Drug Treatment of Metastatic Breast Cancer FDA Approval Overview Patricia Cortazar, MD

Drugs approved for Metastatic Breast Cancer Methotrexate 1953 Cyclophosphamide 1959 Thiotepa 1959 Vinblastine 1961 5-Fluorouracil 1962 Doxorubicin 1974

Drugs approved in 2nd-3rd line Metastatic Breast Cancer Paclitaxel 1994 Docetaxel 1996 Trastuzumab 1998 Capecitabine 1998 Capecitabine + Docetaxel 2001 Abraxane 2005 Lapatinib 2006 Ixabepilone 2007

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 175 mg/m2 3-hour infusion 471 Patients who failed one or two regimens of chemotherapy 67% previous anthracyclines Paclitaxel 135 mg/m2 3-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/m2 Q 6 weeks Vinblastine 6 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 0.61-0.94 P-value (log rank) p=0.01 Survival (months) 11.4 8.7 Risk Ratio* 0.73 0.58-0.93

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 75 mg/m2 Q 3 weeks 511 metastatic breast cancer resistant to Anthracycline 30% 1st line Docetaxel 100 mg/m2 Q 3 weeks

Capecitabine Efficacy Results Full Approval Capeciabine + Docetaxel Docetaxel TTP (median days) 186 128 95% CI (165-198) (105-136) Hazard Ratio 0.643 P-value (log rank) p=0.01 Survival (median days) 442 352 (375-497) (298-387) 0.775 0.0126

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 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 2000 mg/m2 daily for 14 days 399 Locally advanced or metastatic breast cancer HER2+ prior anthracycline, Taxane and Herceptin. Capecitabine 2500 mg/m2 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 0.00013 0.00762 ORR % 23.7 13.9 31.8 17.4

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 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 1250 mg/m2 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 0.58-0.83 P-value (log rank) p <0.0001

Efficacy of Combination Therapy: Kaplan-Meier Curves of PFS log rank p< 0.0001

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.

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 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.

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

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 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