Home Books Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e

Chapter 62: Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies, and Cytokines

Bruce A. Chabner; Jeffrey Barnes; Joel Neal; Erin Olson; Hamza Mujagic; Lecia Sequist; Wynham Wilson; Dan L. Longo; Constantine Mitsiades; Paul Richardson

INTRODUCTION

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Strategies for cancer drug discovery have evolved in step with the explosion of knowledge about the molecular underpinnings of cancer. Many new drugs either recently approved or in late stages of evaluation were designed to block the fundamental mutations that cause specific cancers: aberrant growth factor receptors, dysregulated intracellular signaling pathways, defective DNA repair and apoptosis, and tumor angiogenesis. The primary tools for inhibiting these new targets are either monoclonal antibodies that attack cell surface receptors and antigens, or synthetic small molecules that enter cells and engage critical enzymes. These two classes of drugs have very different pharmacological properties.

Monoclonal antibodies kill tumor cells by blocking cell surface receptor function and by recruiting immune cells and complement to the antigen–antibody complex. They may be armed to carry toxins or radionuclides to the cells of interest, thereby enhancing their cytotoxic effects. They generally are specific for a single receptor, have a long plasma t_1/2, and require only intermittent administration. Small molecules may attack the same targets and pathways as the monoclonals, but may also exert their effect by entering cells and inhibiting enzymatic functions (usually tyrosine kinase reactions). The small molecules often inhibit multiple enzymatic sites, have a broad spectrum of target kinases, and tend to be substrates of hepatic CYPs with a t_1/2 of 12-24 hours, and thus require daily oral administration. The two classes of drug, when targeted against the same pathway, may have significantly different spectra of antitumor activity. Thus, monoclonal antibodies to the epidermal growth factor receptor (EGFR) are effective in the treatment of head and neck and colon cancers, while small molecules, such as erlotinib and gefitinib, attack the intracellular tyrosine kinase function of the same receptor and have a different spectrum of antitumor activity (non–small cell lung cancer).

Because of the central importance of the specific target in cancer chemotherapy, we will center this discussion around the target rather than the specific type of drug.

PROTEIN TYROSINE KINASE INHIBITORS

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Protein kinases are critical components of signal transduction pathways that regulate cell growth and adaption to the extracellular environment. These signaling pathways influence gene transcription and/or DNA synthesis, as well as cytoplasmic events. The human genome contains ~550 protein kinases and 130 phosphoprotein phosphatases that regulate the phosphorylation states of key signaling molecules. Protein kinases can be classified into three different categories: kinases that specifically phosphorylate tyrosine residues, kinases that phosphorylate serine and threonine residues, and kinases with activity toward all three residues. Tyrosine kinases can be further subdivided into proteins that have an extracellular ligand-binding domain (receptor tyrosine kinases) and enzymes that are confined to the cytoplasm or nuclear cellular compartment (nonreceptor tyrosine kinases). Growth factors and other ligands bind to and activate the receptor tyrosine kinases under physiological conditions. In a growing number of human malignancies, mutations that constitutively activate protein tyrosine kinases are implicated in malignant transformation; thus, protein tyrosine kinases are targets for cancer therapy.

Inhibitors of the Bcr-Abl Kinase: Imatinib, Dasatinib, and Nilotinib

Imatinib mesylate (sti 571, gleevec, glivec) was the first molecularly targeted protein kinase inhibitor to receive FDA approval. It targets the BCR-ABL tyrosine kinase, which underlies chronic myelogenous leukemia (CML). A single molecular event, in this case the 9:22 translocation, leads to expression of the Abelson proto-oncogene kinase ABL fused to BCR (breakpoint cluster region), yielding a constitutively activated protein kinase, BCR-ABL, and then the malignant phenotype. Imatinib and the related compounds dasatinib and nilotinib induce clinical and molecular remissions in >90% of CML patients in the chronic phase of disease. Imatinib effectively treats other tumors that carry related tyrosine kinase mutations, including GI stromal tumors (driven by c-KIT mutation) (Blanke et al., 2008), and hypereosinophilia syndrome, chronic myelomonocytic leukemia, and dermatofibrosarcoma protuberans (all driven by mutations that activate the platelet-derived growth factor receptor, PDGFR) (Sirvent et al., 2003).

Chemistry. Imatinib was identified through high-throughput screening against the BCR-ABL kinase. The lead compound of this series, a 2-phenylaminopyrimidine, had low potency and poor specificity, inhibiting both serine/threonine and tyrosine kinases (Buchdunger et al., 2001). The addition of a 3′-pyridyl group at the 3′ position of the pyrimidine enhanced its potency. Further modifications resulted in improved activity against PDGFR and c-KIT and loss of serine/threonine kinase inhibition. Introduction of N-methylpiperazine as a polar side chain greatly improved water solubility and oral bioavailability, yielding imatinib, an inhibitor of the closed, or inactive, configuration of the kinase:

Dasatinib (BMS-354825, sprycel), a second-generation BCR-ABL inhibitor, was developed using a series of substituted 2-(aminopyridyl) and 2-(aminopyrimidinyl) thiazol-5-carboxyamides. It inhibits the Src kinase, and unlike imatinib, it binds both the open and closed configurations of the BCR-ABL kinase (Shah et al., 2004).

Nilotinib (AMN107, tasigna) was designed to have increased potency and specificity compared to imatinib. Its structure, based on crystallographic studies of the BCR-ABL kinase, promotes hydrogen bonding to Glu286 and Asp381 (Weisberg et al., 2005) and overcomes mutations that cause imatinib resistance.

Mechanism of Action. Crystallographic and mutagenesis studies indicate that imatinib and nilotinib bind to a segment of the kinase domain that fixes the enzyme in a closed or nonfunctional state, in which the protein is unable to bind its substrate/phosphate donor, ATP (Weisberg et al., 2005). The three BCR-ABL kinase inhibitors differ in their potency of inhibition, their binding specificities, and their susceptibility to resistance mutations in the target enzyme. Dasatinib [(IC₅₀) = <1 nM] and nilotinib [(IC₅₀) = <20 nM] (Weisberg, 2005) inhibit BCR-ABL kinase more potently than does imatinib [(IC₅₀) = 100 nM].

Mechanisms of Resistance. Resistance to the tyrosine kinase inhibitors arises from point mutations in three separate segments of the kinase domain (Figure 62–1). The contact points between imatinib and the enzyme become sites of mutations in drug-resistant leukemic cells; these mutations prevent tight binding of the drug and lock the enzyme in its open configuration, in which it has access to substrate. Most such mutations hold the enzyme in its open and enzymatically active confirmation. The most common resistance mutations affect amino acids 255 and 315, both of which serve as contact points for imatinib; these mutations confer high-level resistance to imatinib and nilotinib. Dasatinib is unaffected by mutation at 255 but is ineffective in the presence of mutation at 315. Nilotinib retains inhibitory activity in the presence of most point mutations (except at 315) that confer resistance to imatinib (Weisberg et al., 2005; O'Hare et al., 2005).

Other mutations affect the phosphate-binding region and the "activation loop" of the domain with varying degrees of associated resistance. Some mutations, such as at amino acids 351 and 355, do not affect response to dasatinib or nilotinib but confer low levels of resistance to imatinib (O'Hare et al., 2005; Corbin et al., 2003). This finding may explain the clinical response of some resistant patients to dose escalation of imatinib.

Molecular studies of circulating tumor cells have detected resistance-mediating kinase mutations prior to initiation of therapy, particularly in patients with Ph⁺ acute lymphoblastic leukemia (ALL) (Roche-Lestienne et al., 2003) or CML in blastic crisis. This finding strongly supports the hypothesis that drug-resistant cells arise through spontaneous mutation and expand under the selective pressure of drug exposure. Mutations may become detectable in the peripheral blood of patients receiving imatinib in the accelerated phase and in the late (>4 years from diagnosis) chronic phase of CML (Branford et al., 2003), heralding the onset of drug resistance.

Mechanisms other than BCR-ABL kinase mutation play a minor role in resistance to imatinib. Amplification of the wild-type kinase gene, leading to overexpression of the enzyme, has been identified in tumor samples from patients resistant to treatment (Morel et al., 2003). The multidrug resistant (MDR) gene, which codes for a drug efflux protein, confers resistance experimentally but has not been implicated in clinical resistance.

Finally, Philadelphia chromosome-negative clones lacking the BCR-ABL translocation and displaying the karyotype of myelodysplastic cells may emerge in patients receiving imatinib for CML and may progress to myelodysplasia (MDS) and to acute myelocytic leukemia (AML). Their origin is unclear.

Pharmacokinetics.

Imatinib. Imatinib is well absorbed after oral administration and reaches maximal plasma concentrations within 2-4 hours. The elimination t_1/2 of imatinib and its major active metabolite, the N-desmethyl derivative, are ~18 and 40 hours, respectively. Mean imatinib area under the curve (AUC) increases proportionally with increasing dose in the range 25-1000 mg (Peng et al., 2004). Food does not change the pharmacokinetic profile of imatinib. Doses >300 mg/day achieve trough levels of 1 μM, which correspond to in vitro levels required to kill BCR-ABL–expressing cells. Inhibition of the BCR-ABL tyrosine kinase in white blood cells from patients with CML reaches a maximum in the dose range of 250-750 mg/day. Nonrandomized studies suggest that response may be restored in a minority of resistant patients with doses of 600 or 800 mg/day, as opposed to the standard 400 mg/day (Kantarjian et al., 2004). In the treatment of GI stromal cell tumors (GIST), higher doses (600 mg/day) may improve response rates.

CYP3A4 is the major enzyme responsible for metabolism of imatinib. CYPs 1A2, 2D6, 2C9, and 2C19 play minor roles in its metabolism. Clinicians must be cautious in introducing drugs that might interact with imatinib and CYP3A4. A single dose of ketoconazole, an inhibitor of CYP3A4, increases the maximal imatinib concentration in plasma and its plasma AUC by 26% and 40%, respectively. Co-administration of imatinib and rifampin, an inducer of CYP3A4, lowers the plasma imatinib AUC by 70%. Likewise, imatinib, as a competitive CYP3A4 substrate, inhibits the metabolism of simvastatin and increases its plasma AUC by 3.5-fold (O'Brien et al., 2003).

Dasatinib. Dasatinib also is well absorbed after oral administration. As for other BCR-ABL kinase inhibitors, the bioavailability of dasatinib is significantly reduced at neutral gastric pH, resulting from antacids and H₂ blockers, but is unaffected by food. The plasma t_1/2 of dasatinib is 3-5 hours, and clearance depends on CYP3A4 metabolism. Its metabolites are inactive. Dasatinib exhibits dose proportional increases in AUC, and its clearance is constant over the dose range of 15-240 mg/day. No significant changes in dasatinib pharmacokinetics were observed on repeated dosing or administration of food. Dasatinib was originally approved at a dose of 70 mg twice a day. A randomized phase III trial comparing 50 mg twice daily, 70 mg twice daily, 100 mg daily, and 140 mg daily concluded that all four schedules were equally effective in patients with CML, although the 100-mg daily dose improved progression-free survival (Shah et al., 2008).

