Biomedical Engineering Reference
In-Depth Information
4.5.2
Lapatinib
Studies of lapatinib, a dual TK inhibitor (TKI) of EGFR and HER-2
have demonstrated efficacy in the metastatic setting for patients
with tumors that have amplified HER-2 and ongoing studies are
investigating lapatinib in the adjuvant setting [91-101]. Importantly,
two of these phase II studies included patients with HER-2 amplified
and non-amplified tumors allowing assessment of amplification/
overexpression as a biomarker for the efficacy of lapatinib. Johnson
et al.
treated two cohorts of patients with locally advanced or
metastatic inflammatory breast cancer that had progressed on prior
therapy [100]. In one cohort of 30 patients with HER-2 amplified
tumors (defined as IHC 2+ or 3+ or FISH+ with HER-2/CEP19 ≥ 2.0),
the ORR was 50% (2 CRs and 13 PRs), and responses were seen
both in patients previously treated with trastuzumab and those not
treated with trastuzumab. In the second cohort of 15 patients, who
had tumors that did not have amplified/overexpressed HER-2 but
did express EGFR, only one patient had a PR (6.7%) and this arm
was closed to accrual [100]. An expanded cohort of 126 patients
with HER-2 amplified locally advanced or metastatic inflammatory
tumors (IHC 3+ or FISH + defined by HER-2/CEP17 ≥ 2.0) that
had progressed on prior therapy was treated with lapatinib and
demonstrated a 39% ORR [92]. In a study investigating single agent
lapatinib in progressive, previously treated metastatic disease, Toi
et al.
treated 100 patients with HER-2 amplified/overexpressing
tumors (IHC 3+ or IHC 2+ and FISH + defined by HER-2/CEP17 ≥ 2.0)
and 22 patients with HER-2 negative tumors [102]. All of the patients
with HER-2 amplified tumors had been treated with trastuzumab.
Nineteen percent of the patients with HER-2 amplified tumors had a
clinical response and 9% had prolonged stable disease for a clinical
benefit of 28%. In contrast, only one (4.5%) of the 22 patients with
HER-2 negative tumors had a response, and none had stable disease
(for a clinical benefit or 4.5%). No relationship was found between
EGFR expression and the response to lapatinib [100, 102]. These
studies are consistent with HER-2 amplification/overexpression as
a predictive biomarker for response to single agent lapatinib.
Two phase III studies have assessed the efficacy of adding
lapatinib to chemotherapy in patients with metastatic disease
[95-97]. One study enrolled patients with HER-2 amplified (IHC 3+
or IHC 2+ and FISH + defined by HER-2/CEP17 ≥ 2.0) metastatic
