Future therapeutics for HER2 positive
metastatic breast cancer
•William J. Gradishar MD, FACP
•Betsy Bramsen Professor of Breast Oncology
•Director, Maggie Daley Center For Women's Cancer Care
•Robert H. Lurie Comprehensive Cancer Center
•Northwestern University Feinberg School of Medicine
•Chicago, IL
‘Irreversible’ tyrosine kinase inhibitors
 Irreversible TKIs form covalent bonds with tyrosine
kinase
 Irreversible bond
 TK remains inhibited until new receptor/TK complex
can be synthesized
 Afatinib and neratinib are HER1[EGFR]/HER2
TKIs in development
Awada et al, Cancer Treat Rev. 2012;38:494-501.
Afatinib in trastuzumab refractory MBC
 Patients with pretreated MBC (n=41)
 Median prior lines of chemotherapy: 3
 >1 year trastuzumab therapy: 68%
 Response to trastuzumab:
► CR: 2
► PR: 13
► SD: 13
 Response to afatinib:





PR: 4 (10%)
SD: 15 (37%)
(6 patients were not evaluable)
Median PFS: 15 weeks
Median OS: 61 weeks.
 Adverse events:
 Grade 3 or 4 diarrhea
 Rash
Lin et al, Breast Cancer Res Treat. 2012;133:1057-65.
Ongoing LUX-breast clinical trials with
afatinib in breast cancer
Study design
Patients
Treatment arms
Primary endpoint
LUX-breast 11
LUX-breast 22
LUX-breast 33
Randomized Phase III
Open-label Phase II
Randomized Phase II
Target 780
HER2 + MBC
Progression on or after
1 prior trastuzumab
regimen
Target 120
HER2 + MBC
Progression after adjuvant /
neoadjuvant trastuzumab
and / or lapatinib
Target 120
HER2 + MBC
Progressive / recurrent
brain metastases during /
after prior trastuzumab or
lapatinib
Afatinib (40 mg) +
vinorelbine
vs
Trastuzumab +
vinorelbine
Afatinib 40 mg followed by
afatinib + paclitaxel
or
Vinorelbine after
progression
Afatinib (40 mg)
vs
Afatinib (40 mg) +
vinorelbine
vs
Investigator’s choice
PFS
Objective response rate
Patient benefit
(progression or absence
of CNS disease)
1. Harbeck et al, J Clin Oncol. 2012;30 (suppl); abstr TPS649.
2. Hickish et al, J Clin Oncol. 2012;30 (suppl); abstr TPS651.
3. Joensuu & Kaci, J Clin Oncol. 2012;30 (suppl); abstr TPS647.
Neratinib in patients with advanced HER2
positive breast cancer
 Open label study in patients with stage IIIB/C and IV breast
cancer
 n=136 patients
 Prior trastuzumab (n=66; 63 evaluable)
 No prior trastuzumab (n=70; 64 evaluable)
Prior T
(n=63)
No prior T
(n=64)
59
78
22.3
39.6
Objective response rate (%)
24
56
Clinical benefit (PR, SD) rate (%)
33
69
16 week PFS (%)
Median PFS (weeks)
 Main adverse events; Diarrhea (including grade 3/4 in
29 patients), nausea, vomiting, and fatigue
Burstein et al, J Clin Oncol. 2010;28:1301-7.
Summary
 The options available for metastatic/ advanced
HER2 positive breast cancer have changed with the
availability of pertuzumab and, likely in 2013
trastuzumab emtansine
 In addition to antibody based technology, another
promising approach are the ‘irreversible’ tyrosine
kinase inhibitors
 These form covalent, irreversible bonds and thus
demonstrate a prolonged inhibition of the HER2 TK
 Clinical trials are ongoing to confirm the initial
Phase IIa results