Dasatinib is metabolized primarily by CYP3A4, although FMO3 and UGT also contribute to a minor degree. Dasatinib plasma concentrations are affected by inducers and inhibitors of CYP3A4 in a similar fashion to imatinib.

Nilotinib. Approximately 30% of an oral dose of nilotinib (400 mg twice daily) is absorbed after administration, and the drug achieves peak concentrations in plasma 3 hours after dosing. Unlike the other BCR-ABL inhibitors, nilotinib's bioavailability increases significantly in the presence of food (Kantarjian et al., 2006). The drug has a long plasma t_1/2 (~17 hours), and plasma concentrations reach a steady state only after 8 days of daily dosing. Doses >400 mg/day are associated with nonlinear increases in median serum concentrations, indicating saturation of GI absorption.

Like dasatinib and imatinib, nilotinib undergoes elimination through metabolism by CYP3A4; metabolism is affected by inducers, inhibitors, and competitors of the CYP3A4 pathway. Nilotinib is a substrate and inhibitor of P-glycoprotein.

Pharmacokinetics and Clinical Uses. These protein tyrosine kinase inhibitors have efficacy in diseases in which the ABL, kit, or PDGFR have dominant roles in driving the proliferation of the tumor, reflecting the presence of a mutation that results in constitutive activation of the kinase, either by fusion with another protein or via point mutations. Thus, imatinib shows remarkable therapeutic benefits in patients with chronic-phase CML (BCR-ABL), GIST (kit mutation positive), chronic myelomonocytic leukemia (EVT6-PDGFR translocation), hypereosinophilia syndrome (FIP1L1-PDGFR), and dermatofibrosarcoma protuberans (constitutive production of the ligand for PDGFR) (Druker, 2004). It is the agent of choice for GIST patients with metastatic disease and as adjuvant therapy of c-kit– positive GIST (DeMatteo et al., 2009). GIST biology is particularly instructive, as patients with an exon 11 mutation of kit have a significantly higher partial response rate (72%) than those with no detectable kit mutations (9%) (Heinrich et al., 2003). The currently recommended dose of imatinib is 400-600 mg/day. Dasatinib is approved for patients with CML resistant or intolerant to imatinib in both chronic (100 mg/day) and advanced phases of disease (70 mg twice daily), and for use combined with cytotoxic chemotherapy in patients with Ph⁺ ALL who are resistant or intolerant to prior therapies. Nilotinib is approved for patients with CML resistant to or intolerant of prior imatinib therapy.

Toxicity. Imatinib, dasatinib, and nilotinib cause GI distress (diarrhea, nausea, and vomiting), but these symptoms usually are easily controlled. All three drugs promote fluid retention, which may lead to dependent edema, and peri-orbital swelling. Dasatinib may cause pleural effusions. Nilotinib may prolong the QT interval, and should be used with caution in patients with underlying heart disease or arrhythmias, although ventricular arrhythmias have not been reported. Significant myelosuppression occurs infrequently but may require transfusion support, dose reduction, or discontinuation of the drug. All three drugs in this class can be associated with hepatotoxicity. Most nonhematological adverse reactions are self limited and respond to dose adjustments. After the adverse reactions, such as edema, myelosuppression, or GI symptoms have resolved, the drug may be reinitiated and titrated back to effective doses.

Figure 62–1.

The relative frequency of BCR-ABL kinase domain mutations detected at 31 different positions in clinical specimens from 245 patients in whom mutations were detected (219 with chronic myelocytic leukemia and 26 with Ph⁺ acute lymphoblastic leukemia). (Reproduced with permission from Hughes et al., 2006. Copyright © 2006 American Society of Hematology. Copyright restrictions may apply.)

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EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS

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The EGFR belongs to the ErbB family of transmembrane receptor tyrosine kinases. EGFR, also known as ErbB1 or HER1, is essential for the growth and differentiation of epithelial cells. Ligand binding to the extracellular domain of EGFR family members causes receptor dimerization and stimulates the protein tyrosine kinase activity of the intracellular domain, resulting in autophosphorylation of several Tyr residues in the C-terminal domain. Recognition of the phospho-tyrosines by other proteins initiates protein-protein interactions that result in stimulation of a variety of signaling pathways, including MAPK, PI3K/Akt, and STAT pathways (Figure 62–2) (Schlessinger, 2000). In epithelial cancers, overexpression (or mutational activations) of the EGFR is a common finding and, to some extent, creates a dependence on EGFR signaling in these tumors (Hynes and Lane, 2005).

Figure 62–2.

Growth factor signaling. Binding of agonist ligands to growth factor receptors causes receptor dimerization and activation of cytosolic protein kinase domains, leading to activation of multiple signaling pathways. Shown here are the RAS/MAPK/ERK, PI3K, and SMAD pathways, each of which is activated by receptors or cross-talk from adjacent pathways. Their signals regulate proliferation, metabolism, survival, and the synthesis of other growth factors, such as the vascular endothelial growth factor (VEGF).

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Two separate classes of drugs that target the EGFR pathway have become important agents in the therapy of solid tumors. The EGFR tyrosine kinase inhibitors erlotinib and gefitinib bind to the kinase domain and block the enzymatic function of EGFR. The monoclonal antibodies cetuximab and panitumumab bind specifically to the extracellular domain of EGFR. They inhibit EGFR-dependent signaling through inhibition of ligand-dependent activation and receptor dimerization, downregulation of EGFR expression, and induction of antibody-dependent cell-mediated cytotoxicity (Ciardiello and Tortora, 2008).

Gefitinib

Chemistry. Gefitinib was identified through screens that demonstrated its inhibition of EGFR tyrosine kinase activity and ability to kill EGFR-dependent cell lines.

Mechanism of Action. Gefitinib inhibits the EGFR tyrosine kinase by virtue of competitive blockade of ATP binding. Gefitinib has an IC₅₀ of 20-80 nM for the EGFR enzyme but is significantly less potent against HER2 (ErbB2/neu). Gefitinib has antitumor activity in human xenograft tumors that exhibit high levels of EGFR expression.

Absorption, Distribution, and Elimination. Following oral administration of gefitinib, peak plasma concentrations are achieved within 3-7 hours, and oral bioavailability approaches 60%. Administration of 225 mg/day orally results in steady-state levels of 200 ng/mL after 7-10 doses. The mean terminal t_1/2 is 41 hours. Elimination of gefitinib primarily occurs by hepatic CYP3A4 metabolism.

Therapeutic Uses. Gefitinib initially was approved for the third-line treatment of patients with non–small cell lung cancer based on promising results in two small clinical trials. However, a larger, randomized, placebo-controlled trial failed to show an effect on survival, leading the FDA to restrict its use to patients who have previously received clinical benefit from the drug (Thatcher et al., 2005). Gefitinib continues to be widely used outside the U.S. Two large trials have failed to demonstrate a benefit of gefitinib in combination with chemotherapy. The standard dose is 250 mg daily.

Retrospective analysis of multiple studies revealed that patients who were nonsmokers, Asians, or women were most likely to respond to gefitinib. Tumors from these patients frequently have characteristic activating mutations in EGFR (Sequist and Lynch, 2008). These mutations mostly fall into two groups: 1) small in-frame deletions within exon 19 and 2) the L858R point mutation. Trials that randomized never and light-smoking patients to first-line gefitinib or to chemotherapy demonstrated a 70% response rate to gefitinib in patients with an activating EGFR mutation, compared with responses in only 1% in patients without an EGFR mutation. In patients with EGFR-mutant tumors, the response rate to gefitinib was double the response to standard chemotherapy. Therefore, mounting evidence supports the use of gefitinib, and potentially erlotinib, as first-line therapy in patients selected for the presence of sensitizing EGFR mutations.

Adverse Effects and Drug Interactions. Diarrhea and pustular/papular rash occur in ~50% of patients taking gefitinib. Other side effects include dry skin, nausea, vomiting, pruritus, anorexia, and fatigue. Most adverse effects occur within the first month of therapy and are tolerable when managed with supportive medications and dose reductions. Asymptomatic increases in liver transaminases may necessitate dose reduction or discontinuation of therapy. Interstitial lung disease, often associated with symptoms of cough and dyspnea, occurs in <2% of patients receiving gefitinib but may have a fatal outcome.

Exposure to gefitinib is not significantly altered by food; however, co-administration of drugs that cause sustained elevations in gastric pH reduce mean gefitinib AUC by 47%. Metabolism of gefitinib is predominantly via CYP3A4. Substances that induce CYP3A4 activity (e.g., phenytoin, carbamazepine, rifampin, barbiturates, St. John's wort) decrease gefitinib plasma concentrations and efficacy; conversely, inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole) increase plasma concentrations. Patients using warfarin should be monitored closely for elevation of the INR while taking gefitinib.

Erlotinib

Erlotinib (tarceva) is a quinazolinamine inhibitor of HER1/EGFR tyrosine kinase.

Mechanism of Action. Erlotinib is a potent inhibitor of the EGFR tyrosine kinase. Like gefitinib, erlotinib competitively inhibits ATP binding at the active site of the kinase. Erlotinib has an IC₅₀ of 2 nM for the EGFR kinase. Tumors harboring k-ras mutations and EML4-ALK translocations do not respond to EGFR kinase inhibitors.

Absorption, Distribution, and Excretion. Erlotinib is ~60% absorbed after oral administration but should not be taken with food, which increases its bioavailability to ~100%. Peak plasma levels occur 4 hours after an oral dose. Erlotinib has a t_1/2 of 36 hours and is metabolized by CYP3A4 and to a lesser extent by CYPs 1A2 and 1A1. The standard daily dose of erlotinib results in a plasma AUC approximately one order of magnitude greater than the AUC of gefitinib.

Therapeutic Uses. Erlotinib is approved for second-line treatment of patients with locally advanced or metastatic non–small cell lung cancer. FDA approval was based on an improvement in overall survival in a large multi-national trial comparing oral erlotinib, 150 mg daily, to placebo (Shepherd et al., 2005). Results from two subsequent trials showed no clinical benefit from the combination of erlotinib with platinum-based chemotherapy as compared to chemotherapy alone.

Erlotinib also is approved for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer in combination with gemcitabine. A large double-blinded study of 569 patients demonstrated a modest 2-week improvement in overall survival in patients who received 100 mg of erlotinib plus gemcitabine, as compared with patients who received gemcitabine alone (Moore et al., 2007). The recommended dose of erlotinib in non–small cell lung cancer is a 150-mg tablet daily. In pancreatic cancer, the dose is a 100-mg tablet daily. It should be taken at least 1 hour before or 2 hours after a meal.

