Nilotinib is a second-generation phenylamino-pyrimidine molecule that inhibits Bcr-Abl, c-kit, and PDGFR-β tyrosine kinases. It has a higher binding affinity (up to 20to 50-fold) for the Abl kinase when compared with imatinib, and it overcomes imatinib resistance resulting from Bcr-Abl mutations. It was originally approved for chronic phase and accelerated phase CML with resistance or intolerance to prior therapy that included imatinib and was recently approved as first-line therapy of chronic phase CML.
Bosutinib is a potent inhibitor of the Bcr-Abl tyrosine kinase, and it retains activity in 16 of 18 imatinib-resistant Bcr-Abl mutations. However, it is not effective against T315I and V299L mutations, which reside within the ATP-binding domain of the Abl tyrosine kinase. It is currently approved for the treatment of adult patients with chronic, accelerated, or blast phase Ph chromosome– positive CML with resistance or intolerance to prior therapy.
Ponatinib is a potent inhibitor of the Bcr-Abl tyrosine kinase, and it inhibits all known mutant forms of BCR-ABL, including the gatekeeper mutation T315I. It inhibits other kinases, including members of VEGF-R, PDGF, FGF, Flt3, TIE-2, Src family kinases, Kit, TET, and EPH. This agent is currently FDA-approved for adult patients with chronic, accelerated, or blast phase CML that is resistant or intolerant to prior TKI therapy and also approved for Ph+ ALL that is resistant or intolerant to prior TKI therapy.
Imatinib and the other TKIs are metabolized in the liver, mainly by the CYP3A4 liver microsomal enzymes and then eliminated in feces via the hepatobiliary route. It is also important to review the patient’s current list of prescription and nonprescription drugs because these agents have potential drug-drug interactions, especially with those that are also metabolized by the CYP3A4 system. In addition, patients should avoid grapefruit products, starfruit, and pomelos, as they may inhibit the metabolism of these small molecule inhibitors, leading to increased drug levels and toxicity (see Chapter 4).
Cetuximab, Panitumumab, & Necitumumab
The epidermal growth factor receptor (EGFR) is a member of the erb-B family of growth factor receptors, and it is overexpressed in a number of solid tumors, including colorectal cancer, head and neck cancer, NSCLC, and pancreatic cancer. Activation of the EGFR signaling pathway results in downstream activation of several key cellular events involved in cellular growth and proliferation, invasion and metastasis, and angiogenesis. In addition, this pathway inhibits the cytotoxic activity of various anti-cancer agents and radiation therapy, presumably through suppression of key apoptotic mechanisms, thereby leading to the development of cellular drug resistance.