Drug Treatment of Metastatic Breast Cancer
FDA Approval Overview Patricia Cortazar, MD
Drugs approved for Metastatic Breast Cancer
Methotrexate Cyclophosphamide 1959 Thiotepa Vinblastine 5-Fluorouracil 1962 Doxorubicin
Drugs approved in 2nd-3rd line Metastatic Breast Cancer
Paclitaxel Docetaxel Trastuzumab Capecitabine Capecitabine + Docetaxel 2001 Abraxane Lapatinib Ixabepilone
Paclitaxel TAXOL® 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
Paclitaxel 135 mg/m2 3-hour infusion
TAXOL Study Design Paclitaxel mg/m2 3-hour infusion 471 Patients who failed one or two regimens of chemotherapy 67% previous anthracyclines Paclitaxel mg/m hour infusion
TAXOL Efficacy Results Full Approval
Paclitaxel 175 235 Paclitaxel 135 236 Response (months) 28% 22% P-value (log rank) p=0.135 TTP median (months) 4.2 3.0 p=0.027 Survival (months) 11.7 10.5 p=0.321
Docetaxel TAXOTERE® for Injection indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy
Docetaxel Accelerated Approval 1996
3 Phase II studies in total 134 patients Dose 100 mg/m2 q 3 weeks Endpoint: Overall RR 41% (95% CI: 33-49) PMC: Submit data from controlled clinical studies (TAX311, TAX304)
TAX304 Study Design 392 Docetaxel 100 mg/m2 Q 3 weeks
Patients with Prior anthracycline regimens Mytomicin 12 mg/m Q 6 weeks Vinblastine mg/m2 Q 3 weeks
TAX304 Efficacy Results Full Approval
Docetaxel 203 Myt +Vinblastine 189 TTP (months) 4.3 2.5 Risk Ratio 95% CI (RR) 0.75 P-value (log rank) p=0.01 Survival (months) 11.4 8.7 Risk Ratio* 0.73
Trastuzumab Herceptin® 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.
Herceptin MBC Study Design
Trastuzumab 4 mg/kg loading dose 2 mg/kg wkly maintenance 222 Patients with MBC HER2 overexpression 2+3+ 1 or 2 prior CT for MBC Anthracycline and Taxane
Herceptin monotherapy Full Approval
Response Rate 14% CR 2% PR 12% Response Duration median (months) 9 Survival median (months) 12.8
Capecitabine Xeloda® 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.
Capecitabine monotherapy Accelerated Approval
Patients resistant to paclitaxel and anthracycline 43 CR PR 11 Response Rate 95% CI 25.6% (13.5, 41.2) Response Duration median (days) Range 154 (63-233)
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.
Study Design 511 Capecitabine 1250 mg/m2 twice daily for 14 days
Docetaxel mg/m2 Q 3 weeks 511 metastatic breast cancer resistant to Anthracycline 30% 1st line Docetaxel mg/m2 Q 3 weeks
Capecitabine Efficacy Results Full Approval
Capeciabine + Docetaxel Docetaxel TTP (median days) 186 128 95% CI ( ) ( ) Hazard Ratio 0.643 P-value (log rank) p=0.01 Survival (median days) 442 352 ( ) ( ) 0.775 0.0126
Overall Survival median days Docetaxel ---- 352
Capecitabine + Doc Log rank p=0.0126
Lapatinib TYKERB® 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.
Study Design 399 Lapatinib 1250 mg/m2 continuously
Capecitabine mg/m daily for 14 days 399 Locally advanced or metastatic breast cancer HER2+ prior anthracycline, Taxane and Herceptin. Capecitabine mg/m daily for 14 days
Lapatinib Efficacy Results Full Approval
Independent radiology Review Investigator Lap +Cap Cap TTP # events 82 102 121 126 Median (weeks) 27.1 18.6 23.9 18.3 Hazard ratio 95% CI 0.57 (0.43, 0.77) 0.72 (0.56, 0.92) P-value ORR % 23.7 13.9 31.8 17.4
Efficacy of Combination Therapy: Kaplan-Meier Curves of TTP
Lapatinib + Capecitabine Capecitabine p=
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.
Capecitabine 1250 mg/m2 BID Days 1 to 14 q 21 days
Study Design Ixabepilone 40 mg/m2 Days 1 q 21 days Capecitabine 1000 mg/m2 BID Days 1 to 14 q 21 days 752 Resistant to Taxane and anthracycline Capecitabine mg/m BID Days 1 to 14 q 21 days
Ixabepilone Efficacy Results Full Approval
Ixa + Cape 375 Capecitabine 377 PFS (months) 5.7 4.1 Hazard Ratio 95% CI 0.69 P-value (log rank) p <0.0001
Efficacy of Combination Therapy: Kaplan-Meier Curves of PFS
log rank p<
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.
Single-arm Monotherapy Studies (n=126)
Independent radiology Review Investigator ORR (%) 12.4 18.3 95% CI 6.9, 19.9 11.9, 26.1 Response Duration Median (months) 6.0 5.0, 7.6
1st line Metastatic Breast Cancer
Drugs approved in 1st line Metastatic Breast Cancer
Herceptin + Paclitaxel Gemcitabine + Paclitaxel
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.
Herceptin 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+ Chemotherapy Alone
Survival Time (months)
Survival ALL Patients 1.0 0.8 0.6 Proportion Alive 0.4 Herceptin 79% Control 68% 0.2 P < 0.01 0.0 5 10 15 20 25 30 Survival Time (months)
Herceptin Full Approval
Survival All Patients
Time to Progression All Patients Time to Progression (Months)
1.0 0.8 p < 0.001 Herceptin Proportion Progression-Free 0.6 Control 0.4 0.2 0.0 5 10 15 20 25 Time to Progression (Months)
Gemcitabine Gemzar 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.
Study Design 529 Gemcitabine 1250 mg/m2 Days 1 and 8 q 21 days
Paclitaxel 175 mg/m2 Days 1 and 8 q 21 days 529 Unresectable, locally recurrent or metastatic breast cancer Paclitaxel 175 mg/m2 Days 1 and 8 q 21 days
Survival Gemzar/Paclitaxel ---------- 18.6 months
Log rank p=0.0489
Time to Progression
Metastatic Breast Cancer
ENDPOINTS Metastatic Breast Cancer
Survival: Basis of cytotoxic drug approval in 1st line MBC
Cytotoxic and biologic drugs 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 months 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 myth?
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/leucovorin better than 5-FU/leucovorin, in spite of a 40% cross-over rate
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 MBC Paclitaxel Lapatinib
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.
Problems with PFS Needs blinded RCT
Blinded assessment by Independent Radiology Review Problems with patients without measurable disease Problems with missed assessments or incomplete assessments at baseline Problems with infrequent assessments Problems with uneven assessment in each arm
Is the use of PFS in the 1st line treatment of MBC appropriate, especially in a situation were there is no improvement in survival?
NDA submissions based on PFS will affect survival data
Premature stopping trial before accrual is complete or stop following patients for survival Risk for not seeing survival data in future trials
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