Adverse Effects and Drug Interactions. As with gefitinib, the most common adverse reactions in patients receiving erlotinib are diarrhea, an acneform rash, anorexia, and fatigue. Serious or fatal interstitial lung disease occurs with a frequency of 0.7-2.5%. Hepatic function deserves close monitoring because serious or fatal hepatic failure due to erlotinib has been reported, particularly in patients with baseline hepatic dysfunction. Other rare but serious toxicities include GI perforation, renal failure, arterial thrombosis, microangiopathic hemolytic anemia, hand-foot skin reaction, and corneal perforation or ulceration. Erlotinib therapy may cause rare cases of Stevens-Johnson syndrome/toxic epidermal necrolysis.

Concurrent use of proton-pump inhibitors decreases the bioavailability of erlotinib by 50%. As with gefitinib, plasma levels can vary dramatically due to drug interactions with inducers or inhibitors of CYP3A4. Patients using warfarin may experience elevations of the international normalized ratio (INR) while taking erlotinib. Smoking accelerates metabolic clearance of erlotinib by 24% and may decrease its antitumor effects.

Resistance to Gefitinib and Erlotinib.

Patients with non–small cell lung cancer who initially respond to erlotinib or gefitinib have tumors that are dependent on the EGFR signaling pathway. Clinical response to these agents is strongly associated with the presence of sensitizing mutations in EGFR as described in "Therapeutic Uses" under "Gefitinib," but response is less strongly correlated with overexpression or amplification of EGFR (Sequist and Lynch, 2008). Therapy directed at the EGFR may delay disease progression in patients with non–small cell lung cancers that lack activating EGFR mutations, although response rates approach zero in these patients. The subset of non–small cell lung tumors harboring k-ras mutations and EML4-ALK translocations do not respond to EGFR inhibitors.

Tumors containing mutations in EGFR initially respond to erlotinib and gefitinib but eventually progress. Resistance arises through several different mechanisms. A secondary mutation in the EGFR gatekeeper residue, T790M, prevents binding of drug to the kinase domain and confers resistance (Kobayashi et al., 2005). Irreversible EGFR inhibitors currently are in clinical development to overcome this mechanism. Amplification of the met oncogene provides an alternative pathway to clinical resistance by activating cell growth signals downstream of EGFR (Engelman et al., 2007). MET-amplified tumors respond in vitro to the simultaneous inhibition of EGFR and MET. Other potential mechanisms of resistance include activation of downstream mediators, efflux of drug, and altered receptor trafficking.

Cetuximab

Cetuximab is a monoclonal antibody to the extracellular domain of the EGFR. Such antibodies, although sharing the same target with erlotinib and gefitinib and having a similar side effect profile, have a different spectrum of antitumor activity.

Chemistry. Cetuximab (erbitux) is a recombinant chimeric human/mouse immunoglobulin G1 (IgG₁) antibody that binds to the extracellular domain of EGFR. It consists of the Fv regions of a murine anti-EGFR antibody with human IgG₁ heavy- and κ light-chain constant regions.

Mechanism of Action. Cetuximab binds specifically to the extracellular domain of EGFR and prevents ligand-dependent signaling and receptor dimerization, thereby blocking cell growth and survival signals. Cetuximab also may mediate antibody-dependent cellular cytotoxicity against tumor cells.

Absorption, Distribution, and Elimination. Cetuximab exhibits nonlinear pharmacokinetic characteristics. Following intravenous administration, steady-state levels are achieved by the third weekly infusion. The volume of distribution approximates the intravascular space of 2-3 L/m². Therapeutic doses that saturate total body receptor pools of EGFR follow zero-order kinetics for elimination. Clearance occurs via EGFR binding and internalization and by degradation in the reticuloendothelial system.

Therapeutic Uses.

Head and Neck Cancer. Cetuximab won FDA approval based on an improvement in overall survival when used in combination with radiation therapy for locally or regionally advanced squamous cell carcinoma of the head and neck (HNSCC). It received a second indication as monotherapy for patients with metastatic or recurrent HNSCC who had failed platinum-based chemotherapy. It has become a useful agent in combination with cisplatin-based chemotherapy, where it has shown an improvement in survival compared to chemotherapy alone (Vermorken et al., 2008).

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 irinotecan-based 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/m² intravenously, followed by weekly doses of 250 mg/m² 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 antibody-dependent 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 antibody-dependent 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 ErbB1 and ErbB2 and bind to an internal site on the receptor (usually the ATP-binding pocket), compared to the external binding site of trastuzumab. Lapatinib also inhibits a truncated form of the HER2 receptor that lacks a trastuzumab-binding domain. These differences may account for the activity of lapatinib in trastuzumab-resistant patients.

Lapatinib (tykerb) is FDA-approved for HER2-amplified, trastuzumab-refractory breast cancer, in combination with the fluoropyrimidine analog, capecitabine. In its critical phase III trial, lapatinib plus capecitabine improved disease-free survival by 4.4 months and increased the disease response rate to 22% versus 14% in the control group treated with capecitabine alone. As a small molecule, lapatinib crosses the blood-brain barrier more readily than inhibitor antibodies and has produced anecdotal responses in patients with brain metastases and decreased the incidence of brain metastases in its phase III trial (Geyer et al., 2006).

Pharmacokinetics and Toxicity. The drug is administered orally, 1250 mg/day. It is metabolized by CYP3A4 to a number of inactive products, as well as to an oxidized intermediate that has activity against ErbB1 but not ErbB2. The plasma t_1/2 of 14 hours allows parent drug accumulation over the period of treatment. Concurrent administration of inducers and inhibitors of CYP3A4 shorten and prolong the drug's t_1/2, respectively, and may necessitate adjustment of the dose. Lapatinib toxicities include mild diarrhea, cramping, and exacerbation of gastro-esophageal reflux. When lapatinib is combined with capecitabine, diarrhea becomes a significant side effect in one-third of patients. Lapatinib's inhibition of ErbB1 (EGFR) causes an acneform rash in one-third of patients; the rash can be effectively controlled in most cases with topical or oral antibiotics and topical benzoyl peroxide gel. Unlike trastuzumab, lapatinib has not produced a clear signal of cardiac toxicity (Medina and Goodin, 2008); nonetheless, because it targets ErbB2, lapatinib should be used with caution in combination with other cardiotoxic drugs and with careful surveillance in patients who have underlying heart disease.

INHIBITORS OF ANGIOGENESIS

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In 1971, Judah Folkman opened the field of anti-angiogenesis therapy when he hypothesized that the induction of new blood vessel formation—angiogenesis—is an essential property of cancers (Folkman, 1971). Although this revolutionary hypothesis was initially greeted with skepticism, angiogenesis now is firmly established as one of the hallmarks of cancer.

Cancer cells secrete angiogenic factors that induce the formation of new blood vessels and guarantee the flow of nutrients to the tumor cells. Angiogenic factors secreted by tumors include VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), TGF-β (transforming growth factor β) and PDGF (platelet-derived growth factor). Multiple tumor types overexpress these angiogenic factors. Several animal models have demonstrated that tumor secretion of pro-angiogenic factors turns on an "angiogenic switch," a process essential to tumor growth and metastasis. Strikingly, in multiple experimental models, blockade of these pro-angiogenic molecules halts tumor growth, and in human cancers, anti-angiogenic drugs also have inhibitory effects.

Jain has proposed an additional mechanism for the efficacy of angiogenesis inhibitors (Jain, 2009), based on the observation that the leaky capillaries within tumors have increased permeability and cause an increase in tumor interstitial pressure. This increased pressure inhibits blood flow, decreases oxygenation, and prevents drug delivery within the tumor. Antibodies directed at the primary angiogenic factor, VEGF, decrease interstitial pressure within tumors and reverse the changes in oxygenation and blood flow. By "normalizing" interstitial pressure and improving blood flow, anti-angiogenic agents enhance the ability of chemotherapeutic agents to reach the tumor. Hence, an additional benefit of anti-angiogenic molecules may be their ability to increase the delivery of chemotherapy to the tumor. This hypothesis seems to be validated in the synergy observed when cytotoxic chemotherapy is combined with anti-VEGF antibodies.

The best studied of the angiogenic factors is VEGF. VEGF initiates endothelial cell proliferation when it binds to a member of the VEGF receptor (VEGFR) family, a group of highly homologous receptors with intracellular tyrosine kinase domains that includes VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). The binding of VEGF to its receptor activates the intracellular VEGFR tyrosine kinase activity and initiates mitogenic and anti-apoptotic signaling pathways within the endothelial cell.

The cognate interaction between VEGF and its receptor creates several opportunities for pharmacological inhibition of this pathway. Antibodies targeting VEGF, such as bevacizumab, sterically hinder the interaction of VEGF with its receptor. As an alternative to VEGF antibody therapy, the investigational drug aflibercept (VEGF Trap), a recombinant molecule that utilizes the VEGFR1-binding domain to sequester VEGF, acts as a "soluble decoy receptor" for VEGF.

Alternatively, the propagation of pro-angiogenic signals can be abrogated by the inhibition of the tyrosine kinase activity of VEGFR. Three small molecules (pazopanib, sorafenib, and sunitinib) that inhibit the kinase function of VEGFR-2 have been approved for clinical use. Although bevacizumab and the small molecules share a similar spectrum of toxicities, they have somewhat different spectra of clinical activity and significant differences in pharmacokinetics.

Bevacizumab. Bevacizumab (avastin), a humanized antibody directed against VEGF-A, was the first FDA-approved molecule that specifically targeted angiogenesis. As a single agent, it delays progression of renal-cell cancer, and, in combination with cytotoxic chemotherapy, effectively treats lung, colorectal, and breast cancers.

In clear-cell renal-cell carcinoma, a cancer notoriously resistant to traditional chemotherapeutic agents, single-agent bevacizumab increases survival by 3 months (Yang et al., 2003). Clear-cell renal-cell cancer, a highly vascular tumor, presents a particularly attractive target for bevacizumab and other anti-angiogenic agents because mutations or DNA methylation affecting the von Hippel-Lindau (VHL) gene are a constant feature of renal-cell carcinomas. The VHL gene product functions as an inhibitor of the angiogenic pathway. Thus, a loss of VHL protein activates hypoxia inducible factor 2 (HIF-2), a transcription factor that promotes synthesis of VEGF and other hypoxic response proteins. In 2009, the FDA approved bevacizumab in combination with interferon-α for the treatment of metastatic renal-cell carcinoma.

