Miscellaneous Anticancer Drugs

MISCELLANEOUS ANTICANCER DRUGS

A large number of anticancer drugs that do not fit traditional categories have been approved for clinical use by the Food and Drug Administration (FDA); they are listed in Table 54–5.

IMATINIB, DASATINIB, & NILOTINIB

Imatinib is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents phosphorylation of the kinase sub-strate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9:22) Philadelphia chromo-somal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent also inhibits other receptor tyrosine kinases for platelet-derived growth factor recep-tor (PDGFR), stem cell factor, and c-kit.

Imatinib is well absorbed orally, and it is metabolized in the liver, with elimination of metabolites occurring mainly in feces via biliary excretion. This agent is approved for use as first-line ther-apy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior interferon-alfa therapy. Imatinib is also effective in the treatment of gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. The main adverse effects are listed in Table 54–5.

Dasatinib is an oral inhibitor of several tyrosine kinases, includ-ing Bcr-Abl, Src, c-kit, and PDGFR-α. It differs from imatinib in that it binds to the active and inactive conformations of the Abl kinase domain and overcomes imatinib resistance resulting from mutations in the Bcr-Abl kinase. It is approved for use in CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) with resistance or intolerance to imatinib therapy.

Nilotinib is a second-generation phenylamino-pyrimidine mol-ecule that inhibits Bcr-Abl, c-kit, and PDGFR-β tyrosine kinases. It has a higher binding affinity (up to 20- to 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 resis-tance or intolerance to prior therapy that included imatinib and was recently approved as first-line therapy of chronic phase CML.

Imatinib, dasatinib, and nilotinib are all metabolized in the liver, mainly by the CYP3A4 liver microsomal enzyme. A large fraction of each drug is eliminated in feces via the hepatobiliary route. It is 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 and the use of St. John’s wort, as they may alter the metabolism of these small molecule inhibitors .

GROWTH FACTOR RECEPTOR INHIBITORS

Cetuximab & Panitumumab

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, non-small cell lung cancer, and pancreatic cancer. Activation of the EGFR signaling pathway results in downstream activation of several key cellular events involved in cellular growth and prolifera-tion, invasion and metastasis, and angiogenesis. In addition, this pathway inhibits the cytotoxic activity of various anticancer agents and radiation therapy, presumably through suppression of key apoptotic mechanisms, thereby leading to the development of cel-lular drug resistance.

Cetuximab is a chimeric monoclonal antibody directed against the extracellular domain of the EGFR, and it is presently approved for use in combination with irinotecan for metastatic colon cancer in the refractory setting or as monotherapy in patients who are deemed to be irinotecan-refractory. Because cetuximab is of the G ₁ isotype, its antitumor activity may also be mediated, in part, by immunologic-mediated mechanisms. There is growing evi-dence that cetuximab can be effectively and safely combined with irinotecan- and oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer as well. Of note, the efficacy of cetuximab is restricted to only those patients whose tumors express wild-type KRAS. Regimens combining cetuximab with cytotoxic chemotherapy may be of particular benefit in the neoadjuvant therapy of patients with liver-limited disease. Although this antibody was initially approved to be administered on a weekly schedule, pharmacokinetic studies have shown that an every-2-week schedule provides the same level of clinical activity as the weekly schedule. This agent is also approved for use in combination with radiation therapy in patients with locally advanced head and neck cancer. Cetuximab is well tolerated, with the main adverse effects being an acneiform skin rash, hypersensi-tivity infusion reaction, and hypomagnesemia.

Panitumumab is a fully human monoclonal antibody directed against the EGFR and works through inhibition of the EGFR signaling pathway. In contrast to cetuximab, this antibody is of the G₂ isotype, and as such, it would not be expected to exert any immunologic-mediated effects. Presently, panitumumab is approved for patients with refractory metastatic colorectal cancer who have been treated with all other active agents, and as with cetuximab, this antibody is only effective in patients whose tumors express wild-type KRAS. Recent clinical studies have shown that this anti-body is effectively and safely combined with oxaliplatin- and irino-tecan-based chemotherapy in the first- and second-line treatment of metastatic colorectal cancer. Acneiform skin rash and hypomag-nesemia are the two main adverse effects associated with its use. Because this is a fully human antibody, infusion-related reactions are rarely observed.

