DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Metastatic Colon Cancer. Cetuximab received approval as a single
agent for the treatment of EGFR-positive metastatic colorectal cancer;
cetuximab is used in patients who cannot tolerate irinotecanbased
therapy and in combination with irinotecan for patients
refractory to oxaliplatin, irinotecan, and 5-fluorouracil (5-FU). In
the first-line setting, cetuximab may improve survival in combination
with 5-FU/leucovorin and irinotecan or oxaliplatin (Bokemeyer et al.,
2009). Numerous trials now have shown that the 40-50% of colorectal
tumors carrying mutations in the k-ras oncogene are resistant to
the effects of cetuximab. The antibody yields a response rate of 1%
in patients with mutant tumors, compared to 12% in k-ras wild-type
tumors (Karapetis et al., 2008). Cetuximab enhances the effectiveness
of chemotherapy in patients with k-ras mutant tumors but not
k-ras wild-type tumors (Bokemeyer et al., 2009).
The standard dose of cetuximab is a single loading dose of
400 mg/m 2 intravenously, followed by weekly doses of 250 mg/m 2
intravenously for the duration of treatment.
Adverse Effects. Side effects associated with cetuximab treatment
include an acneform rash in the majority of patients. Patients also
may experience pruritus, nail changes, headache, and diarrhea. Other
rare but serious adverse effects include cardiopulmonary arrest, interstitial
lung disease, and hypomagnesemia. In addition, patients can
develop anaphylactoid reactions during infusion, which may be
related to pre-existing IgE antibodies that are more prevalent in
patients from the southern U.S.
Panitumumab
Chemistry. Panitumumab (VECTIBIX) is a recombinant, fully humanized
IgG 2κ
antibody that binds specifically to the extracellular
domain of EGFR. Unlike cetuximab, it does not mediate antibodydependent
cell-mediated cytotoxicity.
Absorption, Distribution, and Elimination. Panitumumab exhibits
nonlinear pharmacokinetic characteristics. Following intravenous
administration every 2 weeks, steady-state levels are achieved by the
third infusion. The mean elimination t 1/2
is 7.5 days.
Therapeutic Uses. Panitumumab improves progression-free survival
in patients with metastatic colorectal carcinoma, as demonstrated in
patients with EGFR-expressing tumors who had two or more previous
therapies (Van Cutsem et al., 2008). The dose of panitumumab
is 6 mg/kg intravenously given once every 2 weeks.
Adverse Effects. The adverse effects with panitumumab are similar
to cetuximab and include rash and dermatological toxicity, severe
infusion reactions, pulmonary fibrosis, and electrolyte abnormalities.
HER2/neu Inhibitors
Both antibodies (trastuzumab) and small molecules
(lapatinib and others in clinical trial) have striking antitumor
effects in patients with HER2-positive breast
cancer, and have become essential therapeutic agents
in combination with cytotoxic chemotherapy for this
aggressive malignancy.
Trastuzumab. Trastuzumab (HERCEPTIN) is a humanized
monoclonal antibody that binds to the external domain
of HER2/neu (ErbB2).
Thirty percent of breast cancers overexpress this receptor due
to gene amplification on chromosome 17. Amplification of the receptor
is associated with lower response rates to hormonal therapies and
to most cytotoxic drugs, with the exception of anthracyclines
(Slamon et al., 1989). Patients with HER2/neu-amplified tumors
have higher recurrence rates after standard adjuvant therapy and poorer
overall survival, as compared to patients with HER2-nonamplified
tumors. The internal domain of the HER2/neu glycoprotein encodes
a tyrosine kinase that activates downstream signal, enhances metastatic
potential, and inhibits apoptosis. Trastuzumab exerts its antitumor
effects through several putative mechanisms of action (Nahta
and Esteva, 2003): inhibition of homo- or heterodimerization of
receptor, thereby preventing receptor kinase activation and downstream
signaling; initiation of Fcγ-receptor-mediated antibodydependent
cellular cytotoxicity; and blockade of the angiogenetic
effects of HER2 signaling.
Trastuzumab was the first monoclonal antibody to be
approved for the treatment of a solid tumor. Currently, it is approved
for HER2/neu-overexpressing metastatic breast cancer, in combination
with paclitaxel as initial treatment or as monotherapy following
chemotherapy relapse (Vogel et al., 2002). Trastuzumab
synergizes with other cytotoxic agents in HER2/neu-overexpressing
cancers (Slamon et al., 2001). HER2/neu expression also is found
in subsets of patients with gastric, esophageal, lung, and other solid
tumors, but clinical studies of the effects of trastuzumab in these
tumors have not yet been completed.
Pharmacokinetics and Toxicity. Trastuzumab has dose-dependent
pharmacokinetics with a mean t 1/2
of 5.8 days on the 2-mg/kg maintenance
dose. Steady-state levels are achieved between 16 and
32 weeks, with mean trough and peak concentrations of ~79 and
123 μg/mL, respectively (Baselga, 2000). The infusional effects of
trastuzumab are typical of other monoclonal antibodies and include
fever, chills, nausea, dyspnea, and rashes. Premedication with
diphenhydramine and acetaminophen is indicated. The most serious
toxicity of trastuzumab is cardiac failure; reasons for cardiotoxicity
are poorly understood, although the HER2 antigen is highly
expressed in the developing heart during embryogenesis, and HER2
knockout mice fail to survive because of cardiomyopathy (Crone
et al., 2002). Cardiac failure is a potentially disabling or fatal side
effect unless it is recognized early and the drug is discontinued
(Seidman et al., 2002). Before initializing therapy, baseline
electrocardiogram and cardiac ejection fraction measurement should
be obtained to rule out underlying heart disease, and patients deserve
careful clinical follow-up thereafter for signs or symptoms of congestive
heart failure, such as cough, weight gain, or edema. When
trastuzumab is used as a single agent, <5% of patients will experience
a decrease in left-ventricular ejection fraction, and 1% will have clinical
signs of congestive failure. However, left-ventricular dysfunction
occurs in up to 20% of patients who received the antibody in combination
with doxorubicin and cyclophosphamide. The risk of cardiac
toxicity is greatly reduced with taxane–trastuzumab combinations.
Lapatinib. Small molecules can inhibit receptor tyrosine
kinase activity of ErbB2 (HER2/neu) and have
antitumor activity in patients who have developed progressive
disease on trastuzumab (Moy and Goss, 2007).
Lapatinib and other pan-HER inhibitors block both
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CHAPTER 62
TARGETED THERAPIES: TYROSINE KINASE INHIBITORS, MONOCLONAL ANTIBODIES, AND CYTOKINES