDocetaxel → 3 monthsCapecitabine + Docetaxel → 3 months
44 Survival as a basis of approval: Examples 1st Line MBC:Herceptin + PaclitaxelGemcitabine + Paclitaxel2nd Line MBCDocetaxel monoterapyandCapecitabine + Docetaxel after failure of prior chemotherapy
45 Cross-over therapy confounds survival effect: truth or myth? According to ODAC 6/99: NoNo literature to support this 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
47 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
48 TTP as the basis of approval: Examples 2nd and 3rd Line MBCPaclitaxelLapatinib
49 Progression Free Survival Has not been used as basis for approval in 1st line MBC.Has been used for basis of approval of Ixabepilone in 2nd-3rd line therapy.
50 Problems with PFS Needs blinded RCT Blinded assessment by Independent Radiology ReviewProblems with patients without measurable diseaseProblems with missed assessments or incomplete assessments at baselineProblems with infrequent assessmentsProblems with uneven assessment in each arm
51 Is the use of PFS in the 1st line treatment of MBC appropriate, especially in a situation were there is no improvement in survival?
52 NDA submissions based on PFS will affect survival data Premature stopping trial before accrual is complete or stop following patients for survivalRisk for not seeing survival data in future trials