97 - Clinical Trial Design
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 113 - Novel Systemic Therapy for Advanced Non Small-Cell Lung Cancer
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Chapter 113
Novel Systemic Therapy for Advanced Non Small-Cell Lung Cancer
Roy S. Herbst
Merrill S. Kies
Lung cancer is the leading cause of cancer-related deaths in the United States. Based on 2003 statistics, 171,900 patients were diagnosed, and of those, 157,200 will succumb to the disease. This accounts for about 31% of cancer deaths according to the American Cancer Society Information Database of March 2002, as reported by Jemal and colleagues (2003).
Non small-cell lung cancer (NSCLC) is a heterogeneous aggregate of malignancies with at least three distinct histologic presentations: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The term non small-cell carcinoma is used because, when localized, all have the potential for cure after surgical resection. Moreover, there is variability in diagnosis from case to case with attempts to separate these subtypes, affecting about one-third of the diagnoses. Thus, to ensure accuracy while allowing for histologic variability, the term non small-cell carcinoma is used to distinguish these cancers from small cell subtypes, which have a different natural history and sensitivity to treatment.
Recent discoveries in cellular regulatory molecules and genetics involved in the development of malignancies have provided new therapeutic strategies. Improved understanding of the role of growth factors, the epidermal growth factor receptors (EGFRs), and the discovery of genes that regulate the cell cycle (e.g., p53 and ras) have led to the identification of potentially important therapeutic targets.
The treatment for NSCLC and other malignancies is evolving. This chapter focuses on novel targets for lung cancer therapy and the early clinical experience with new compounds. Please see Chapters 111 and 112 for a discussion of more standard current therapeutic approaches.
GROWTH FACTORS IN MALIGNANCY
Growth factors are targets for novel therapy. Cross and Dexter (1991) have noted that more than three dozen growth factors have been identified that may be important in regulating cellular processes such as proliferation, differentiation, and survival. Families of growth factors and receptors share similarities in structure and function, including HER1 (EGFR or c-erbB-1), HER2 (neu or c-erbB-2), HER3 (c-erbB-3), and HER4 (c-erbB-4). All but HER3 possess intrinsic tyrosine kinase activity. Carpenter (1987) and Carpenter and Cohen (1990) have pointed out that the EGFR is a 170-kd transmembrane glycoprotein that is encoded by the c-erbB-1 protooncogene. HER2 is a protooncogene with extensive sequence homology to EGFR that plays an important role in regulating epithelial cell growth and shares 82% homology in the tyrosine kinase domain, according to Coussens and associates (1985) and Prigent and Lemoine (1992). However, as noted by Klapper and associates (1999), unlike other HER subfamily members, HER2 is not strictly a receptor because it appears to respond to no high-affinity endogenous ligand and acts instead as a signaling network coordinator and amplifier when it heterodimerizes with other HER family members. HER3 is about 40% homologous to EGFR. Finally, HER4 is the most recently discovered of the group and, as reported by Salomon and coinvestigators (1995), is a receptor for heregulin alpha and beta. Salomon and associates (1995), as well as Yarden and Ullrich (1988), have recorded that growth factors and ligands for these receptors include epidermal growth factor (EGF), growth hormone growth factor (somatotropin), platelet-derived growth factor (PDGF) for the EGFR; heregulin, EGF, PDGF, tumor growth factor (TGF) for the HER2 receptor; insulin for the HER3 receptor; and the heregulin alpha and beta proteins for the HER4 receptor. One of the most evaluated receptors in this group as a target for novel therapies is EGFR.
Epidermal Growth Factor Receptor
Schlessinger (1988) and Thompson and Gill (1985) have pointed out that the EGFR is expressed on the surface of
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normal cells, particularly those of epithelial origin, including the skin, liver, and gastrointestinal tract; EGFR is not found on hematopoietic cells. In addition, EGFR has been identified and shown to be overexpressed in human solid tumors, including NSCLC by Salomon and associates (1995). In normal cells, the concentration of EGFR ranges from 40,000 to 100,000 per cell according to the studies of Carpenter and Cohen (1979). In malignant cells, EGFR expression is much greater; for example, up to 2 million receptors per cell were found in breast cancer cells by Ennis and colleagues (1991). Large variation among human tumors may be due, in part, to differences in detection methods and tumor stage.
EGFR overexpression has been reported in 40% to 80% of patients with NSCLC in the studies of Salomon (1995), Fujino (1996), and Rusch (1997) and their co-workers. Further, EGFR overexpression is more typical of patients with squamous cell carcinoma than in patients with adenocarcinoma according to Ohsaki and associates (2000). Pederson and coinvestigators (2001) reported that EGFR VIII is an uncommon variant of EGFR that is reported in NSCLC and may be a negative prognostic indicator reflective of a more malignant phenotype. The prognostic implications of EGFR overexpression in NSCLC are summarized in the following sections.
Epidermal Growth Factor Receptor Structure and Function
Harari and Huang (2000) have recorded that the EGFR is composed of three domains: an extracellular ligand-binding domain, a transmembrane lipophilic domain, and an intracellular protein tyrosine kinase domain (Fig. 113-1). The studies of Carpenter and Cohen (1990) and Schlessinger (1988) have shown that the glycosylated extracellular domain that represents the ligand-binding site is anchored to the cellular membrane through a single hydrophobic membrane,
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which, in turn, is attached to the intracellular portion that possesses intrinsic tyrosine kinase activity. Ligands for EGFR include EGF, transforming growth factor- ; (TGF- ), heparin-binding EGF, amphiregulin, and betacellulin according to Salomon and colleagues (1995). Upon ligand binding to the EGFR, Carpenter and Cohen (1979) have recorded that the ligand-receptor complex undergoes dimerization and internalization and is thus no longer available on the cell surface. Yarden and Ullrich (1988) and Yarden and Sliwkoski (2001) have pointed that EGFR dimerization activates intracellular protein kinase through autophosphorylation, which then stimulates a signal transduction cascade leading to activation of a complex network of mitogenic mechanisms involved in cell proliferation, differentiation, and survival.
