Trastuzumab in Metastatic Breast Cancer

• Teaching an old dog new tricks

• Rama Suresh, M.D.

• Fellow, Division of Hematology-Oncology

HER 2

Discovered in 1980

• Member of EGFR family

• Overexpressed in 25 to 30% of breast cancers

• Shortened survival and relative resistance to therapies

IHC

HER2 protein expression

• Grading – 0, 1+(negative)– 2+ (indeterminant) – 3+(positive)

• Low volume labs correlate poorly with the reference labs (JNCI 2002;94: 852-854 and 855-857)

FISH

HER2 gene overexpression

• PathVysion HER2 DNA probe– positive if HER2 to CEP17 is> 2

• Gold standard

• Results are similar with IHC 3+

• Indicated when IHC 2+ or aggressive tumor with IHC 0+/1+

Trastuzumab

• Binds to the EC domain of HER2

• FDA approved (1998)

• Only in IHC 3+ or FISH +

Dosage

• Loading 4mg/kg over 90min – weekly 2mg/kg over 30min

• Half life 30days (Washington CB, Clin Pharmacol Ther 2002;71:12.Abstract)

• Loading 8mg/kg maintenance – 6mg/kg q 3wks – Gelmon (ASCO 2001;20:271 Abstract)

Cardiotoxicity

John Horton,Cancer control 9(6):499-507,2002

Other toxicity

• Infusion reaction 40%– Fever,chills, nausea, vomiting, body pain, rigors,

Headache, dizziness, rash, hypotension

• Diarrhea 25%

• Grade 3 hematological toxicity <1%• Anaphylaxis/pulmonary events• Glomerulopathy

Monotherapy

Study “Line” of therapy

RR TTP

Cobleigh MA et alJ Clin Oncol 1999;17:2639-2648

N= 222

Prior chemo 15% 9.1M

Vogel CL et alJ Clin Oncol 2002;20:719-726

1st line 26%IHC 3+ (35%vs 0%)FISH + (34%vs 7%)

18.8M

Interaction of Trastuzumab with chemotherapy in cell lines

Interaction Agent

Synergy Cisplatin, Carboplatin, DocetaxelVinorelbine, Etoposide, Thiotepa, XRTPaclitaxel, Doxorubicin

Addition Vinblastine, Methotrexate

Antagonism 5-FU

Nabholtz et al,Clinical Breast Cancer3S2:75-79,Oct 2002Based on articles of Pegram, Oncogene1999 and Konecny, Breast Cancer Res Treat 1999

Trastuzumab and Taxanes

John Horton,Cancer control 9(6):499-507,2002

Trastuzumab and Docetaxel

Study Criteria Docetaxel Dosage

RR

Montemurro N=25 IHC3+ 16,1st, 2nd line

75mg/m2 q3Wks

70%IHC3+ (79%)IHC2+(56%)

Meden N=12 evaluable1,2 and 3rd line

35mg/m2/wk on 6 off 1Wk

50%

Malik N=25, >1 prior chemo,

33mg/m2/wk+/- trastuzumab

ORR 41%, D25%,5of6ptD+H,

Trastuzumab and Vinorelbine

John Horton,Cancer control 9(6):499-507,2002

Trastuzumab and Vinorelbine

Study Criteria Dosage RR

Chan et alSABC 2002 Abstr#434

FISH+ or IHC3+MBC1st line

V 30mg/m2 T 4mg/kg then 2mg/kg/wk

70%

Filipovich et alSABC 2002 Abstr#431

IHC 3+Prior chemo allowed

V 25mg/m2/wkT 4mg/kg then 2mg/kg/wk

72%

Trastuzumab and other chemotherapy

John Horton,Cancer control 9(6):499-507,2002

HET regimen

• Epirubicin 75 mg/m2 D1, Taxotere 75mg/m2 D1 Q21days• Trastuzumab as usual• 1st step 29pts presented • IHC2+/3+• 1 CHF • 2 decrease in LVEF (no CHF)• Gr 3/4 neutropenia 16% of cycles, 3 febrile neutropenia• Gr 1/2 nonhematological toxicity