Bevacizumab is approved as a single agent following prior therapy for glioblastoma. In all other cancers, bevacizumab has little apparent single-agent activity but improves survival in epithelial cancers in combination with standard chemotherapeutic agents (Sandler et al., 2006). Bevacizumab with carboplatin and paclitaxel increases survival in non–small lung cancer by 2 months. Likewise, bevacizumab combined with FOLFOX (5-FU, leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan) improves survival by 5 months in metastatic colon cancer. Finally, the combination of bevacizumab with docetaxel increases progression-free survival in patients with metastatic breast cancer (Miller et al., 2007). Trials testing bevacizumab in glioblastoma multiforme have yielded promising results with minimal evidence of intracranial hemorrhage.

Clinical uses of bevacizumab now have expanded beyond the realm of oncology. In wet age-related macular degeneration, abnormal choroidal neovascularization often leads to rapid visual loss. A slightly altered version of bevacizumab called ranibizumab (lucentis), in which the Fc region has been deleted, effectively treats wet macular degeneration. Bevacizumab restores hearing in patients with progressive deafness due to neurofibromatosis type 2–related tumors (Plotkin et al., 2009).

Clinical Pharmacology. Bevacizumab is administered intravenously as a 30- to 90-minute infusion. In metastatic colon cancer, in conjunction with combination chemotherapy, the dose of bevacizumab is 5 mg/kg every 2 weeks. In metastatic non–small cell lung cancer, doses of 15 mg/kg are given every 3 weeks with chemotherapy. For treatment of metastatic breast cancer, patients receive 10 mg/kg of bevacizumab every 2 weeks in combination with paclitaxel or docetaxel. The differing doses of bevacizumab reflect the varying designs of approval-directed trials. The optimal dosage in each case has not yet been defined. The antibody has a plasma t_1/2 of 4 weeks.

Toxicity. Bevacizumab causes a wide range of class-related adverse effects. A prominent concern with this class of agents was the potential for vessel injury and bleeding, noticed in patients with squamous-cell lung cancer (Johnson et al., 2004). Bevacizumab is contraindicated for patients who have a history of hemoptysis, brain metastasis, or a bleeding diathesis, but in appropriately selected patients, the rate of life-threatening pulmonary hemorrhage is <2% (Sandler et al., 2006).

The safety of operating on patients treated with bevacizumab continues to be a major concern because of the risk of bleeding and poor wound healing. In a pooled analysis of two large clinical trials of colon cancer, patients who needed surgery while being treated with bevacizumab had a higher rate (13% versus 3.4%) of serious wound healing complications than patients treated with placebo (Scappaticci et al., 2007). In light of these data and because of the long t_1/2 of bevacizumab, elective surgery should be delayed for at least 4 weeks from the last dose of antibody, and treatment should be not resumed for at least 4 weeks after surgery.

Other toxicities characteristic of anti-angiogenic drugs include hypertension and proteinuria. A majority of patients receiving the drug require antihypertensive therapy, particularly those receiving higher doses and more prolonged treatment (Sandler et al., 2006; Hurwitz et al., 2004; Miller et al., 2007). The mechanism driving this hypertension is still unclear but may relate, in part, to decreased endothelial nitric oxide production. Physicians should carefully monitor the blood pressure of all patients on bevacizumab and intervene with antihypertensives when appropriate. Case reports describe patients with poorly controlled hypertension developing a reversible posterior leukoencephalopathy during bevacizumab treatment. Bevacizumab also is rarely associated with congestive heart failure, probably secondary to hypertension (Miller et al., 2007).

Patients often develop proteinuria during bevacizumab treatment, but it usually is an asymptomatic finding and rarely associated with nephrotic syndrome (Gressett and Shah, 2009).

The most dreaded vascular toxicity of anti-angiogenic agents is an arterial thromboembolic event (i.e., stroke or myocardial infarction). A meta-analysis found that the rate of arterial thromboembolic events in patients receiving bevacizumab-containing regimens reached 3.8% compared to the control rate of 1.7% (Scappaticci et al., 2007). To reduce the risk of arterial thromboembolic events, clinicians should carefully evaluate a patient's risk factors (age >65 years, clotting diathesis, a past history of arterial thromboembolic events) before starting the drug.

GI perforation, a potentially life-threatening complication of bevacizumab, has been observed with particular frequency (up to 11%) in patients with ovarian cancer, perhaps related to the presence of peritoneal carcinomatosis and to prior abdominal surgery. In colon cancer patients, colonic perforation occurs infrequently during bevacizumab treatment but increases in frequency in patients with intact primary colonic tumors, peritoneal carcinomatosis, peptic ulcer disease, chemotherapy-associated colitis, diverticulitis, or prior abdominal radiation treatment (Gressett and Shah, 2009). The rate of colon perforation is <1% in breast and lung cancer patients receiving the antibody.

Sunitinib. Sunitinib (sutent) competitively inhibits the binding of ATP to the tyrosine kinase domain on the VEGF receptor-2, a mechanism it shares with sorafenib (see "Sorafenib"). Sunitinib also inhibits other protein tyrosine kinases (FLT3, PDGFR-α, PDGFR-β, RET, CSF-1R, and c-KIT) at concentrations of 5-100 nM (Fabian et al., 2005).

Sunitinib has activity in metastatic renal-cell cancer, producing a higher response rate (31%) and a longer progression-free survival than any other approved anti-angiogenic drug (Motzer et al., 2007). Sunitinib also is approved for treatment of advanced renal-cell carcinoma and GIST that have developed resistance to imatinib as a consequence of c-KIT mutations (Heinrich et al., 2008). Specific c-KIT mutations correlate with response to sunitinib. For example, patients with c-KIT exon 9 mutations have a response rate of 37%, whereas patients with c-KIT exon 11 mutations have only a 5% response rate.

Pharmacokinetics and Dosing. Sunitinib is administered orally in doses of 50 mg once a day. The typical cycle of sunitinib is 4 weeks on treatment followed by 2 weeks off treatment. The dosage and schedule of sunitinib can be increased or decreased according to toxicity (hypertension, fatigue). Dosages <25 mg/day typically are ineffective. Sunitinib is metabolized by CYP3A4 to produce an active metabolite, SU12662, the t_1/2 of which is 80-110 hours; steady-state levels of the metabolite are reached after ~2 weeks of repeated administration of the parent drug. Further metabolism results in the formation of inactive products. The pharmacokinetics of sunitinib are not affected by food intake.

Toxicity. The main toxicities of bevacizumab are shared by all anti-angiogenic inhibitors, including sunitinib and sorafenib. Specifically, patients taking sunitinib can experience bleeding, hypertension, proteinuria, and, uncommonly, arterial thromboembolic events and intestinal perforation. However, because sunitinib is a multi-targeted tyrosine kinase inhibitor, it has a broader side-effect profile than bevacizumab.

Fatigue, the most common side effect of sunitinib, affects 50-70% of patients and may be disabling. Hypothyroidism occurs in 40-60% of patients. Bone marrow suppression and diarrhea also are common side effects; severe neutropenia (neutrophils <1000/mL) develop in 10% of patients. Less common side effects include congestive heart failure (usually in association with hypertension) and hand-foot syndrome. To monitor for these side effects, it is essential to check blood counts and thyroid function at regular intervals. Periodic echocardiograms also are recommended.

Sorafenib. Sorafenib (nexavar), like sunitinib, targets multiple protein tyrosine kinases (VEGFR1, VEGFR2, VEGFR3, PDGFR-β, c-KIT, FLT-3, and b-RAF) and inhibits their catalytic activities at concentrations of 20-90 nM (Fabian et al., 2005).

Absorption, Distribution, and Elimination. Sorafenib, an oral medication, is given in daily doses of 400 mg twice a day. Patients typically begin treatment taking 200 mg once a day and increase dosage as tolerated. Unlike sunitinib, sorafenib is given every day without treatment breaks. Sorafenib is metabolized to inactive products by CYP3A4 with a t_1/2 of 20-27 hours; with repeated administration, steady-state concentrations are reached within 1 week.

Therapeutic Uses. Sorafenib is the only drug currently approved for treatment of hepatocellular carcinoma. In these otherwise refractory patients, sorafenib increased median survival by 3 months compared to placebo (10.7 versus 7.9 months) (Llovet et al., 2008). The response rate to sorafenib was low (2%), suggesting that sorafenib primarily has a cytostatic effect. Sorafenib also is approved in metastatic renal-cell cancer, based on improvement in progression-free survival in patients with previously treated disease (Escudier et al., 2007). Because of its higher initial response rate, sunitinib generally is the preferred first-line therapy in this disease.

Adverse Effects. Sorafenib patients can experience the vascular toxicities (bleeding, hypertension, and arterial thromboembolic events) seen with other anti-angiogenic medications. More common adverse effects include fatigue, nausea, diarrhea, anorexia, and rash; uncommonly, one may notice bone marrow suppression and GI perforation (Escudier et al., 2007).

THALIDOMIDE

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Among agents with anti-angiogenic activity, the immunomodulatory analogs (IMiDs), thalidomide and lenalidomide, have a most unusual history and a multiplicity of biological and immunological effects. Their classification as anti-angiogenics is convenient but tentative. Thalidomide originally entered development in the 1950s for the treatment of pregnancy-associated morning sickness but was withdrawn from the market due to the tragic consequences of teratogenicity and dysmelia (stunted limb growth) (Franks et al., 2004). It re-entered clinical practice, initially because of its clinical efficacy in erythema nodosum leprosum, for which it received approval in 1998 (see Chapter 56). Further research revealed its anti-angiogenic and immunomodulatory effects, and these findings triggered experimental trials in cancer, most notably against multiple myeloma (MM). Both thalidomide and lenalidomide possess potent activity in newly diagnosed and heavily pretreated relapsed/refractory MM patients (Richardson et al., 2007). Lenalidomide also has striking clinical activity in the 5q− subset of myelodysplastic syndrome (MDS) and has been approved for this indication. A specific gene array profile identifies MDS patients who lack the 5q− abnormality but respond to lenalidomide (Ebert et al., 2008).

Mechanisms of Action. The precise mechanisms responsible for these drugs' clinical effects are unclear. Thalidomide's enantiomeric interconversion and spontaneous cleavage to multiple short-lived and poorly characterized metabolites, as well as its species-specific in vivo metabolic activation, confound the interpretation of preclinical in vitro and in vivo mechanistic studies. At least four distinct, but potentially complementary, mechanisms have been proposed to explain the antitumor activity of IMiDs (Figure 62–3):

Direct anti-proliferative/pro-apoptotic antitumor effects. They inhibit the anti-apoptotic effects of NF-κB and the anti-apoptotic Bcl-2 family member A1/Bfl-1 (Mitsiades et al., 2002a).
Indirect inhibition of tumor cell growth and survival by abrogation of cell interactions with adhesion molecules (Hideshima et al., 2000).
Inhibition of interleukin-6 (IL-6) and tumor necrosis factor α (TNF α) production, release, and signaling, leading to anti-angiogenic effects.
Immunomodulation through enhancement of natural killer (NK) and T cell–mediated cytotoxicity. Their antagonism of anti-apoptotic pathways and their anti-angiogenic effects could account for the clinical synergy with glucocorticoids and bortezomib against MM (Mitsiades et al., 2002b).

