Trastuzumab in Metastatic Breast Cancer

1
Trastuzumab in Metastatic Breast Cancer

• Teaching an old dog new tricks
• Rama Suresh, M.D.
• Fellow, Division of Hematology-Oncology

2
HER 2

• Discovered in 1980
• Member of EGFR family
• Overexpressed in 25 to 30 of breast cancers
• Shortened survival and relative resistance to
  therapies

3
IHC

• HER2 protein expression
• Grading
• 0, 1(negative)
• 2 (indeterminant)
• 3(positive)
• Low volume labs correlate poorly with the
  reference labs (JNCI 200294 852-854 and
  855-857)

4
FISH

• HER2 gene overexpression
• PathVysion HER2 DNA probe
• positive if HER2 to CEP17 isgt 2
• Gold standard
• Results are similar with IHC 3
• Indicated when IHC 2 or aggressive tumor with
  IHC 0/1

5
Trastuzumab

• Binds to the EC domain of HER2
• FDA approved (1998)
• Only in IHC 3 or FISH

6
Dosage

• Loading 4mg/kg over 90min
• weekly 2mg/kg over 30min
• Half life 30days (Washington CB, Clin Pharmacol
  Ther 20027112.Abstract)
• Loading 8mg/kg maintenance
• 6mg/kg q 3wks
• Gelmon (ASCO 200120271 Abstract)

7
Cardiotoxicity
John Horton,Cancer control 9(6)499-507,2002
8
Other toxicity

• Infusion reaction 40
• Fever,chills, nausea, vomiting, body pain,
  rigors, Headache, dizziness, rash, hypotension
• Diarrhea 25
• Grade 3 hematological toxicity lt1
• Anaphylaxis/pulmonary events
• Glomerulopathy

9
Monotherapy
10
Interaction of Trastuzumab with chemotherapy in
cell lines
Nabholtz et al,Clinical Breast Cancer3S275-79,Oct
2002 Based on articles of Pegram, Oncogene1999
and Konecny, Breast Cancer Res Treat 1999
11
Trastuzumab and Taxanes
John Horton,Cancer control 9(6)499-507,2002
12
Trastuzumab and Docetaxel
13
Trastuzumab and Vinorelbine
John Horton,Cancer control 9(6)499-507,2002
14
Trastuzumab and Vinorelbine
15
Trastuzumab and other chemotherapy
John Horton,Cancer control 9(6)499-507,2002
16
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 Abstr1973
17
TrastuzumabPaclitaxelGemcitabine

• 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 Abstr437
18
First and second line
John Horton,Cancer control 9(6)499-507,2002
19
Trastuzumab and Platins
Cancer control 9(6)499-507,2002
20
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
• ? (gt30 m) 19 m
• Yardley DA, SABC Abstract 439, December 12, 2002

21
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
• gt50 hepatic involvement
• Prior adjuvant therapy in 33
• Newly diagnosed stage IV in 20

22
Paclitaxel 70mg/m2 with Carboplatin AUC 2
(6wks) Break (2 wks)
CP
PD
SD
CPT
Trastuzumab
CR
T
CP
23
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)

24
BCIRG
25
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

26
Phase III comparitive study of TrastuzumabPaclita
xel /-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 gt360mg/m2
• 2/3 IHC 3

US Oncology Group Robert N, Leyland-Jones SABC
Abstr 35, Dec 2002
27
Dosage Schedule

• Trastuzumab 4mg/kg loading and 2mg/kg q week
• Paclitaxel 175mg/m2 q 3 wks
• Carboplatin AUC 6 q 3wks

28
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

29
Proposed trial

• Carboplatin, Navelbine and Trastuzumab in
  Metastatic Breast Cancer