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Fig. 113-1. Epidermal growth factor receptor (EGFR) pathways. EGFR regulates cellular processes through multiple mechanisms. From Harari PM, Huang S-M. Modulation of molecular targets to enhance radiation. Clin Cancer Res 6:323, 2000. American Association for Cancer Research. With permission. |
Fang and Chen (1999), as well as Al Moustafa (1999), Damstrup (1998), Hamada (1995), Lei (1998), and Sorscher (1995), and their colleagues have reported that EGFR overexpression in lung cancer cells has been associated with increased proliferation, invasion, tumor differentiation, and adhesion. The EGFR signaling pathway, according to Perry (1998) and Rodeck (1997) and their associates, may be important in regulating cell cycle survival, promoting progression and inhibiting apoptosis (programmed cell death). Further, Xie (1995), Engebraaten (1993), Price (1996), and Shibata (1996) and their co-workers note that the EGFR pathway affects regulation of tumor cell motility and metastases.
Fox and associates (1996) have documented that EGF and other growth factors (e.g., TGF- ) promote angiogenesis (the process of new blood vessel formation), fueling tumor growth and the process of metastasis. Fox and colleagues further demonstrated that both EGF and TGF- are inducers of angiogenesis in the hamster cheek pouch assay. Further, De Jong and co-workers (1998) have identified that coexpression of EGF and TGF- correlates with increased microvessel density in invasive breast cancer. According to the studies of Battegay (1995), Pluda (1997), Risau (1997), and Zetter (1998), arresting angiogenesis deprives tumors of vascular supply and induces a state of tumor dormancy; a balance may occur between proliferation and apoptosis with the result, as noted by Holmgren and associates (1995), that growth is inhibited.
Growth Factors in Prognosis and Chemotherapy Selection
Molecular markers have been studied as biomarkers of disease progression. The role of EGFR expression as a prognostic factor in NSCLC remains controversial. Although Fontanini and colleagues (1998) showed a significantly higher expression of EGFR in patients with nodal involvement than in patients without nodal metastasis, Rusch and co-workers (1997) did not find a correlation between EGFR or TGF- overexpression and overall survival in previously untreated patients with resectable NSCLC. Both, however, showed EGFR to be overexpressed in most patients. Also, in vitro, high levels of EGFR expression may correlate with reduced sensitivity to chemotherapy.
In addition to EGFR, other prognostic molecular markers for cancer recurrence and death have been evaluated by D'Amico and colleagues (1999). The five markers identified in this study, which were representative of the independent metastatic pathways, included p53 (apoptosis), factor VIII (angiogenesis), CD44 (adhesion), the retinoblastoma recessive oncogene (cell cycle regulation), and HER2 (growth regulation). In another study by Nemunaitis and associates (1998), overexpression of p21, a cellular signal transduction protein that directs cell growth and differentiation, and K-ras gene mutations, were associated with lower survival rates in patients with adenocarcinoma or large cell carcinoma of the lung. Shackney and colleagues (1999) have reported data suggesting that the sequence of p53 protein, HER2, and K-ras overexpression often occurs in the same tumor cells.
HER2 OVEREXPRESSION
HER2 is overexpressed in many solid tumors (e.g., NSCLC, 20%; breast, 25% to 30%), as noted by Kern (1990), Shi (1992), Slamon (1987, 1989), Tateishi (1991), and Weiner (1990) and their associates. Graziano (1998) and Osaki (1995) and their co-workers have observed that HER2 overexpression may be a prognostic indicator for decreased survival and poorer response to chemotherapy in NSCLC. Overexpression of HER2 results in reduced expression of E-cadherin, as described by D'Souza and Taylor-Papadimitriou (1994), and integrin-2 and, consequently, a reduction in signal transduction for terminal differentiation. When NSCLC cells are experimentally induced to express HER2, as was done by Yu and coinvestigators (1994), the cells develop increased ability to secrete matrix-degrading enzymes and undergo enhanced migration in in vitro models and demonstrated increased metastasis in a murine system. Regulatory molecules such as HER2 also can be used to monitor the course of treatment, as observed by Luftner and associates (1999). In patients with advanced breast cancer, serum levels of HER2 decrease with paclitaxel treatment.
Epidermal Growth Factor Receptor Inhibitors
There are various approaches to block the EGFR (Table 113-1). Anti-EGFR monoclonal antibodies bind extracellularly to the ligand-binding domain of the EGFR and prevent binding of endogenous ligands (e.g., EGF and TGF- ). As described by Baselga and Mendelsohn (1994), as well as by Modjtahedi (1993) and Prewett (1996a) and their co-workers, extracellular blockade prevents receptor dimerization and autophosphorylation from occurring and thus inhibits signal transduction. Specific antibodies have been described by Baselga (2001) and Fry (1999) for HER1 (IMC-C225) and HER2 (trastuzumab). Small molecular inhibitors
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or tyrosine kinase inhibitors (e.g., ZD-1839, OSI-774, CI-1033) act intracellularly on the cytoplasmic domain of the EGFR. To date, specificity of the tyrosine kinase inhibitors for the EGFR pathways has been variable, and Modjtahedi and associates (1998) have reported that high concentrations may be needed to inhibit the EGFR pathway. Toxin conjugates, comprising both ligand and immunoconjugates, bind extracellularly to the EGFR. In this way, as pointed out by Azemar (2000) and Chandler (1998), and their associates as well as by Schmidt and Weis (1996), toxic and lethal compound is delivered to the cell after internalization of the ligand toxin conjugate, resulting in cell death. Finally, antisense oligonucleotides prevent the translation of messenger RNA (mRNA) into the protein. Antisense therapy is in the very early stages of clinical study by such groups as He (1998), Moroni (1992), and Rubin Grandis (1997) and their coinvestigators.