Figure 62–3.

Schematic overview of proposed mechanisms of antimyeloma activity of thalidomide and its derivatives. Some biological hallmarks of the malignant phenotype are indicated in light-blue boxes. The proposed sites of action for thalidomide (letters inside red and green circles) are hypothesized to also be operative for thalidomide derivatives. A. Direct anti–multiple myeloma (MM) effect on tumor cells, including G₁ growth arrest and/or apoptosis, even against MM cells resistant to conventional therapy. This is due to the disruption of the anti-apoptotic effect of BCL-2 family members, blocking NF-κB signaling, and inhibition of the production of interleukin-6 (IL-6). B. Inhibition of MM-cell adhesion to bone marrow stromal cells partially due to the reduction of IL-6 release. C. Decreased angiogenesis due to the inhibition of cytokine and growth factor production and release. D. Enhanced T-cell production of cytokines, such as IL-2 and interferon-γ (IFN-γ), that increase the number and cytotoxic functionality of natural killer (NK) cells. VEGF, vascular endothelial growth factor.

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Thalidomide

Pharmacokinetics and Therapeutic Use. Thalidomide (thalomid) exists at physiological pH as a racemic mixture of cell-permeable and rapidly interconverting non-polar S(–) and R(+) isomers, the equilibrium favoring the R product. The R-enantiomer is associated with the teratogenic and biological activities, while the S accounts for the sedative properties of thalidomide.

Thalidomide is given in dosages of 200-1200 mg/day. In treating MM, doses usually are escalated by 200 mg/day every 2 weeks until dose-limiting side effects (sedation, fatigue, constipation, or a sensory neuropathy) supervene. With extended treatment, the neuropathy may necessitate dose reduction or discontinuation of treatment for a period of time. Thalidomide absorption from the GI tract is slow and highly variable [4 hours mean time to reach peak concentration (T_max), with a range of 1-7 hours]. It distributes throughout most tissues and organs, without significant binding to plasma proteins. Peak levels are achieved in 3-4 hours, and the t_1/2 of disappearance of the enantiomers is ~6 hours. Elimination of thalidomide is mainly by spontaneous hydrolysis in all body fluids; the S-enantiomer is cleared more rapidly than the R-enantiomer. Thalidomide and its metabolites are excreted in the urine, while the non-absorbed portion of the drug is excreted unchanged in feces, but clearance of active drug is primarily attributable to hydrolysis. The inactive hydrolysis products undergo a complex pattern of CYP-mediated metabolism. Studies in elderly prostate cancer patients showed a significantly longer plasma t_1/2 at highest doses (1200 mg daily) versus lowest doses (200 mg daily) (Figg et al., 1999). No dose adjustment is necessary in the presence of renal failure.

Thalidomide enhances the sedative effects of barbiturates and alcohol and the catatonic effects of chlorpromazine and reserpine. Conversely, CNS stimulants (such as methamphetamine and methylphenidate) counteract the depressant effects of thalidomide.

Lenalidomide. Lenalidomide (revlimid) constitutes the lead compound in the new class of immunomodulatory thalidomide derivatives and exhibits a panoply of pharmacological properties (direct suppression of the tumor cell growth in culture, T-cell and NK-cell activation, suppression of TNF α and other cytokines, anti-angiogenesis, and promotion of hematopoietic stem cell differentiation) (List, 2007).

Pharmacokinetics and Therapeutic Use. The standard dosage of lenalidomide is 25 mg/day for 21 days of a 28-day cycle. The drug is rapidly absorbed following oral administration, reaching peak plasma levels within 1.5 hours. The C_max and AUC values increase proportionately with increasing dose, over a single-dose range of 5-400 mg. The t_1/2 of parent drug in plasma is 9 hours at the 400-mg dose. Approximately 70% of the orally administered dose of lenalidomide is excreted intact by the kidney. The AUC progressively rises in patients with moderate to severe renal failure (creatinine clearance <50 mL/min). Based on pharmacokinetic considerations, downward dose adjustments to 10 mg/day for creatinine clearance of 30-50 mL/h and to the same dose every 2 days for creatinine clearance <30 mL/h are recommended for patients with renal failure. The safety and efficacy of these adjusted doses have not been established in prospective studies (Chen et al., 2007).

This orally administered agent has exhibited potent antitumor activity in MM, MDS, and chronic lymphocytic leukemia (CLL); causes fewer adverse side effects; and lacks the teratogenicity of thalidomide.

Adverse Effects of Thalidomide and Lenalidomide.

Thalidomide is well tolerated at doses <200 mg daily. The most common adverse effects reported in cancer patients are sedation and constipation, while the most serious one is peripheral sensory neuropathy, which occurs in 10-30% of patients with MM or other malignancies in a dose- and time-dependent manner (Richardson et al., 2004). Thalidomide-related neuropathy is an asymmetrical, painful, peripheral paresthesia with sensory loss, commonly presenting with numbness of toes and feet, muscle cramps, weakness, signs of pyramidal tract involvement, and carpal tunnel syndrome. The incidence of peripheral neuropathy increases with higher cumulative doses of thalidomide, especially in elderly patients. Although symptoms improve upon drug discontinuation, long-standing sensory loss may not reverse. Particular caution should apply in cancer patients with pre-existing neuropathy (e.g., related to diabetes) or prior exposure to drugs that can cause peripheral neuropathy (e.g., vinca alkaloids, bortezomib), especially because there has been little progress in defining effective strategies to alleviate neuropathic symptoms.

Adverse effects of lenalidomide are much less severe, as it causes little sedation, constipation, or neuropathy. The drug depresses bone marrow function and is associated with significant leukopenia in 20% of patients. In rare instances, patients develop hepatotoxicity and renal dysfunction. In some CLL patients, lenalidomide causes dramatic lymph node swelling and tumor lysis, a syndrome called the tumor flare reaction. Patients with renal dysfunction receiving the standard dose of 25 mg/day are particularly prone to this reaction; thus, clinical trials in CLL are proceeding at much lower doses of 10 mg/day, with escalation as tolerated. CLL patients should receive pretreatment hydration and allopurinol to avoid the consequences of tumor swelling and tumor lysis. A negative interaction with rituximab, an anti-CD20 antibody, may result from lenalidomide's downregulation of CD20, an interaction that has clinical implications for their combined use in lymphoid malignancies (Lapalombella et al., 2008).

Thromboembolic events occur with increased frequency in patients receiving thalidomide or lenalidomide, but particularly in combination with glucocorticoids and with anthracyclines (Musallam et al., 2008). Anticoagulation reduces this risk and seems indicated in patients presenting with risk factors for clotting, but anticoagulant prophylaxis has not been evaluated prospectively.

PROTEASOME INHIBITION: BORTEZOMIB

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Bortezomib (velcade), an inhibitor of proteasome-mediated protein degradation, has earned a central role in the treatment of MM.

Chemistry. Bortezomib, [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid, has a unique boron-containing structure:

Mechanism of Action. Bortezomib binds to the β5 subunit of the 20S core of the 26S proteasome and reversibly inhibits its chymotrypsin-like activity (Adams, 2004). This event disrupts multiple intracellular signaling cascades, leading to apoptosis. A most important consequence of proteasome inhibition is its effect on NF-κB, a key transcription factor that promotes cell damage response and cell survival. Most NF-κB is found in the cytosol bound to IκB; in this form, NF-κB is restricted to the cytosol and cannot enter to the nucleus to regulate transcription. In response to stress signals resulting from hypoxia, chemotherapy, and DNA damage, IκB becomes ubiquitinated and then degraded via the proteasome. Its degradation releases NF-κB, which enters the nucleus, where it transcriptionally activates a host of genes involved in cell survival (e.g., cell adhesion proteins E-selectin, ICAM-1, and VCAM-1), as well as proliferative (e.g., cyclin-D1) or anti-apoptotic molecules (e.g., cIAPs, BCL-2). NF-κB is highly expressed in many human tumors, including MM, and may be a key factor in tumor cell survival in a hypoxic environment and during chemotherapy. Bortezomib blocks proteasomal degradation of IκB, thereby preventing the transcriptional activity of NF-κB and downregulating survival responses.

NF-κB inhibition may not account for the full spectrum of effects triggered by proteasome inhibition, because bortezomib also disrupts the ubiquitin-proteasomal degradation of p21, p27, p53, and other key regulators of the cell cycle and initiators of apoptosis. Bortezomib activates the cell's stereotypical "unfolded protein response" or UPR, in which abnormal protein conformation activates adaptive signaling pathways in the cell. The composite effect leads to irreversible commitment of MM cells to apoptosis (Mitsiades et al., 2002). In clinical trials, bortezomib also sensitizes tumor cells to cytotoxic drugs, including alkylators and anthracyclines, and to IMiDs and inhibitors of histone deacetylase (Orlowski et al., 2007).

Absorption, Fate, and Excretion. The recommended starting dose of bortezomib is 1.3 mg/m² given as an intravenous bolus on days 1, 4, 8, and 11 of every 21-day cycle (with a 10-day rest period per cycle). At least 72 hours should elapse between doses. Drug administration should be withheld until resolution of any grade 3 nonhematological toxicity or grade 4 hematological toxicity, and subsequent doses should be reduced 25%.

After intravenous administration of 1-1.3 mg/m² of bortezomib, the drug exhibits a terminal t_1/2 in plasma of 5.5 hours (Papandreou et al., 2004). The median peak plasma concentration averages 509 ng/mL after a 1.3-mg/m² bolus injection. Peak proteasome inhibition reaches 60% within 1 hour and declines thereafter, with a t_1/2 of ~24 hours.

Bortezomib clearance results from the deboronation of 90% of the parent compound, followed by hydroxylation of the boron-free product by CYPs 3A4 and 2D6; administration of this drug with potent inducers or inhibitors/substrates of CYP3A4 requires caution. No dose adjustment is required for patients with renal dysfunction.

Therapeutic Uses and Toxicity. Bortezomib is FDA approved as initial therapy for MM and as therapy for MM after relapse from other drugs (Kane et al., 2003). It also has received approval for relapsed or refractory mantle cell lymphoma. The drug is active in myeloma, including the induction of complete responses in up to 30% of patients when used in combination with other drugs (i.e., thalidomide, lenalidomide, liposomal doxorubicin, or dexamethasone) (San Miguel et al., 2008).

