Page 981 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 54 Cancer Chemotherapy 967

IMATINIB & OTHER TYROSINE KINASE eliminated in feces via the hepatobiliary route. It is also important
INHIBITORS (TKIs) to review the patient’s current list of prescription and nonpre-
scription drugs because these agents have potential drug-drug
Imatinib is an inhibitor of the tyrosine kinase domain of the interactions, especially with those that are also metabolized by
Bcr-Abl oncoprotein and prevents phosphorylation of the kinase the CYP3A4 system. In addition, patients should avoid grapefruit
substrate by ATP. It is indicated for the treatment of chronic products, starfruit, and pomelos, as they may inhibit the metabo-
myelogenous leukemia (CML), a pluripotent hematopoietic stem lism of these small molecule inhibitors, leading to increased drug
cell disorder characterized by the t(9:22) Philadelphia chromo- levels and toxicity (see Chapter 4).
somal translocation. This translocation results in the Bcr-Abl
fusion protein, the causative agent in CML, and is present in up GROWTH FACTOR RECEPTOR
to 95% of patients with this disease. This agent also inhibits other INHIBITORS
receptor tyrosine kinases for platelet-derived growth factor recep-
tor (PDGFR), and c-kit. Cetuximab, Panitumumab,
Imatinib is well absorbed orally, and it is metabolized in the
liver, with elimination of metabolites occurring mainly in feces & Necitumumab
via biliary excretion. This agent is approved for use as first-line The epidermal growth factor receptor (EGFR) is a member of the
therapy in chronic phase CML, in blast crisis, and as second-line erb-B family of growth factor receptors, and it is overexpressed
therapy for chronic phase CML that has progressed on prior in a number of solid tumors, including colorectal cancer, head
IFN-α therapy. Imatinib is also effective in the treatment of gas- and neck cancer, NSCLC, and pancreatic cancer. Activation of
trointestinal stromal tumors (GIST) expressing the c-kit tyrosine the EGFR signaling pathway results in downstream activation of
kinase. The main adverse effects are listed in Table 54–5. several key cellular events involved in cellular growth and prolif-
Dasatinib is an oral inhibitor of several tyrosine kinases, eration, invasion and metastasis, and angiogenesis. In addition,
including Bcr-Abl, Src, c-kit, and PDGFR-α. It differs from this pathway inhibits the cytotoxic activity of various anti-cancer
imatinib in that it binds to the active and inactive conforma- agents and radiation therapy, presumably through suppression of
tions of the Abl kinase domain and overcomes imatinib resistance key apoptotic mechanisms, thereby leading to the development of
resulting from mutations in the Bcr-Abl kinase. It is approved for cellular drug resistance.
use in CML and Philadelphia chromosome-positive (Ph+) acute Cetuximab is a chimeric monoclonal antibody directed against
lymphoblastic leukemia (ALL) with resistance or intolerance to the extracellular domain of the EGFR, and it is presently approved
imatinib therapy. for use in combination with irinotecan for metastatic colon cancer
Nilotinib is a second-generation phenylamino-pyrimidine mol- in the refractory setting or as monotherapy in patients who are
ecule that inhibits Bcr-Abl, c-kit, and PDGFR-β tyrosine kinases. deemed to be irinotecan-refractory. Because cetuximab is of the
It has a higher binding affinity (up to 20- to 50-fold) for the Abl G isotype, its antitumor activity may also be mediated, in part, by
1
kinase when compared with imatinib, and it overcomes imatinib immunologic-mediated mechanisms. There is growing evidence
resistance resulting from Bcr-Abl mutations. It was originally that cetuximab can be effectively and safely combined with irino-
approved for chronic phase and accelerated phase CML with resis- tecan- and oxaliplatin-based chemotherapy in the first-line treat-
tance or intolerance to prior therapy that included imatinib and ment of metastatic colorectal cancer as well. Of note, the efficacy
was recently approved as first-line therapy of chronic phase CML. of cetuximab is restricted to only those patients whose tumors
Bosutinib is a potent inhibitor of the Bcr-Abl tyrosine kinase, express the wild-type RAS gene, which includes both KRAS and
and it retains activity in 16 of 18 imatinib-resistant Bcr-Abl muta- NRAS. Combination regimens of cetuximab with cytotoxic che-
tions. However, it is not effective against T315I and V299L muta- motherapy may be of particular benefit in the neoadjuvant therapy
tions, which reside within the ATP-binding domain of the Abl of patients with liver-limited disease. Although this antibody was
tyrosine kinase. It is currently approved for the treatment of adult initially approved to be administered on a weekly schedule, phar-
patients with chronic, accelerated, or blast phase Ph chromosome– macokinetic studies have shown that an every-2-week schedule
positive CML with resistance or intolerance to prior therapy. provides the same level of clinical activity as the weekly schedule.
Ponatinib is a potent inhibitor of the Bcr-Abl tyrosine kinase, This agent is also approved for use in combination with radiation
and it inhibits all known mutant forms of BCR-ABL, includ- therapy in patients with locally advanced head and neck cancer.
ing the gatekeeper mutation T315I. It inhibits other kinases, Cetuximab is well tolerated, with the main adverse effects being
including members of VEGF-R, PDGF, FGF, Flt3, TIE-2, Src an acneiform skin rash, hypersensitivity infusion reaction, and
family kinases, Kit, TET, and EPH. This agent is currently FDA- hypomagnesemia. However, when cetuximab is combined with
approved for adult patients with chronic, accelerated, or blast radiation therapy for head and neck cancer, there is a very low but
phase CML that is resistant or intolerant to prior TKI therapy real increased risk (1%) of sudden death, which has resulted in a
and also approved for Ph+ ALL that is resistant or intolerant to black-box warning for the drug.
prior TKI therapy. Panitumumab is a fully human monoclonal antibody directed
Imatinib and the other TKIs are metabolized in the liver, against the EGFR and works through inhibition of the EGFR
mainly by the CYP3A4 liver microsomal enzymes and then signaling pathway. In contrast to cetuximab, this antibody is