(asthenia,N/V,mucositis,fever,bone pain)• 2nd step 30 additional pts being recruited

Bighin et al, ASCO 2002 Abstr#1973

Trastuzumab+Paclitaxel+Gemcitabine

• FISH+ or IHC 2-3+• T dosage as usual weekly • Paclitaxel 175mg/m2 on D1+• Gemcitabine 1200mg/m2 on days 1 and 8 q3wks+• Max 6 cycles. Responding and stable patients

continued on T till progression• 45pts • RR 62%, MTP 18M• Gr 4 neutropenia (20), Pulm toxicity (5), CHF(3)

Hoosier Oncology Group trial Miller et al, SABC 2002 Abstr#437

First and second line

John Horton,Cancer control 9(6):499-507,2002

Trastuzumab and Platins

Cancer control 9(6):499-507,2002

Paclitaxel/Carboplatin/Trastuzumabin metastatic breast cancer

• Result All

• ORR 66%• Median TTP 12 m• Median survival 29.3 m

• HER2/neu (FISH) (49)• + -

• 89% 44%• 19 m 8.5 m• ? (>30 m) 19 m

• Yardley DA, SABC Abstract# 439, December 12, 2002

Paclitaxel/Carboplatin/Trastuzumabin metastatic breast cancer

• Phase II multicenter pilot• 61 patients

– HER2 overexpression (IHC 2+ or 3+)– 52 years (median) – ECOG 0-1– 50% ER+ – >50% hepatic involvement

– Prior adjuvant therapy in 33– Newly diagnosed stage IV in 20

CP

Trastuzumab

PD

SD

CR

CP

Paclitaxel 70mg/m2 with Carboplatin AUC 2 (6wks)

Break (2 wks)

CPT

T

Toxicity

• 33% had Grade 3/4 leukopenia (no febrile neutropenia)

• Rare 3/4 non-hematological toxicity– 7% fatigue, 4% diarrhea, 4% neuropathy– 4% asymptomatic LVEF decline (recovered)

BCIRG

101 102

Cisplatin+Docetaxel q3W +Trastuzumab q1W

Carboplatin+Docetaxel q3W +Trastuzumab q1W

No prior chemo Prior taxane allowed

RR 79% RR 56%

Toxicity

• 1 pt Grade 3 infection • 3pts febrile neutropenia

• Grade 3/4 non-hematological side effect rare– Fatigue 11%– Stomatitis 11%– Nausea 7%

– Vomiting, diarrhea, myalgia, edema and skin disorder in 1 pt each

– 1pt with LVEF decline

Phase III comparitive study of Trastuzumab+Paclitaxel

+/-carboplatin• 194 patients• 83% Caucasian

• ECOG PS 0/1/2 were 60%/36%/4%• median age 55• No prior chemo for metastatic disease

• 40% had adj chemo• Cumulative anthracycline not >360mg/m2• 2/3 IHC 3+

US Oncology GroupRobert N, Leyland-Jones SABC Abstr # 35, Dec 2002

Dosage Schedule

• Trastuzumab 4mg/kg loading and 2mg/kg q week

• Paclitaxel 175mg/m2 q 3 wks

• Carboplatin AUC 6 q 3wks

Results

• With Carboplatin• RR 57%

• IHC 3+ RR 67%• TTP 17M• Nausea 5%

• Gr3/4 toxicity– neutropenia 54%– thrombocytopenia 8%

• No carboplatin• RR 38%

• IHC 3+ RR 37%• TTP 7M• Nausea 1%

• Gr 3/4 toxicity– neutropenia 23%– Thrombocytopenia 1%

Proposed trial

• Carboplatin, Navelbine and Trastuzumab in Metastatic Breast Cancer