Bortezomib toxicities include thrombocytopenia (28%), fatigue (12%), peripheral neuropathy (12%), and neutropenia, anemia, vomiting, diarrhea, limb pain, dehydration, nausea, or weakness. Peripheral neuropathy, the most chronic of the toxicities, develops most frequently in patients with a prior history of neuropathy secondary to prior drug treatment (e.g., thalidomide) or diabetes or with prolonged use. Dose reductions or discontinuation of bortezomib ameliorates the neuropathic symptoms. Injection of bortezomib may precipitate hypotension, especially in volume-depleted patients, in those who have a history of syncope, or in patients taking antihypertensive medications. High-dose bortezomib causes hypotension and congestive heart failure in animals; cardiac toxicity occurs rarely in humans, but congestive failure and prolonged QT-interval have been reported.

mTOR INHIBITORS: RAPAMYCIN ANALOGS

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Rapamycin (sirolimus) is a fungal fermentation product that inhibits the proper functioning of a serine/threonine protein kinase in mammalian cells eponymously named mammalian target of rapamycin, or mTOR, an effector PI3 kinase signaling. The PI3K/PKB(Akt)/mTOR pathway responds to a variety of signals from growth factors (e.g., insulin, interleukins, EGF) that modulate cell growth, translation, metabolism, and apoptosis. The activation of the PI3K pathway is opposed by the phosphatase activity of the tumor suppressor, PTEN. Activating mutations and amplification of genes in the receptor-PI3K pathway, and loss of function alterations in PTEN, occur frequently in cancer cells, with the result that PI3K signaling is exaggerated and cells lose growth control and exhibit enhanced survival (decreased apoptosis).

Rapamycin and its congeners, temsirolimus and everolimus, are well-established first-line drugs in post-transplant immunosuppression. More recently, mTOR inhibitors have found important applications in oncology for treatment of renal and hepatocellular cancer and mantle cell lymphomas.

Mechanisms of Action and Resistance. The rapamycins inhibit an enzyme complex, mTORC1, which occupies a downstream position in the PI3 kinase pathway (Figure 62–4). mTOR forms the mTORC1 complex with a member of the FK506-binding protein family, FKBP12. Among other actions, mTORC1 phosphorylates S6 kinase and also relieves the inhibitory effect of 4EBP on initiation factor elf-4E, therby promoting protein synthesis and metabolism. The antitumor actions of the rapamycins result from their binding to FKBP12 and inhibition of mTORC1. Rapamycin and its congeners have immunosuppressant effects, inhibit cell-cycle progression and angiogenesis, and promote apoptosis.

Resistance to mTOR inhibitors is incompletely understood but may arise through the action of a second mTOR complex, mTORC2, which is unaffected by rapamycins and which regulates AKT kinase. Experimental work suggests that inhibition of mTORC1 leads to mTORC2 activation of AKT kinase and the MAP kinase pathway, and these actions may be responsible for incomplete responses or resistance of rapamycins (Carracedo et al., 2008). Dual mTORC1 and mTORC2 inhibitors are in clinical development.

Absorption, Fate, and Excretion. The FDA has approved both temsirolimus and everolimus for treatment of renal cancer. Temsirolimus prolongs survival and delays disease progression in patients with advanced and poor- or intermediate-risk renal cancer, as compared to standard interferon-α treatment. Everolimus, as compared to placebo, prolongs survival in patients who had failed initial treatment with anti-angiogenic drugs (Motzer et al., 2008). mTOR inhibitors also have antitumor activity against mantle cell lymphomas (Ansell et al., 2008) and are under active investigation in combination with hormonal therapies, EGFR inhibitors, and cytotoxic drugs.

For renal-cell cancer, temsirolimus is given in weekly doses of 25 mg, intravenously, while everolimus is administered orally in doses of 10 mg daily. Both drugs should be administered in the fasting state at least 1 hour before a meal. Both parent molecules are metabolized by CYP3A4. Temsirolimus has a plasma t_1/2 of 30 hours; its primary metabolite, sirolimus, has a longer t_1/2 of 53 hours. Because sirolimus has equivalent activity as an inhibitor of mTORC1, and has a greater AUC, sirolimus is likely the more important contributor to antitumor action in patients (Hutson et al., 2008). Everolimus has a plasma t_1/2 of 30 hours, and on a weekly schedule at doses of 20 mg, it maintains inhibition of mTORC1 for 7 days in white blood cells (O'Donnell et al., 2008). At their usual clinical doses, both agents provide peak drug levels of ~1 μM.

Both drugs are susceptible to interactions with other agents that affect CYP3A4 activity. Ketoconazole, a CYP3A4 inhibitor, causes a 2- to 3-fold increase in the AUCs of both temsirolimus and sirolimus, while inducers of metabolism such as rifampin or phenytoin can decrease the C_Pmax of temsirolimus by 36% and decrease the AUC of its metabolite by >50%. The dose of temsirolimus should be doubled in the presence of inducers and reduced by half in the presence of ketoconazole (Hutson et al., 2008). Hepatic dysfunction delays drug clearance; for everolimus, the dose should be reduced to 5 mg daily for patients with moderate hepatic impairment (Child-Pugh class B); guidelines for dose reduction of temsirolimus in such patients have not been established. The drugs' pharmacokinetics do not depend on renal function, and hemodialysis does not hasten temsirolimus clearance.

Higher-dose intravenous temsirolimus regimens, up to 175 mg/week, have been explored in mantle cell lymphoma and in other diseases, as has oral temsirolimus administration. Poor oral bioavailability hampers the oral route of administration, as <20% of drug or active metabolite reaches the plasma (Buckner et al., 2010).

Clinical Toxicity. The rapamycin analogs have very similar patterns of toxicity. The most prominent side effects are a mild maculopapular rash, mucositis, anemia, and fatigue, each occurring in 30-50% of patients. A minority of patients will develop leukopenia or thrombocytopenia with progressive cycles of treatment, and these effects are reversed if therapy is discontinued. Less common side effects include hyperglycemia, hypertriglyceridemia, and, rarely, pulmonary infiltrates and interstitial lung disease. Pulmonary infiltrates emerge in 8% of patients receiving everolimus and in a smaller percentage of those treated with temsirolimus. In patients showing minor radiological changes, but without symptoms, drug administration may be continued. If symptoms such as cough or shortness of breath develop or radiological changes progress, the drug should be discontinued. Prednisone may hasten the resolution of radiological changes and symptoms (Hutson et al., 2008).

Figure 62–4.

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase (TK) growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. The various downstream outputs of the two complexes are shown. Phosphorylation of 4EBP by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism. 4EBP, eukaryotic initiation factor 4e (eif-4E) binding protein; S6K1, S6 kinase 1; FKBP12, the immunophilin target (binding protein) for tacrolimus (FK506).

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BIOLOGICAL RESPONSE MODIFIERS

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Biological response modifiers include cytokines or monoclonal antibodies that beneficially affect the patient's biological response to a neoplasm. Included are agents that act indirectly to mediate their antitumor effects (e.g., by enhancing the immunological response to neoplastic cells) or directly, binding to receptors on the tumor cells and delivering toxins or radionuclides. Recombinant DNA technology has greatly facilitated the identification and production of a number of human proteins with potent effects on the function and growth of both normal and neoplastic cells. Proteins that currently are in clinical use include the interferons (see Chapters 35 and 58); interleukins (see Chapter 35); hematopoietic growth factors such as erythropoietin, filgrastim [granulocyte colony-stimulating factor (G-CSF)], and sargramostim [granulocyte-macrophage colony-stimulating factor (GM-CSF)] (see Chapter 37); and monoclonal antibodies.

Monoclonal Antibodies

Since the discovery of methods for fusing mouse myeloma cells with B lymphocytes, it has been possible to produce a single species of murine antibody that recognizes a specific antigen. Cancer cells express antigens that are attractive targets for monoclonal antibody–based therapy (Table 62–1). Immunization of mice with human tumor cell extracts has led to the isolation of monoclonal Abs reactive against unique or highly expressed target antigens, and a few of these monoclonals possess antitumor activity. Because murine antibodies have a short t_1/2 in humans, activate human immune effector mechanisms poorly, and induce a human anti-mouse antibody immune response, they usually are chimerized by substituting major portions of the human IgG molecule. Presently, monoclonal antibodies have received FDA approval for lymphoid and solid tumor malignancies. Available agents include rituximab (Coiffier et al., 2002) and alemtuzumab (Keating et al., 2002) for lymphoid malignancies, trastuzumab (Vogel et al., 2002) for breast cancer, bevacizumab (Sandler et al., 2006) for colon and lung cancer, and cetuximab and panitumumab (Van Cutsem et al., 2007) for colorectal cancer and head and neck cancer. The nomenclature adopted for naming therapeutic monoclonal antibodies is to terminate the name in -ximab for chimeric antibodies and -umab for fully humanized antibodies.

Table 62-1Monoclonal Antibodies Approved for Hematopoietic and Solid Tumors

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Table 62-1 Monoclonal Antibodies Approved for Hematopoietic and Solid Tumors

ANTIGEN AND TUMOR CELL TARGETS

ANTIGEN FUNCTION

NAKED ANTIBODIES

RADIOISOTOPE- BASED ANTIBODIES

TOXIN-BASED ANTIBODIES

Antigen: CD20

Tumor type: B-cell lymphoma and CLL

Proliferation/differentiation

Rituximab (chimeric)

¹³¹I-tositumomab; ⁹⁰Y-ibritumomab tiuxetan

None

Antigen: CD52

Tumor type: B-cell CLL and T-cell lymphoma

Unknown

Alemtuzumab (humanized)

None

Antigen: CD33

Tumor type: acute Myelocytic Leukemia

Unknown

Gemtuzumab (humanized)

None

Gemtuzumab Ozogamicin

Antigen: HER2/neu (ErbB2)

Tumor type: Breast cancer

Tyrosine kinase

Trastuzumab (humanized)

None

Antigen: EGFR (ErbB1)

Tumor type: colorectal, NSCLC, pancreatic, breast

Tyrosine kinase

Cetuximab (chimeric)

None

Antigen: VEGF

Tumor type: colorectal cancer

Angiogenesis

Bevacizumab (humanized)

None

CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; NSCLC, non–small cell lung cancer; VEGF, vascular endothelial growth factor.

Unmodified monoclonal antibodies may kill tumor cells by a variety of mechanisms [e.g., antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct induction of apoptosis by antigen binding], but the clinically relevant mechanisms for most antibodies are uncertain (Villamor et al., 2003). Monoclonal antibodies also may be linked to a toxin (immunotoxins), such as gemtuzumab ozogamicin (mylotarg) (Larson et al., 2005) or denileukin diftitox (ontak) (Negro-Vilar et al., 2007), or conjugated to a radioactive isotope, as in the case of ⁹⁰Yttrium (⁹⁰Y)-ibritumomab tiuxetan (zevalin) (Witzig et al., 2002) (Table 62–1). Genetic polymorphisms affecting the target antigen or complement receptors may influence response (Cartron et al., 2002).