Table 113-1. Mechanism of Action and Examples of Epidermal Growth Factor Receptor (EGFR) Inhibition | ||||||||||||
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Trastuzumab
Trastuzumab, an anti-HER2 humanized monoclonal antibody, has been successfully targeted to growth factor in solid tumors by Hirte and collaborators (1999). A mouse anti-HER2 monoclonal antibody was humanized by the aforementioned authors (1999), in order to avoid the inhibitory effects anti-mouse migG antibodies would have on a nonhumanized mouse monoclonal antibody when used as treatment in humans. Trastuzumab binds selectively and with high affinity to the extracellular domain of HER2, according to the studies of Salmon and associates (1989). Upon binding with the receptor, the trastuzumab receptor complex is internalized, which interferes with phosphorylation and downstream signal transduction. This alteration in cell signaling alters multiple phenotypes, including cellular proliferation of tumors that overexpress HER2 and reverses of resistance to traditional cytotoxic agents that appear related to upregulation of HER2, as discussed by Colnaghi (1991) and Nicholson (2000) as well as by Dion (1999), LoBuglio (1989), and Sliwkowski (1999) and their co-workers. Petit and associates (1997) report that trastuzumab may have an antiangiogenic effect with reduction of vascular endothelial growth factor (VEGF) production; it may also act by inducing antibody-dependent cell-mediated cytotoxicity (ADCC), as suggested by Sliwkowski and colleagues (1999). ADCC is triggered when antibody-coated (opsonized) target cancer cells interact with Fc receptors present on effector cells. In vitro data suggest that trastuzumab-dependent ADCC occurs mainly through interactions with CD16 found primarily on natural killer cells, some monocytes, and activated T cells, as pointed out by the aforementioned authors (1999).
Trastuzumab (Herceptin) was first approved for the treatment of patients with metastatic breast cancer who relapsed on a previous course of chemotherapy and whose tumors overexpress HER2. Baselga (1996) and Cobleigh (1999) and their co-workers reported that results with trastuzumab have been encouraging, with response rates ranging from 11.6% to 15% in women with HER2-overexpressing refractory breast cancer. When added to first-line chemotherapy in women with metastatic breast disease, response rates of 45% were obtained in the combined treatment group, compared with 29% in the chemotherapy group alone (p < 0.001), as recorded by Pegram and Slamon (1999) and Slamon and associates (2001). Used in a phase III breast cancer study, trastuzumab, in combination with chemotherapy, was shown by Slamon and colleagues (2001) to improve survival. The statistically significant lower rate of death at 1 year, longer survival, and 20% reduction in risk for death have inspired current clinical efforts to evaluate trastuzumab for the treatment of other cancers, including NSCLC.
Trastuzumab was recently evaluated by Langer (2001) and Krug (2001) and their coinvestigators for use in NSCLC. In a phase II trial, trastuzumab plus either docetaxel or paclitaxel was given to patients with previously untreated advanced NSCLC, of whom 23% had grade 2 or 3+ HER2-expressing tumor. The overall response rate to combination therapy reported by Krug and colleagues (2001) was 26%. Early analysis of another phase II trial by Langer and associates (2001) in patients with HER2-positive advanced NSCLC who were treated with trastuzumab plus paclitaxel and carboplatin demonstrated that toxicity was no different or worse with combination therapy than with cytotoxic treatment alone. At 6 months, 18% of evaluable patients responded; 34% remained on treatment, and 64% were still alive. Projected median survival was 9.2
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months.Another phase II trial is ongoing to establish the efficacy of the combination of trastuzumab with cisplatin and gemcitabine in HER2-overexpressing patients with untreated, advanced NSCLC. Despite the few HER2-positive patients (17% with enzyme-linked immunosorbent assay 15 ng/mL, of whom 46% had immunohistochemistry 1+), preliminary results reported by Zinner and coinvestigators (2001) are encouraging (partial response 50%, stable disease 42%, progressive disease 8%), with some patients (33%) still receiving the combination of trastuzumab and chemotherapy. Additionally, there is a multinational two-arm randomized phase II study by Zinner and associates (2000), with one treatment arm consisting of cisplatin and gemcitabine plus trastuzumab and the other, the control arm, consisting of cisplatin and gemcitabine alone. This study has completed accrual, and the results will soon be available. Further evaluation is required to determine the effect of trastuzumab on survival and progression in NSCLC.
IMC-C225
IMC-C225 is a human:murine chimeric antiEGFR immunoglobulin G1 (IgG1) monoclonal antibody described by Ennis and colleagues (1989) that competes with EGF for binding to the EGFR and inhibits EGF-induced tyrosine kinase dependent phosphorylation. One of us (RSH) and co-workers (2001a) noted that the antitumor efficacy of IMC-C225 results from multiple mechanisms that include inhibition of cell cycle progression, promotion of apoptosis, antiangiogenesis, and potential enhancement of immunologic activity (ADCC) (Fig. 113-2). Further, O-Charoenrat and associates (2000) suggested that IMC-C225 may reduce metastasis formation by downregulating the expression of matrix metalloproteinases.
