Drug Treatment of Metastatic Breast Cancer

FDA Approval OverviewFDA Approval Overview

Patricia Cortazar, MDPatricia Cortazar, MD

Drugs approved for Metastatic Breast Cancer

MethotrexateMethotrexate 19531953 CyclophosphamideCyclophosphamide 19591959 ThiotepaThiotepa 19591959 VinblastineVinblastine 19611961 5-Fluorouracil5-Fluorouracil 19621962 DoxorubicinDoxorubicin 19741974

PaclitaxelPaclitaxel 19941994 DocetaxelDocetaxel 19961996 Trastuzumab Trastuzumab 19981998 CapecitabineCapecitabine 19981998 Capecitabine + DocetaxelCapecitabine + Docetaxel 20012001 AbraxaneAbraxane 20052005 LapatinibLapatinib 20062006 IxabepiloneIxabepilone 20072007

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 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 regimensof chemotherapy67% previous anthracyclines

TAXOL Efficacy ResultsFull Approval

Paclitaxel Paclitaxel 175175

235235

Paclitaxel 135Paclitaxel 135

236236

Response (months)(months) 28% 22%

P-value (log P-value (log rank)rank)

p=0.135

TTPTTP median median (months)(months)

4.24.2 3.03.0

P-value (log rank)P-value (log rank) p=0.027

Survival (months) (months) 11.711.7 10.510.5

P-value (log P-value (log rank)rank)

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

DocetaxelAccelerated Approval 1996

3 Phase II studies in total 134 patients3 Phase II studies in total 134 patients Dose 100 mg/mDose 100 mg/m22 q 3 weeks q 3 weeks Endpoint: Endpoint: Overall RROverall RR

41%41% (95% CI: 33-49) (95% CI: 33-49) PMC: Submit data from controlled PMC: Submit data from controlled

clinical studies (TAX311, TAX304)clinical studies (TAX311, TAX304)

Mytomicin 12 mg/m2

Q 6 weeks Vinblastine 6 mg/m2

Q 3 weeks

TAX304 Study DesignTAX304 Study Design

Docetaxel 100 mg/m2

Q 3 weeks

392

Patients with Prior anthracyclineregimens

TAX304 Efficacy ResultsFull Approval

DocetaxelDocetaxel

203203Myt Myt

+Vinblastine+Vinblastine

189189

TTP (months)(months) 4.3 2.5

Risk Ratio 95% CI (RR)

0.750.61-0.94

P-value (log P-value (log rank)rank)

p=0.01

SurvivalSurvival (months) (months) 11.411.4 8.78.7

Risk Ratio* 95% CI (RR)

0.73

0.58-0.93

P-value (log P-value (log rank)rank)

p=0.01

Trastuzumab

HerceptinHerceptin®® is indicated for treatment of is indicated for treatment of patients with metastatic breast cancer patients with metastatic breast cancer whose tumors overexpress the HER2 whose tumors overexpress the HER2 protein and who have received one or protein and who have received one or more chemotherapy regimens for their more chemotherapy regimens for their metastatic disease. metastatic disease.

Trastuzumab 4 mg/kg loading dose2 mg/kg wkly maintenance

Herceptin MBC Study Design

222

Patients with MBCHER2 overexpression2+3+1 or 2 prior CT for MBCAnthracycline and Taxane

Herceptin monotherapy Full Approval

Response RateResponse Rate 14%14%

CRCR 2%2%

PRPR 12%12%

Response Duration median Response Duration median (months)(months)

99

Survival median (months)Survival median (months) 12.812.8

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 Patients resistant to paclitaxel and anthracyclineand anthracycline

4343

CRCR 00

PRPR 1111

Response RateResponse Rate

95% CI95% CI25.6%25.6%

(13.5, (13.5, 41.2)41.2)

Response Duration median Response Duration median (days)(days)

RangeRange

154154

(63-233)(63-233)