Unarmed Monoclonal Antibodies

Rituximab. Rituximab (rituxan) is a chimeric monoclonal antibody that targets the CD20 B-cell antigen (Tables 62–1 and 62–2) (Maloney et al., 1997). CD20 is found on cells from the pre–B cell stage through its terminal differentiation to plasma cells and is expressed on 90% of B-cell neoplasms. The biological functions of CD20 are uncertain, although incubation of B cells with anti-CD20 antibody has variable effects on cell-cycle progression, depending on the monoclonal antibody type. Monoclonal antibody binding to CD20 generates transmembrane signals that produce autophosphorylation and activation of serine/tyrosine protein kinases, induction of c-myc oncogene expression, and expression of major histocompatibility complex class II molecules. CD20 also may regulate transmembrane Ca²⁺ conductance through its function as a Ca²⁺ channel. It is unclear which of these actions relates to the pharmacological effect of rituximab.

Rituximab is approved as a single agent for relapsed indolent lymphomas and significantly enhances response and survival in combination with chemotherapy for the initial treatment of diffuse large B-cell lymphoma. It remains effective in patients who relapse after initial treatment with rituximab-based combinations. Rituximab improves response rates when added to combination chemotherapy for other indolent B-cell non-Hodgkin's lymphomas (NHLs), including CLL, mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphomas (Cheson and Leonard, 2008). Maintenance of remission with rituximab delays time to progression and improves overall survival in indolent NHL (van Oers et al., 2006). It is increasingly used for treatment of autoimmune diseases such as rheumatological disease, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemias, cryoglobulin-induced renal disease and multiple sclerosis.

Pharmacokinetics and Dosing. Rituximab has a t_1/2 of ~22 days (Maloney et al., 1997). The drug is administered by intravenous infusion both as a single agent and in combination with chemotherapy at a dose of 375 mg/m². As a single agent, it is given weekly for 4 weeks, with maintenance dosing every 3-6 months. In combination regimens, the drug may be administered every 3-4 weeks, with chemotherapy, for up to eight doses. As maintenance therapy following 6-8 cycles of combination chemotherapy, rituximab may be given once weekly for four doses, at 6-month intervals, for up to 16 doses.

During the first administration, the rate of infusion should be increased slowly to prevent serious hypersensitivity reactions. Infusions should begin at 50 mg/h, and in the absence of infusion reactions, the rate can increase in 50-mg/h increments every 30 minutes to a maximum rate of 400 mg/h. On subsequent infusion in the absence of reactions, infusions may start at 100 mg/hr and increase in 100-mg/h increments every 30 minutes to a maximum rate of 400 mg/h. Pretreatment with antihistamines, acetaminophen, and glucocorticoids decreases the risk of hypersensitivity reactions.

Patients with large numbers of circulating tumor cells (as in CLL) are at increased risk for tumor lysis syndrome; in these patients, the initial dose should be no more than 50 mg/m² on day 1 of treatment, and patients should receive standard tumor lysis prophylaxis. The remainder of the dose can then be given on day 3.

Resistance and Toxicity. Resistance to rituximab may emerge through downregulation of CD20, impaired antibody-dependent cellular cytotoxicity, decreased complement activation, limited effects on signaling and induction of apoptosis, and inadequate blood levels (Maloney et al., 2002). Polymorphisms in two of the receptors for the antibody Fc region responsible for complement activation, Fcγ RIIIa and Fcγ RIIa, may predict the clinical response to rituximab monotherapy in patients with follicular lymphoma but not in CLL (Cartron et al., 2002).

Rituximab infusional reactions can be life-threatening, but with pretreatment are usually mild and limited to fever, chills, throat itching, urticaria, and mild hypotension. All respond to decreased infusion rates and antihistamines. Uncommonly, patients may develop severe mucocutaneous skin reactions, including Stevens-Johnson syndrome. Rituximab may cause reactivation of hepatitis B virus or rarely, JC virus (with progressive multifocal leukoencephalopathy) (Kranick et al., 2007). Patients should be screened for hepatitis B before initiation of therapy. Hypogammaglobulinemia and autoimmune syndromes (idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, pure red cell aplasia, and delayed neutropenia) may supervene 1-5 months after administration (Cattaneo et al., 2006).

Ofatumumab. Ofatumumab (arzerra) is a second monoclonal antibody that binds to CD20 at sites on the major and minor extracellular loops of CD20, distinct from the site targeted by rituximab. Binding of the drug results in B-cell lysis (both CDC and ADCC). Ofatumumab is approved for treating patients with CLL after failure of fludarabine and alemtuzumab.

A complex dosing scheme is used, beginning with small (300 mg) doses on day 1, followed by higher doses (up to 2 g/week) for 7 weeks, followed by 2 g every 4 weeks for four additional doses. Slow rates of infusion are recommended for the initial dose and for the first 2 hours of subsequent infusions.

Ofatumumab's primary toxicities consist of immunosuppression and opportunistic infection, hypersensitivity reactions during antibody infusion, and myelosuppression, which may be prolonged. Blood counts should be monitored during treatment. Rarely, patients may develop reactivation of viral infections, leading to progressive multifocal leukoencephalopathy or hepatitis B progression. The drug should not be administered to patients with active hepatitis B infection; liver function should be monitored closely in hepatitis B carriers.

Alemtuzumab. Alemtuzumab (campath) is a humanized IgG-κ monoclonal antibody, composed of a rat antigen–binding region within human constant regions and variable framework. The drug binds to CD52 antigen present on the surface of a subset of normal neutrophils and on all B and T lymphocytes, on testicular elements and sperm, and on most B- and T-cell lymphomas (Kumar et al., 2003). Consistently high levels of CD52 expression on lymphoid tumor cells and the lack of CD52 modulation with antibody binding make this antigen a favorable target for unconjugated monoclonal antibodies. Alemtuzumab can induce tumor cell death through ADCC and CDC.

Pharmacokinetics and Dosing. Alemtuzumab is administered intravenously in dosages of 30 mg/day three times per week. Premedication with diphenhydramine (50 mg) and acetaminophen (650 mg) should precede drug infusion. Because of hypersensitivity, dosing begins with a 3-mg infusion, followed by a 10-mg dose 2 days later and, if well tolerated, a 30-mg dose 2 days later. The drug has an initial mean t_1/2 of 1 hour, but after multiple doses, the t_1/2 extends to 12 days, and steady-state plasma levels are reached at approximately week 6 of treatment, presumably through saturation of CD52-binding sites. Clinical activity has been demonstrated in both B- and T-cell low-grade lymphomas and CLL, including patients with disease refractory to purine analogs (Hillmen et al., 2007). In chemotherapy-refractory CLL, overall response rates are ~40%, with complete responses of 6% in multiple series. Response rates in patients with untreated CLL are higher (overall response rates of 83% and complete responses of 24%).

Toxicity. The most concerning toxicities include acute infusion reactions and depletion of normal neutrophils and T cells (Table 62–2). Serious myelosuppression, with depletion of all blood lineages, occurs in the majority of patients and may represent either direct marrow toxicity or auto-immune responses. Immunosuppression by the antibody leads to a significant risk of fungal, viral, and other opportunistic infections (Listeria), particularly in patients who have previously received purine analogs (Keating et al., 2002; Hillmen et al., 2007). Patients should receive antibiotic prophylaxis against Pneumocystis carinii and herpes virus during treatment and for at least 2 months following therapy with alemtuzumab. Because reactivation of cytomegalovirus (CMV) infections may follow antibody use, patients should be monitored for symptoms and signs of viremia, hepatitis, and pneumonia. CD4⁺ T-cell counts may remain profoundly depleted (<200 cells/μL) for 1 year. Alemtuzumab does not combine well with chemotherapy in standard regimens because of significant infectious complications (Gallamini et al., 2007).

Table 62-2Dose and Toxicity of Monoclonal Antibody–Based Drugs

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Table 62-2 Dose and Toxicity of Monoclonal Antibody–Based Drugs

DRUG

MECHANISM

DOSE AND SCHEDULE

MAJOR TOXICITY

Rituximab

ADCC; CDC; apoptosis

375-mg/m² IV infusion

Infusion-related toxicity weekly for 4 weeks with fever, rash, and dyspnea; B-cell depletion; late-onset neutropenia

Alemtuzumab

ADCC; CDC; apoptosis

Escalating doses of 3, 10, 30 mg/m² IV three times/week followed by 30 mg/m² three times/week for 4-12 weeks

Infusion-related toxicity, T-cell depletion with increased infection; hematopoietic suppression; pancytopenia

Trastuzumab

ADCC; apoptosis; inhibition of arrest HER2 signaling with G₁ arrest

Loading dose of 4-mg/kg infusion followed by

Cardiomyopathy; infusion-related toxicity 2 mg/kg weekly

Cetuximab

Inhibition of EGFR signaling; apoptosis; ADCC

Loading dose of 400-mg/kg infusion followed by 250 mg/kg weekly

Infusion-related toxicity; skin rash in 75%

Bevacizumab

Inhibition of angiogenesis/neovascularization

5 mg/kg IV every 14 days until disease progression

Hypertension; pulmonary hemorrhage; GI perforation; proteinuria; congestive heart failure

Denileukin diftitox

Targeted diphtheria toxin with inhibition of protein synthesis

9-18 μg/kg/day IV for the first 5 days every 3 weeks

Fever; arthralgia; asthenia; hypotension

Gemtuzumab ozogamicin

Double-strand DNA breaks and apoptosis

Two doses of 9 mg/m² IV separated by 14 days

Infusion-related toxicity; hematopoietic suppression; mucosal hepatic (VOD); skin toxicity

⁹⁰Y-ibritumomab tiuxetan

Targeted radiotherapy

0.4 mCi/kg IV

Hematological toxicity; myelodysplasia

¹³¹I-tositumomab

Targeted radiotherapy

Patient-specific dosimetry

Hematological toxicity; myelodysplasia

ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; EGFR, epidermal growth factor receptor; intravenous; VOD, veno-occlusive disease.

Monoclonal Antibody–Cytotoxic Conjugates

Gemtuzumab Ozogamicin. Gemtuzumab ozogamicin (mylotarg) consists of a humanized monoclonal antibody against CD33 covalently linked to a semisynthetic derivative of calicheamicin, a potent enediyne antitumor antibiotic (Bernstein, 2000). The CD33 antigen is present on most hematopoietic cells, on >80% of AMLs, and on most myeloid cells in patients with myelodysplasias. However, other normal cell types lack CD33 expression, making this antigen attractive for targeted therapy. CD33 has no known biological function, although monoclonal antibody cross-linking inhibits normal and myeloid leukemia cell proliferation. Following its binding to CD33, gemtuzumab ozogamicin undergoes endocytosis, and cleavage of calicheamicin from the antibody takes place within the lysosome. The potent toxin then enters the nucleus, binds in the minor groove of DNA, and causes double-strand DNA breaks and cell death (Zein et al., 1988).