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Fig. 113-2. Proposed mechanisms of action of IMC-C225. Antitumor efficacy of IMC-C225 results from multiple mechanisms that include inhibition of cell cycle progression, promotion of apoptosis, antiangiogenesis, and potential enhancement of immunologic activity (ADCC). |
IMC-C225 has been evaluated by Baselga (2000a) and Shin (2001) and their collaborators for various solid tumors in clinical trials. Initial phase I studies of IMC-C225 have been evaluated in combination therapy with cisplatin for refractory squamous cell carcinoma of the head and neck, and have demonstrated promising biologic activity. A small phase I dose-escalation study of IMC-C225 plus cisplatin was conducted in 12 patients with recurrent or metastatic EGFR-positive head and neck squamous cell carcinoma. In nine evaluable patients, Shin and associates (2003) recorded that there were one mixed, three partial, and one complete response. Adverse effects attributed to IMC-C225 included allergic reactions and an acne-like rash that was limited to grades 2 and 3 in severity. The rash resolved completely after cessation of therapy within 4 to 6 weeks. Other adverse effects included fatigue, peripheral neuropathy, and orthostatic hypotension and were most likely related to cisplatin. Based on these promising results, phase II and III studies have been initiated, as reviewed by one of us (MSK) and Harari (2002), and are ongoing in patients with metastatic, recurrent, or locoregionally advanced head and neck cancer and in patients with metastatic or recurrent colorectal cancer refractory to irinotecan. Recently, in vitro effects of IMC-C225 were evaluated in NSCLC cell lines, with high, moderate, and low EGFR expression alone and in combination with radiation and chemotherapy [cisplatin, paclitaxel (Taxol), and vinorelbine (Navelbine)]. IMC-C225 alone inhibits growth in high EGFR-expressing NSCLC cells. IMC-C225, in combination with radiation therapy or chemotherapy, inhibits growth in high and moderate EGFR-expressing cells. Currently, IMC-C225 is
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being evaluated in human lung cancer xenografts. If data remain promising, clinical trials for IMC-C225 in NSCLC should be considered.
Preclinical studies evaluating the addition of IMC-C225 to cisplatin by Fan (1993) and Prewett (1996b) and their coinvestigators, doxorubicin by Prewett (1996a, 1996b), Baselga (1993) and Goldstein (1995) and associates, 5-fluorouracil (5-FU) by Overholser and colleagues (2000), gemcitabine by Bruns and associates (2000), paclitaxel by Wen and co-workers (2000), and topotecan by Ciardiello and collaborators (1999) have demonstrated significant inhibition of tumor cell growth, enhanced cytotoxic effect, and tumor regression in various human cancer xenografts. Harari and Huang (2001) and Huang and colleagues (1999) report that, similarly, IMC-C225 plus radiation treatment of human epidermoid cancer xenografts increased tumor radiosensitivity, radiation-induced apoptosis, inhibition of angiogenesis, and, ultimately, tumor regression and increased survival.
IMC-C225 has been administered alone and in combination with chemotherapy and radiation therapy in more than 750 patients. Overall, IMC-C225 is well tolerated and is not associated with serious toxicity, as noted by Cohen and associates (2000). In a review of clinical studies using IMC-C225 therapy as monotherapy, the latter authors (2000) found that most adverse events were mild to moderate; only 12% were considered to be grade 3 or 4 in severity. Allergic reactions and acnelike rashes were the most clinically important adverse events. Of the 89 patients evaluated, 8 (4%) had grade 3 or 4 allergic reactions; all patients, however, recovered without sequelae after empiric therapy (i.e., antihistamine, corticosteroids). Skin reactions appear to be a common toxicity among other EGFR inhibitors; there is even some suggestion, as noted by Saltz and colleagues (2003), that the intensity of the rash might correlate with survival. In contrast to the small molecules (e.g., tyrosine kinase inhibitors), monoclonal antibodies against EGFR are not likely to produce clinically significant diarrhea because of their inability to cross into the lumen of the gastrointestinal tract and intravenous administration.
EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS
Extracellular blockade prevents ligand binding to EGFR and thereby inhibits receptor autophosphorylation and signal transduction according to Mendelsohn and Baselga (2003). In addition to extracellular inhibition of signal transduction, intracellular inhibition of tyrosine kinase is also a target for novel cancer therapies. Increased tyrosine kinase activity, as noted by Mendelsohn and Baselga (2003) as well as by Noonberg and Benz (2000), is a primary marker for neoplastic cells. Overexpression of mutated tyrosine kinases may increase tyrosine kinase activity and transform normal cells into neoplastic ones. Use of specific tyrosine kinase inhibitors can reverse the neoplastic transformation. Some have even suggested there might be an enhanced effect by a dual inhibition of the intracellular and extracellular receptors by using the drugs together.
Recent work has led to the discovery of quinazoline inhibitors (e.g., ZD-1839, OSI-774, CI1033) and other tyrosine kinase inhibitors with promising preclinical activity: pyrazolo- or pyrrolo-pyridopyrimidines (e.g., PKI 166), and dianilinophthalimides (e.g., CGP 54211, CGP 53353). One of the earlier quinazolines evaluated was PD-153035, a brominated quinazoline with potent inhibition of EGF-mediated mitogenesis and cell proliferation in vitro, but less activity in vivo, as shown by the investigations of Bos (1997) and Fry (1994) and their colleagues. Molecular modeling studies have helped to redesign PD-153035 into a number of compounds, including two analogues: PD-168393 and PD-160678. These molecules in vivo demonstrate prolonged tyrosine kinase inhibition and tumor stasis activity according to Fry and associates (1998). Another compound extensively studied is PD-158780. This molecule has in vitro and in vivo activity against human MCF-7 breast cancer and A431 cell lines, but Ciardiello and colleagues (2001) have recorded that it lacks selectivity for EGFR and has poor solubility; PD-165557 was subsequently developed by Klohs and co-workers (1997) with improved solubility. Among the EGFR-tyrosine kinase inhibitors, several have entered clinical testing for NSCLC: ZD-1839, CI-1033, and OSI-774.