Capecitabine

Xeloda® is indicated in combinationwith Taxotere (docetaxel) 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

metastaticbreast cancer resistant to Anthracycline30% 1st line

Capecitabine Efficacy Results

Full ApprovalCapeciabine Capeciabine + Docetaxel+ Docetaxel

DocetaxelDocetaxel

TTPTTP (median days)(median days) 186 128

95% CI (165-198)(165-198) (105-136)(105-136)

Hazard RatioHazard Ratio 0.6430.643

P-value (log rank)P-value (log rank) p=0.01

SurvivalSurvival (median (median days)days)

442442 352352

95% CI95% CI (375-497)(375-497) (298-387)(298-387)

Hazard RatioHazard Ratio 0.775

P-value (log rank)P-value (log rank) 0.0126

Overall SurvivalOverall Survivalmedian days

Docetaxel ---- 352Capecitabine + 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.

Capecitabine 2500 mg/m2 daily for 14 days

Study Design

Lapatinib 1250 mg/m2

continuouslyCapecitabine 2000 mg/m2

daily for 14 days

399

Locally advancedor metastaticbreast cancerHER2+ prior anthracycline,Taxane andHerceptin.

Lapatinib Efficacy ResultsFull Approval

Independent Independent radiology radiology ReviewReview

InvestigatorInvestigator

Lap Lap +Cap+Cap

CapCap Lap Lap +Cap+Cap

CapCap

TTPTTP # events# events 82 102 121 126126

Median (weeks)Median (weeks) 27.127.1 18.618.6 23.923.9 18.318.3

Hazard ratio Hazard ratio

95% CI95% CI0.570.57

(0.43, 0.77)(0.43, 0.77)0.720.72

(0.56, 0.92)(0.56, 0.92)

P-valueP-value 0.000130.00013 0.00762

ORRORR %% 23.723.7 13.913.9 31.831.8 17.417.4

Efficacy of Combination Therapy:Efficacy of Combination Therapy:Kaplan-Meier Curves of TTPKaplan-Meier Curves of TTP

Lapatinib + Capecitabine -----------

Capecitabine ---------

p= 0.00013

IxabepiloneCombination 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 days752

Resistant to Taxane andanthracycline

Ixabepilone Efficacy ResultsFull Approval

Ixa + CapeIxa + Cape

375375CapecitabineCapecitabine

377377

PFSPFS (months)(months) 5.7 4.1

Hazard Ratio 95% CI

0.690.58-0.83

P-value (log P-value (log rank)rank)

p <0.0001p <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)

IndependenIndependent radiology t radiology

ReviewReview

InvestigatorInvestigator

ORRORR (%)(%) 12.4 18.3

95% CI95% CI 6.9, 19.96.9, 19.9 11.9, 26.111.9, 26.1

Response Duration

Median (months)Median (months) 6.06.0

95% CI95% CI 5.0, 7.6

1st line Metastatic Breast

Cancer

Drugs approved in 1st line Metastatic Breast Cancer

Herceptin + PaclitaxelHerceptin + Paclitaxel 19981998

Gemcitabine + PaclitaxelGemcitabine + Paclitaxel 20042004

Trastuzumab

HerceptinHerceptin®® in combination with in combination with paclitaxel is indicated for treatment of paclitaxel is indicated for treatment of patients with metastatic breast cancer patients with metastatic breast cancer whose tumors overexpress HER2 whose tumors overexpress HER2 protein and who have not received protein and who have not received chemotherapy for their metastatic chemotherapy for their metastatic disease.disease.

Chemotherapy Alone

Herceptin 1st line MBC Study Design

Chemotherapy (AC or Paclitaxel) Herceptin loading: 4 mg/kg weekly: 2 mg/kg

469

Patients with untreated MBCHER2 overexpression2+3+

Survival Time (months)

Pro

po

rtio

n A

live

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

Herceptin Full ApprovalHerceptin Full Approval

Survival All PatientsSurvival All Patients

Time to Progression (Months)

Pro

po

rtio

n P

rog

res

sio

n-F

ree

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 Gemzar in combination with paclitaxel is indicated for the first-line treatment is indicated for the first-line treatment of patients with metastatic breast of patients with metastatic breast cancer after failure of prior cancer after failure of prior anthracycline-containing adjuvant anthracycline-containing adjuvant chemotherapy, unless anthracyclines chemotherapy, unless anthracyclines were clinically contraindicated.were clinically contraindicated.