Clinical Pharmacology. The antibody conjugate produces a 30% complete response rate in relapsed AML, when administered at a dose of 9 mg/m² for up to 3 doses at 2-week intervals (Sievers et al., 2001). Pharmacokinetics of gemtuzumab ozogamicin at the standard 9-mg/m² dose are described by a t_1/2 of total and unconjugated calicheamicin of 41 and 143 hours, respectively (Dowell et al., 2001). Following a second dose, the t_1/2 of drug-antibody conjugate increases to 64 hours and the AUC increases to twice that of the initial dose. Most patients require two to three doses to achieve remission. The drug currently is approved in patients >60 years of age with AML in first relapse.

The primary toxicities of gemtuzumab ozogamicin include myelosuppression in all patients treated and hepatocellular damage in 30-40% of patients, manifested by hyperbilirubinemia and enzyme elevations. It also causes a syndrome that resembles hepatic veno-occlusive disease (tender, enlarged liver and rising serum bilirubin) when patients subsequently undergo myeloablative therapy or when gemtuzumab ozogamicin follows high-dose chemotherapy (Wadleigh et al., 2003). This syndrome reflects injury to hepatic sinusoids rather than venules. Defibrotide, an orphan drug, may prevent severe or fatal hepatic injury in patients who develop signs of hepatic failure while receiving a stem cell transplant following gemtuzumab ozogamicin (Versluys et al., 2004). Prolonged myelosuppression, particularly delayed recovery of platelet counts, may complicate the patient's course following remission induction with gemtuzumab ozogamicin.

Radioimmunoconjugates

Radioimmunoconjugates provide targeted delivery of radionuclides to tumor cells (Tables 62–1 and 62–2) (Witzig et al., 2002; Horning et al., 2005). ¹³¹Iodine (¹³¹I) is a favored radioisotope because it is readily available, relatively inexpensive, and easily conjugated to a monoclonal antibody. The γ particles emitted by ¹³¹I can be used for both imaging and therapy, but protein-iodine conjugates have the drawback of releasing free ¹³¹I and ¹³¹I-tyrosine into the blood, and thus present a health hazard to caregivers, family, and others in contact with the patient. The β-emitter ⁹⁰Y has emerged as an attractive alternative to ¹³¹I, based on its higher energy and longer path length. These features suggest that it may be more effective in tumors with larger diameters. It also has a short t_1/2 and remains conjugated, even after endocytosis, providing a safer profile for outpatient use.

Currently available radioimmunoconjugates consist of murine monoclonal antibodies against CD20 conjugated with ¹³¹I [tositumomab (bexxar)] or ⁹⁰Y [ibritumomab tiuxetan (zevalin)]. Both drugs have shown responses rates in relapsed lymphoma of 65-80%. They require significant collaboration between medical oncologists and nuclear medicine departments for administration. When using Zevalin, an initial dose of unlabeled rituximab is administered, followed by an imaging dose of Indium-111-labeled Zevalin. Biodistribution is determined, allowing calculation of a therapeutic dose of ⁹⁰Y Zevalin. A pretreatment dose of rituximab then is administered to saturate nonspecific binding sites, followed by the therapeutic dose of ⁹⁰Y Zevalin. The steps in Bexxar administration closely follow those of Zevalin. An imaging dose precedes the therapeutic dose given 1 week later. These agents cause antibody-related hypersensitivity, bone marrow suppression, and secondary leukemias.

Interleukin-2

IL-2 is a 133–amino acid glycoprotein encoded by a gene on chromosome 4q26-27; its molecular weight is 15 kDa (Smith, 1988). It bears structural homology to IL-4, IL-15, and GM-CSF. IL-2 is produced by activated T cells and NK cells; it acts to promote activated T-cell proliferation and enhanced killing by NK cells. Responsiveness depends on expression of the IL-2 receptor. Resting T cells and nearly all types of tumor cells lack receptor expression and are unresponsive to IL-2.

The IL-2 receptor has three components: 1) an α chain, a 55-kDa protein (CD25) involved mainly in IL-2 binding; 2) a β chain, a 75-kDa protein involved in intracellular signaling; and 3) a γ chain, a 64-kDa protein that is a component of many cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) and also is involved in signaling (Waldmann, 1991). IL-2 affinity for the three-component receptor is 10 pM; in the absence of the α chain, IL-2-binding affinity is reduced by a factor of 100.

Mechanism of Action. IL-2 stimulates the proliferation of activated T cells and the secretion of cytokines from NK cells and monocytes. IL-2 stimulation increases cytotoxic killing by T cells and NK cells. The mechanism of tumor cell killing has not been precisely defined but is presumed to be the result of enhanced killing by immune effector cells.

Pharmacokinetics. The serum t_1/2 of IL-2 after intravenous administration has an α phase of about 13 minutes and a β phase of about 90 minutes (Konrad et al., 1990). After a bolus dose of 6 million IU/m², peak serum levels are nearly 2,000 IU/mL. The same dose given subcutaneously achieves peak levels of 32-42 IU/mL in 2-6 hours. Six million IU/m² given by continuous intravenous infusion reaches a steady-state level of 123 IU/mL within 2 hours. IL-2 is excreted in the urine as an inactive metabolite. Encapsulation of IL-2 in liposomes or conjugation of IL-2 to polyethylene glycol alters its distribution and t_1/2; these forms are not FDA-approved.

Clinical Use. Aldesleukin (proleukin) possess the biological activities of human native IL-2. The drug is approved for use in metastatic renal-cell cancer (Rosenberg, 2000) and metastatic melanoma (McDermott, 2009). High-dose IL-2 produces an overall response rate of ~19% in patients with renal-cell cancer, and 8% achieve a complete response. Responses last a median of 8-9 years. Patients whose tumors express carbonic anhydrase IX have a higher likelihood of response (Atkins, 2009). High-dose IL-2 induces an overall response rate of ~16% in patients with metastatic melanoma, and 6% achieve a complete response. Responses last a median of ~5 years. Low-dose IL-2 also produces responses, but the duration of the responses may be less than with high-dose IL-2. The issue of appropriate dosage is controversial.

Aldesleukin may be administered in several ways. High-dose IL-2 is 600,000-720,000 IU/kg administered by intravenous bolus every 8 hours until dose-limiting toxicity appears or 14 total doses have been given; the schedule may be repeated after 9 days of rest for a maximum of 28 doses. Low-dose IL-2 is 60,000 or 72,000 IU/kg given by intravenous bolus every 8 hours for 15 doses. A third regimen involves delivery of 18 million units/m² daily by continuous intravenous infusion for 5 days. Chronic administration doses are 250,000 IU/kg subcutaneously daily for 5 days followed by 125,000 IU/kg daily for 6 weeks.

Toxicity. IL-2 toxicities are dominated by the capillary leak syndrome (Schwartz et al., 2002). Intravascular fluid leaks into the extravascular space, tissues, and lung, producing hypotension, edema, respiratory difficulties, confusion, tachycardia, oliguric renal failure, and electrolyte problems, including hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia. Symptoms include fever, chills, malaise, nausea, vomiting, and diarrhea. Laboratory abnormalities include thrombocytopenia, abnormal liver function tests, and neutropenia. Most patients develop a pruritic skin rash over most of the body surface. Hypothyroidism may occur. Arrhythmias are a rare complication.

These toxicities can be variable in grade but are often life-threatening, yet nearly all are reversible within 24-48 hours of discontinuing therapy. In view of the toxicities, patients should have a good performance status and normal renal and hepatic function before beginning therapy and should be closely supervised during drug administration.

Denileukin Diftitox. Denileukin diftitox (ontak) is an immunotoxin made from the genetic recombination of IL-2 and the catalytically active fragment of diphtheria toxin (Foss et al., 2001). The limited tissue expression of the high-affinity IL-2R makes this an attractive target for an immunotoxin, as cells that do not express the IL-2R or express only the intermediate- or low-affinity receptor types are significantly less sensitive to this agent. Introduction of the diphtheria toxin fragment into cells leads to ADP-ribosylation and inactivation of eukaryotic elongation factor EF-2, inhibition of protein synthesis, and thence, cell death.

Denileukin diftitox is FDA-approved for the treatment of recurrent/refractory cutaneous T-cell lymphomas. It should be administered at 9 or 18 μg/kg/day by intravenous infusion over 30-60 minutes for 5 consecutive days every 21 days for eight cycles. Response rates of 30-37% have been achieved in such patients with denileukin diftitox, with a median response duration of 6.9 months (Olsen et al., 2001). Additional patients derived clinical benefit but did not meet the objective criteria for response. The systemic exposure to denileukin diftitox is variable but proportional to dose. The drug has a distribution t_1/2 of 2-5 minutes with a terminal t_1/2 of ~70 minutes. Immunological reactivity to denileukin diftitox can be detected in virtually all patients after treatment but does not preclude clinical benefit with continued treatment. Denileukin diftitox clearance in later cycles of treatment accelerates by 2- to 3-fold as a result of development of antibodies, but serum levels exceed those required to produce cell death in IL-2R-expressing cell lines (1-10 ng/mL for >90 minutes). Patients with a history of hypersensitivity reactions to diphtheria toxin or IL-2 should not be treated. Significant toxicities associated with denileukin diftitox typically are acute hypersensitivity reactions, a vascular leak syndrome, and constitutional toxicities; glucocorticoid premedication significantly decreases toxicity (Foss et al., 2001).

Colony-Stimulating Factors

As noted in the preceding sections, many agents used for cancer chemotherapy suppress the production of multiple types of hematopoietic cells, and bone marrow suppression often has limited the delivery of chemotherapy on schedule and at prescribed doses. The availability of recombinant growth factors for erythrocytes (i.e., erythropoietin), granulocytes (i.e., G-CSF), and granulocytes and macrophages (i.e., GM-CSF) have advanced the ability to use combination therapy or high-dose therapy with diminished complications such as febrile neutropenia. The individual growth factors and specifics of supportive use of these agents are described in detail in Chapter 37.

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Chapter 62: Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies, and Cytokines

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INTRODUCTION

PROTEIN TYROSINE KINASE INHIBITORS

Inhibitors of the Bcr-Abl Kinase: Imatinib, Dasatinib, and Nilotinib

Figure 62–1.

EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS

Figure 62–2.

Gefitinib

Erlotinib

Cetuximab

Panitumumab

HER2/neu Inhibitors

INHIBITORS OF ANGIOGENESIS

THALIDOMIDE

Figure 62–3.

PROTEASOME INHIBITION: BORTEZOMIB

mTOR INHIBITORS: RAPAMYCIN ANALOGS

Figure 62–4.

BIOLOGICAL RESPONSE MODIFIERS

Monoclonal Antibodies

Unarmed Monoclonal Antibodies

Monoclonal Antibody–Cytotoxic Conjugates

Radioimmunoconjugates

Interleukin-2

Colony-Stimulating Factors

BIBLIOGRAPHY

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