ZD-1839 is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks signal transduction pathways involved in the proliferation and survival of neoplastic cells. In A431 squamous carcinoma cells, Woodburn and associates (2000) reported that ZD-1839 specifically inhibited autophosphorylation of EGFR tyrosine kinase, and had little effect on other tyrosine kinases. Mendelsohn and Baselga (2003) found that ZD-1839 has a dose-dependent effect on apoptosis, growth inhibition, reduced cell line proliferation, and inhibition of growth factors [TGF- , basic fibroblast growth factor (bFGF), VEGF] in cell lines derived from various tumors (i.e., colon, breast, ovarian, and gastric).
Based on the encouraging preclinical data, phase I clinical studies (n = 54) by Baselga (2000b), Ferry (2000), Goss (2000), Kris (2000), and Uejima (2000) and their coinvestigators were initiated in patients with various tumors, including 99 patients NSCLC patients from the United States, Europe, and Japan. Antitumor activity has been observed in NSCLC: of the 99 patients with NSCLC, 8 patients who were treated had a partial response ranging between 1 and 16 months, and two patients had major regression of nonmeasurable disease as reported by Kris (2000) and Uejima (2000) and their colleagues. Further, approximately one third of patients had stable disease that lasted 3 or 4 months, including 4 patients who had stable disease lasting more than 1 year. Preliminary data from Kris and associates (2000) also indicate an improvement or no change in disease-related symptoms in 20 patients who had a response. Final results from the Japanese study by Negoro and colleagues (2001) were recently presented. All 23 patients with
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NSCLC were previously treated with cytotoxic therapy (up to four regimens); these included 16 who received platinum-based regimens. Five patients had partial responses (ranging between 1 and more than 11 months), and one patient had stable disease for more than 3 months. This study showed that ZD-1839 has clinical activity, even in patients who received previous chemotherapy. A phase II randomized trial of ZD-1839 as second- or third-line monotherapy for patients with advanced NSCLC has been recently published by Fukuoka and coinvestigators (2003). Two hundred ten patients have been enrolled in this trial, and 208 were evaluable for responses. The response rate was 18.7%, and the disease control rate was 52.9%; median progression-free survival was 84 days, with 34% of patients progression free after 4 months. A dose of 250 mg/day of ZD-1839 has been shown by Baselga and associates (2001) to be as active as the higher dose (500 mg/day), with a lower frequency of adverse events; no correlation was seen between the incidence of rash or diarrhea and responses. A second U.S.-based study (IDEAL2) was conducted on third-line or higher lung cancer patients who had failed cisplatin or docetaxel treatment. In this study, 12% of the patients responded at the 250-mg dose and 9% at the 500-mg dose, which again was slightly more toxic. Symptom improvement in approximately 40% of patients was observed in both groups according to Kris and colleagues (2003). Based on these data, Iressa was approved.
A pilot study of ZD-1839 plus carboplatin and paclitaxel by Miller and co-workers (2003) in 25 patients with chemo-na ve stage IIIB and IV NSCLC was performed to evaluate the safety and pharmacokinetics of ZD-1839. In part 1 of the study (dose escalating), intermittent ZD-1839 (250 or 500 mg) was combined with carboplatin and paclitaxel; in part 2, the safest dose of ZD-1839 determined in part 1 (500 mg) was given continuously with carboplatin and paclitaxel. In part 1, no dose-limiting toxicities were observed with the 250 mg dose; however, at 500 mg, a grade 3 rash was observed in one patient. No new, increased, or cumulative toxicities have been observed; further, no significant pharmacokinetic drug interactions have been observed, although there was a slightly reduced clearance of Iressa in patients receiving chemotherapy, likely secondary to effects on hepatic metabolism. The combination of ZD-1839 and carboplatin and paclitaxel or gemcitabine and cisplatin was subsequently evaluated for survival benefits in two large phase III placebo-controlled studies in chemo-na ve patients with NSCLC. Unfortunately, both these studies, as reported by one of us (RSH) (2004) and Giaccone (2004) and our respective colleagues, failed to reach their primary end point showing no benefit to adding Iressa to chemotherapy. Reasons for this failure are still unclear but include a lack of patient selection and potential antagonism between anti-EGFR therapy and chemotherapy (denote the positive preclinical models). Further, two phase two trials are ongoing to evaluate the effects of ZD-1839 monotherapy on objective response rate and improvement in disease-related symptoms in chemoresistant patients with advanced NSCLC.
CI-1033 is an orally active quinazoline tyrosine kinase inhibitor. Preclinical studies by Garrison and co-workers (2001) have shown that it is a potent inhibitor of EGFR (IC50 = 1.7 nM) and heregulin-induced (IC50 = 9 nM) tyrosine phosphorylation. In vitro, CI-1033 also was shown by Erlichman and associates (2001) to enhance cytotoxicity of topoisomerase inhibitors in transfected cells encoding breast cancer-resistant proteins. Recently, preliminary results were presented from a phase I clinical study by Shin and colleagues (2001) evaluating the use of CI-1033 in 37 patients with solid tumors, of whom 15 had NSCLC. When biomarkers were measured, cellular proliferation (i.e., Ki-67) was downregulated, and the cell cycle inhibitor protein (p27) was increased. Among all 37 patients to date, there was 1 patient (squamous cell carcinoma) with a partial response and 10 patients with stable disease (at 12 weeks). Further, most common adverse events, including acneiform rash, emesis, and diarrhea, were grade 1 and 2 in severity.
