Defining the HER2 Positive (+) Breast Cancer Kinome Response to Trastuzumab, Pertuzumab, Combination Trastuzumab +Pertuzumab, or Combination Trastuzumab + Lapatinib
Until recently, our understanding of the kinome has been limited to just 5-10% of the
genome-encoded kinases. This limited knowledge prevents a thorough understanding of
resistance mechanisms, and precludes individualizing HER2-targeted therapy in HER2+ disease.
Fortunately, we have now developed a chemical proteomics approach to define comprehensive
kinome activity in cells and tumors (MIB/MS).
We hypothesize that our proteomics approach can be used to characterize the heterogeneity of
the kinome activation profiles in HER2+ breast cancer and permit us to identify if adaptive
response to HER2 inhibition differs depending on the anti-HER2 drug mechanism of action.
This will allow rational prediction of new combinatorial therapies in future clinical
To explore kinome activation in this population, we propose a window trial in stage I-IV
HER2+ patients scheduled to undergo definitive surgery (either lumpectomy, mastectomy or
surgical resection of oligometastatic disease). Enrolled patients will be randomized to one
of four treatment arms; A) single dose trastuzumab; B) single dose pertuzumab; C)
combination trastuzumab + pertuzumab for one dose each; or D) combination single dose
trastuzumab plus lapatinib daily for one week.
Dosing in each arm will be initiated 7 days prior to surgery, with pre- and post-dosing
tissue samples analyzed for kinome response and resistant signatures. To ensure adequate
levels of trastuzumab and pertuzumab at the time of surgery, a loading dose of each agent (8
mg/kg IV for trastuzumab, and 840 mg IV fixed dose for pertuzumab) were chosen. The dose
of lapatinib was based on prior studies of lapatinib administered in combination with
trastuzumab. Given the varied pharmacokinetic profiles of the three agents and limited
dosing, we expect exposure levels of the agents to be different relative to respective
steady state levels. Therefore qualitative rather than quantitative measures will be key.
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic
difference in kinome activation pre and post treatment
To identify differential kinome activation before and after treatment with a single dose of trastuzumab, pertuzumab, the combination of trastuzumab + pertuzumab, or the combination of single dose trastuzumab+once daily lapatinib for 7 days, in patients with HER2+ breast cancer
7-10 days prior to surgery and at surgery
Lisa A Carey, MD
University of North Carolina, Chapel Hill
United States: Food and Drug Administration
|Lineberger Comprehensive Cancer Center, UNC||Chapel Hill, North Carolina 27599-7295|