Gefitinib & Erlotinib

Gefitinib and erlotinib are small molecule inhibitors of the tyrosine kinase domain associated with the EGFR, and both are used in the treatment of non-small cell lung cancer that is refractory to at least one prior chemotherapy regimen. Patients who are nonsmokers and who have a bronchoalveolar histologic subtype appear to be more responsive to these agents. In addition, erlotinib has been approved for use in combination with gemcitabine for the treat-ment of advanced pancreatic cancer. Both agents are metabolized in the liver by the CYP3A4 enzyme system, and elimination is mainly hepatic with excretion in feces. Caution must be taken when using these agents with drugs that are also metabolized by the liver CYP3A4 system, such as phenytoin and warfarin, and the use of grapefruit products should be avoided. An acneiform skin rash, diarrhea, and anorexia and fatigue are the most common adverse effects observed with these small molecules (Table 54-5).

Bevacizumab, Sorafenib, Sunitinib, & Pazopanib

The vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors. The growth of both primary and metastatic tumors requires an intact vasculature. As a result, the VEGF-signaling pathway represents an attractive target for chemo-therapy. Several approaches have been taken to inhibit VEGF sig-naling; they include inhibition of VEGF interactions with its receptor by targeting either the VEGF ligand with antibodies or soluble chimeric decoy receptors, or by direct inhibition of the VEGF receptor-associated tyrosine kinase activity by small mole-cule inhibitors.

Bevacizumab is a recombinant humanized monoclonal anti-body that targets all forms of VEGF-A. This antibody binds to and prevents VEGF-A from interacting with the target VEGF receptors. Bevacizumab can be safely and effectively combined with 5-FU-, irinotecan-, and oxaliplatin-based chemotherapy in the treatment of metastatic colorectal cancer. Bevacizumab is FDA approved as a first-line treatment for metastatic colorectal cancer in combination with any intravenous fluoropyrimidine-contain-ing regimen and is now also approved in combination with che-motherapy for metastatic non-small lung cancer and breast cancer. One potential advantage of this antibody is that it does not appear to exacerbate the toxicities typically observed with cytotoxic che-motherapy. The main safety concerns associated with bevacizumab include hypertension, an increased incidence of arterial throm-boembolic events (transient ischemic attack, stroke, angina, and myocardial infarction), wound healing complications, gastrointes-tinal perforations, and proteinuria.

Sorafenib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), especially VEGF-R2 and VEGF-R3, platelet-derived growth factor-β (PDGFR-β), and raf kinase. It was initially approved for advanced renal cell cancer and is also approved for advanced hepatocellular cancer.

Sunitinib is similar to sorafenib in that it inhibits multiple RTKs, although the specific types are somewhat different. They include PDGFR-α and PDGFR-β, VEGF-R1, VEGF-R2, VEGF-R3, and c-kit. It is approved for the treatment of advanced renal cell cancer and for the treatment of gastrointestinal stromal tumors (GIST) after disease progression on or with intolerance to imatinib. 

Pazopanib is a small molecule that inhibits multiple RTKs, espe-cially VEGF-R2 and VEGF-R3, PDGFR-β, and raf kinase. This oral agent is approved for the treatment of advanced renal cell cancer.

Sorafenib, sunitinib, and pazopanib are metabolized in the liver by the CYP3A4 system, and elimination is primarily hepatic with excretion in feces. Each of these agents has potential interac-tions with drugs that are also metabolized by the CYP3A4 system, especially warfarin. In addition, patients should avoid grapefruit products and the use of St. John’s wort, as they may alter the clinical activity of these agents. Hypertension, bleeding complica-tions, and fatigue are the most common adverse effects seen with both agents. With respect to sorafenib, skin rash and the hand-foot syndrome are observed in up to 30–50% of patients. For sunitinib, there is also an increased risk of cardiac dysfunction, which in some cases can lead to congestive heart failure.

ASPARAGINASE

Asparaginase (L-asparagine amidohydrolase) is an enzyme used to treat childhood ALL. The drug is isolated and purified from Escherichia coli or Erwinia chrysanthemi for clinical use. It hydro-lyzes circulating L-asparagine to aspartic acid and ammonia. Because tumor cells in ALL lack asparagine synthetase, they require an exogenous source of L-asparagine. Thus, depletion of L-asparagine results in effective inhibition of protein synthesis. In contrast, normal cells can synthesize L-asparagine and thus are less susceptible to the cytotoxic action of asparaginase. The main adverse effect of this agent is a hypersensitivity reaction manifested by fever, chills, nausea and vomiting, skin rash, and urticaria. Severe cases can present with bronchospasm, respiratory failure, and hypotension. Other side effects include an increased risk of both clotting and bleeding as a result of alterations in various clot-ting factors, pancreatitis, and neurologic toxicity with lethargy, confusion, hallucinations, and in severe cases, coma.