OSI-774 is another oral quinazoline with potent activity against EGFR autophosphorylation and cell proliferation in human tumor cell lines that has been studied by Moyer and co-workers (1997). In a phase II study, OSI-774 was evaluated by Bonomi and associates (2000) in patients with advanced NSCLC (IIIB, IV) who have EGFR-expressing tumors that failed or developed progressive disease with platinum-based therapy. Of 56 patients evaluable for tumor response, 1 had a complete response, 7 had a partial response, and 15 had stable disease. The response rate was 14.3%, with a median survival of 257 days. Further, treatment appeared to be well tolerated, as noted by Perez-Soler and colleagues (2001); an acneiform rash was the most common adverse event, occurring in half of the patients. Although the results are promising, larger studies are required to confirm the possible survival benefit. Additionally, surrogate marker studies would be informative to analyze receptor phosphorylation or downstream markers for inactivation. Nonetheless, this study confirms that EGFR is a good target for novel biologic therapies against NSCLC.
ANTIANGIOGENESIS INHIBITORS
Folkman (1989), as well as Hori (1991) and Kim (1993) and their associates, have noted that angiogenesis, or formation of new blood vessels from preexisting vessels, is necessary for the growth and development of solid tumors (>1 to 2 mm3) and metastases. Angiogenesis is a multistep process: endothelial cells, which line the lumen of the blood vessels, first degrade the basement membrane, migrate through to form a sprout, and then proliferate to extend the new vessel. Liotta (1995) stated that tumor metastasis involves five main steps: (a) angiogenesis, (b) adhesion to endothelial cell basement membrane, (c) proteolytic destruction of the basement membrane, (d) migration to secondary sites, and (e) proliferation at the secondary sites.
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Tumor angiogenesis was found by Chodak and associates (1980) to be associated with increased incidence of metastases, worsening prognosis, and reduced survival in NSCLC. The increased frequency of metastases with adenocarcinoma may be attributed to the higher microvessel density as noted by Sikora and colleagues (1997) than in other forms of NSCLC (e.g., squamous cell carcinoma).
Angiogenesis is stimulated by various angiogenic growth factors, including VEGF and bFGF. However, tumors also stimulate endogenous inhibitors of angiogenesis, described by Chen and co-workers (1995). Some of these were: (a) angiostatin, as reported by O'Reilly and associates (1994); (b) endostatin, also reported by O'Reilly and colleagues (1997); and (c) thrombospondin, which was identified by Good and co-workers (1990). The angiogenic process is determined by the net balance of angiogenic inducer activity over angiogenic inhibitor activity.
Multiple trials are ongoing. Both angiostatin and endostatin have been evaluated in preclinical models of lung carcinoma, but clinical studies in NSCLC have not been initiated. TNP-470, a synthetic compound based on fumagillin, a naturally occurring antifungal agent with potent antiangiogenic activity, has demonstrated clinical activity in various solid tumors, including NSCLC, by the studies of Baidas (2000a) and one of us (RSH) (2000) and respective associates. VEGF monoclonal antibodies (i.e., rhuMAb) and VEGF tyrosine kinase inhibitors (SU5416, SU6668, ZD6474) are also compounds being evaluated extensively for antiangiogenic potential, and are under study in NSCLC (i.e., RhuMAb VEGF, SU5416).
Endostatin
As noted by O'Reilly and associates (1997), endostatin is a 20-kd C-terminal fragment of collagen XVIII produced by hemangioendotheliomas. Endostatin completely suppresses tumor angiogenesis by blocking the development of blood vessel supply to tumors, according to the investigations of O'Reilly and co-workers (1997). Boehm and coinvestigators (1997) showed that treatment with endostatin was effective against three types of neoplastic tumors in mice, without the need for continuous repeated therapy. Furthermore, O'Reilly and associates (1997) have reported that endostatin-treated animals showed regression of primary tumors to microscopic dimensions. Further, immunohistologic data indicate blocked angiogenesis accompanied by a high rate of proliferation balanced by a high rate of apoptosis. There was no evidence of toxicity in these animal studies. It is possible that the effectiveness of endostatin is dependent on the tissue of origin. One of us (RSH) and colleagues (2001b) demonstrated, in a phase I trial, that endostatin is safe, behaves with linear and reproducible pharmacokinetic parameters, and has some limited antitumor efficacy. Further studies exploring administration of endostatin in different schedules or in combination with chemotherapy are in progress by one of us (RSH) and colleagues (2001b), as well as by Fogler (2001), Thomas (2001), and Eder (2001) and their associates.
TNP-470
TNP-470 is a synthetic form of the naturally occurring antiangiogenic compound fumagillin. Originally, this was an antifungal agent believed to have potent angiogenic activity by Ingber and colleagues (1990). TNP-470 is a potent inhibitor of endothelial cell migration, endothelial cell proliferation, and capillary tube formation, as noted by Brem (1991), Ingber (1990), and Parangi (1996) and their co-workers, respectively.
Preclinical trials have been conducted in animal models, as noted by Mysliwski (1998), Ohta (1997), and Singh (1997) and their respective associates. TNP-470 reduced the rate of development and metastasis of human tumor xenografts in rats according to the study of Mysliwski and colleagues (1998). The activity of TNP-470 on tumors and metastases appears to be dose related. Dose-related antitumor effects were observed on HT-1080 cells at the primary site and reduced lymph node metastases in nude athymic mice by Ohta and associates (1997). Further, Singh and co-workers (1997) showed that TNP-470 inhibited in vitro growth of three human cell lines and four murine cell lines in a dose-dependent manner and also reduced in vivo tumor growth and metastatic spread.
In preclinical combination studies by one of us (RSH) and colleagues (1998), TNP-470 plus paclitaxel and carboplatin reduced tumor growth and metastasis of NSCLC breast cancer in mice. In animals with Lewis lung carcinoma, TNP-470 in combination with minocycline increased the responsiveness of primary tumors and lung metastases to cytotoxic agents. Parangi (1996) and Teicher (1996) and their associates, as well as Kakeji and Teicher (1997), suggested that the most effective combination was TNP-70, minocycline, and cyclophosphamide. In a phase I clinical trial conducted by Kudelka and co-workers (1997), 3 of 18 patients with inoperable cervical cancer had some benefit. One patient had complete recovery; two patients with progressive disease became stable. The antiangiogenic effects of TNP-470 appear to work synergistically with existing cytotoxic agents.