Paclitaxel 175 mg/m2

Days 1 and 8 q 21 days

Study Design

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 recurrentor metastaticbreast cancer

SurvivalSurvivalGemzar/Paclitaxel ---------- 18.6 months

Paclitaxel ---------- 15.8 months

Log rank p=0.0489

SURVIVAL

Time to Progression

ENDPOINTS

Metastatic Breast CancerMetastatic Breast Cancer

Survival: Basis of cytotoxic drug approval in 1st line MBC

Cytotoxic and biologic drugs are toxicCytotoxic and biologic drugs are toxic Survival is both a safety and an Survival is both a safety and an

efficacy parameterefficacy parameter Deaths are caused by toxicity orDeaths are caused by toxicity or

progressive disease or bothprogressive disease or both

Efficacy Reasons for using Survival as basis of approval

in 1st line MBC

Effective drugs prolong life:Effective drugs prolong life:

Doxorubicin based regimens→ 6 monthsDoxorubicin based regimens→ 6 months Herceptin → 5 monthsHerceptin → 5 months Docetaxel → 3 months Docetaxel → 3 months Capecitabine + Docetaxel → 3 months Capecitabine + Docetaxel → 3 months

Survival as a basis of approval: Examples

11stst Line MBC: Line MBC: Herceptin + PaclitaxelHerceptin + Paclitaxel Gemcitabine + PaclitaxelGemcitabine + Paclitaxel22ndnd Line MBC Line MBC Docetaxel monoterapy Docetaxel monoterapy

andand Capecitabine + Docetaxel after failure Capecitabine + Docetaxel after failure

of prior chemotherapyof prior chemotherapy

Cross-over therapy confounds survival effect:

truth or myth? According to ODAC 6/99: NoAccording to ODAC 6/99: No No literature to support this statementNo literature to support this statement A drug used after tumor progression should A drug used after tumor progression should

have the same effect in both arms, and have the same effect in both arms, and should not obscure the effect of the drug should not obscure the effect of the drug tested. Examples:tested. Examples:

Herceptin + chemo better than chemo, Herceptin + chemo better than chemo, in spite of a 65% cross-over ratein spite of a 65% cross-over rate

Camptosar + 5-FU/leucovorin better than Camptosar + 5-FU/leucovorin better than 5-FU/leucovorin, in spite of a 40% cross-5-FU/leucovorin, in spite of a 40% cross-over rateover rate

SUMMARYSUMMARY

See ODAC transcript for Monday See ODAC transcript for Monday June 7, 1999, posted on the FDA June 7, 1999, posted on the FDA

websitewebsite

TTP: Not acceptable for traditional approval in 1st line cytotoxic therapy for metastatic breast cancer

TTP as the basis of approval: Examples

22nd nd and 3and 3rdrd Line MBC Line MBC Paclitaxel Paclitaxel

LapatinibLapatinib

Progression Free Survival

Has not been used as basis for Has not been used as basis for approval in 1approval in 1stst line MBC. line MBC.

Has been used for basis of approval of Has been used for basis of approval of Ixabepilone in 2Ixabepilone in 2ndnd-3-3rdrd line therapy. line therapy.

Problems with PFS

Needs blinded RCTNeeds blinded RCT Blinded assessment by Independent Radiology Blinded assessment by Independent Radiology

ReviewReview Problems with patients without measurable Problems with patients without measurable

disease disease Problems with missed assessments or incomplete Problems with missed assessments or incomplete

assessments at baseline assessments at baseline Problems with infrequent assessmentsProblems with infrequent assessments Problems with uneven assessment in each armProblems 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