In another phase I study of TNP-470 with paclitaxel compared with paclitaxel alone in 32 patients with solid tumors (including NSCLC), carried out by one of us (RSH) and associates (2000), the combination appeared safe, with myelosuppression and peripheral neuropathy similar in both treatment groups. Further, 15 of the evaluable patients had NSCLC. Of these patients, 5 (33%) had partial responses; 2 of these patients had previously received one course of chemotherapy. None of the 5 patients who received prior taxane therapy responded. The median survival for patients was more than 14 months. The combination of
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TNP-470 appeared well tolerated and demonstrated encouraging activity. The safety of this combination has been confirmed in another phase I study in patients with advanced tumors by Baidas and colleagues (2000a). However, another phase I study by Tran and co-workers (2001) demonstrated that the combination of TNP-470 with paclitaxel and carboplatin in solid tumors might warrant dosage adjustments in the carboplatin dosage to decrease toxicity. Further evaluation of this interaction is needed.
VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS
VEGF is an important endothelial cell specific mitogen involved in tumor neovascularization. Ferrera (1993) recorded that VEGF has two identified receptors: (a) Flt-1 (fms-like tyrosine kinase-1), and (b) Flk-1/KDR (fetal liver kinase-1/kinase domain region). Both receptors for VEGF are upregulated on tumor vasculature as well as in other actively developing tissues and in wound healing. Further, Takahashi and associates (1996) have reported that the expression of VEGF and its Flk-1/KDR receptor was found in the intestinal form of gastric cancer and correlated with metastases to the liver. VEGF and its receptors were found by Warren and colleagues (1995) in the blood vessels of human colorectal tumors implanted in mice. The VEGF receptor Flk-1/KDR has been demonstrated by Millauer and associates (1996) in other mammary, ovarian, lung, and glioma tissues, indicating roles for VEGF in these forms of cancer and in the identification of this receptor as a potential target.
VASCULAR ENDOTHELIAL GROWTH FACTOR MONOCLONAL ANTIBODIES
Antibodies to VEGF were shown by the investigations of Kim and co-workers (1993) to inhibit the growth of subcutaneous human xenografts in the nude mouse. Further, Warren and colleagues (1995) reported that antibodies to VEGF reduced human tumor growth and hepatic metastases in a dose- and time-dependent manner and reduced the number of VEGF receptors in mice. A humanized version of the murine antibody (mu MAb) to VEGF has been developed by Presta and coinvestigators (1997) that inhibits endothelial cell proliferation in vitro and in vivo and that reduces tumor growth in vivo.
Early clinical studies, such as that of Margolin and associates (1999) of recombinant humanized monoclonal antibody to VEGF (rhuMAb VEGF, Genentech, San Francisco, CA), produced undetectable serum concentrations of VEGF. In a subsequent phase Ib trial, Margolin and co-workers (2001) reported that no pharmacologic interactions were observed between rhuMAb VEGF and cytotoxic agents, including doxorubicin, carboplatin and paclitaxel, or 5-fluorouracil (5-FU) and leucovorin (LV). Notable toxicities possibly related to drug were diarrhea (with 5-FU), thrombocytopenia (with carboplatin and paclitaxel), and leukopenia.
In a phase II study by DeVore and colleagues (2000), rhuMAb VEGF (7.5 or 15 mg/kg) was evaluated in combination with carboplatin and paclitaxel compared with control (carboplatin and paclitaxel) in 99 patients with stage IIIB or IV NSCLC. Response rates with the antibody were about 10% higher, and the time-to-tumor progression was prolonged by about 3 months (4.5 to 7.5 months) in the high-dose antibody group. However, a development warranting concern was that 6 patients developed severe hemoptysis (four episodes were fatal). In an evaluation of potential risk factors, it was found that squamous histology and rhuMAb treatment were the only factors associated with hemoptysis. After much deliberation, this drug entered phase III studies in NSCLC in patients with nonsquamous cell histology. Recent findings by Johnson and coinvestigators (2001) suggest that the addition of rhuMAb to carboplatin and paclitaxel may prolong survival in patients with nonsquamous NSCLC without excess toxicity of deaths. Objective response rates (32% vs. 12%) and time to progression (30 vs. 17 weeks) were higher in patients in the rhuMAb arms compared with control in this randomized phase II trial. However, given the small number of patients enrolled, no meaningful comparison of efficacy end points can be made in this study. The Eastern Cooperative Oncology Group (2001) is currently evaluating the effect of adding 15 mg/kg rhuMAb to carboplatin and paclitaxel therapy in patients with advanced nonsquamous NSCLC.
Clinical trials with another recombinant humanized monoclonal antibody, HuMV833, are under way. Jayson and colleagues (2001) presented preliminary results of a phase I dose-finding study of anti-VEGF antibody HuMV833. Preliminary safety data suggest that HuMV833 is well tolerated, with no attributable grade 3 toxicities. Further, plasma concentrations of HuMV833 can serve as a surrogate marker for intratumor concentrations. Additional studies of this agent in various tumors are anticipated.
Monoclonal antibodies also have been developed against the extracellular domain of the VEGF receptor. For example, DC101 (Imclone Systems, New York, NY) is a rat antimouse Flk-1 that competitively blocks VEGF binding that inhibits growth of human ovarian, epidermoid, pancreatic, renal, and glioblastoma tumor xenografts. According to Inoue (2000) and Klement (2000) and their associates, this is associated with decreased tumor microvessel density (MVD), increased tumor cell apoptosis with decreased proliferation, and extensive tumor necrosis. The chimeric antihuman VEGF receptor antibody, IMC-1C11, is currently being evaluated in a phase I study.
Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors
Inhibition of VEGF activity, as recorded by Mendel (2000), Rosen (1998), and Vajkoczy (2000) and their colleagues, can
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also occur through inhibition of the VEGF receptor tyrosine kinase by small molecule compounds. SU5416 (Sugen/Pharmacia), a VEGF receptor tyrosine kinase inhibitor, has shown in vitro activity against VEGF-stimulated proliferation of human endothelial cells; further, in vivo, the agent inhibited the growth and metastasis of lung, colon, breast, and prostate cancers as well as melanoma and sarcoma xenografts. Other agents are in development because they did not meet their pharmacokinetic targets.
In a phase I dose-ranging trial conducted by Cropp and Hannah (2000), SU5416 (4.4 to 190 mg/m2) was administered intravenously twice weekly to 63 patients with various malignancies. Dose-limiting toxicities, including headache, nausea, and projectile vomiting, occurred at the highest dosage but were reversible within 48 hours. A phase Ib and IIa trial of SU5416 showed an improvement in disease-related symptoms in patients with acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma. SU5416 also has been evaluated in combination with cytotoxic agents. Twenty-eight patients with untreated metastatic colorectal cancer received SU5416 intravenously at either 85 mg/m2 or 145 mg/m2 twice weekly with 5-FU/LV on either the Roswell Park or Mayo Clinic regimen. Rosen and co-workers (2001) recorded that toxicities experienced were common to 5-FU and LV therapy. Six patients had objective tumor responses, whereas 9 patients experienced stable disease. In an ongoing randomized phase III trial, SU5416 is being evaluated with CPT11 in patients with advanced colorectal cancer.
SU6668 (Sugen/Pharmacia) competitively inhibits several angiogenic receptor tyrosine kinases: Flk-1/KDR, PDGFR, and FGFR. Further, SU6668 inhibits the growth of various human tumor xenografts in athymic mice. Laird and associates (2000) noted the most marked inhibitory effect to be on the A431 human epidermoid tumor. In a phase I study, SU6668 induced high levels of apoptosis in tumor microvessels within 6 hours of a single dose and significantly reduced tumor microvessel density by 24 hours. However, similar significant results were not observed as quickly in other tumor xenografts, Colo205 and SF767T. The delay in response may be partially explained by greater sensitivity of A431 vasculature to SU6668. Phase I experience in the study of Rosen and colleagues (2001) in 68 patients with various advanced tumors demonstrated that SU6668 is well tolerated at a wide range of dose levels (100 to 2,400 mg/m2/day), and only mild to moderate side effects occurred, including nausea, diarrhea, fatigue, and dyspnea. Stable disease for greater than 4 weeks was observed in 31 of 51 patients, and 1 patient with a desmoid tumor had maintained stable disease for more than 5 months. Data show minor decline in tumor markers and softening of palpable tumors in several patients. However, like SU5416, the drug is also no longer in clinical development because of a failure to achieve adequate pharmacology with toxicity observed at levels below the primary active dose. Ongoing studies are being conducted to identify patients most likely to respond to SU6668 therapy and to find markers of response.
ZD6474 (AstraZeneca) is an oral VEGFR-2 TKI shown preclinically to inhibit the growth of prostate xenografts and to induce regressions. Further, tumor growth resumed with cessation of ZD6474; conversely, tumor regression could be reinduced upon reintroduction of ZD6474. In an ongoing phase I dose-escalation study by Basser and co-workers (2001), 41 patients with various solid tumors to date have been treated with ZD6474. Reported drug-related toxicity has been minimal, with only two National Cancer Institute (NCI) grade 1 (facial flushing, facial rash) and one NCI grade 2 (fatigue) events, thus far. No grade 3 or 4 toxicities have been reported. Stable disease has been reported in two patients (gastrointestinal stromal tumor, melanoma) after 56 days of treatment. Patient accrual is ongoing. Studies are currently ongoing looking at this drug with Taxotere in second-line NSCLC and with carboplatin and paclitaxel in the first-line setting.
Other Antiangiogenesis Inhibitors
Neovastat (<AE>-941), an aqueous extract derived from shark cartilage that has anti-VEGF and metalloproteinase inhibitory activity, exhibits antitumor and antimetastatic activity in human tumor xenografts. Although it has antiangiogenic properties, the fact that it is an extract from shark with no single activity that can be measured in serum makes it alternative medicine. In two phase I and II safety trials discussed by Francois and associates (2001), Neovastat was evaluated as monotherapy or in combination with chemotherapy in 331 patients with various solid tumors; 124 of these patients had lung cancer. The most frequent adverse events were nausea (7%), vomiting (3%), dyspepsia (2%), and anorexia (2%). Exploratory data analysis in a subgroup of 48 patients with unresectable NSCLC demonstrated an increase in survival time (6.15 versus 4.63 months, p = 0.026) and a decrease in risk for death of about 50% (p = 0.02) in patients receiving more than 2.63 mL/kg per day. A phase II trial of <AE>-941 in addition to combined modality treatment (computed tomography and radiation therapy) under investigation in locally advanced stage IIIB NSCLC is ongoing. Phase III randomized, double-blind trials are also under way at the NCI (2001).
LY317615 is an inhibitor of protein kinase and VEGF-stimulated angiogenesis by inhibiting protein kinase C- (PKC- ). Antitumor activity has been demonstrated with this compound in the Lewis lung carcinoma model in mice. When given with chemotherapy, LY317615 augments tumor growth delay with concomitant paclitaxel, gemcitabine, and carboplatin by 5-fold, 2-fold, and 1.7-fold, respectively. This compound appears to be a promising antiangiogenesis drug and is currently in phase I human studies.
Thalidomide, after having been withdrawn from the market for almost three decades because of to its teratogenic profile, was recently (1998) approved by the U.S. Food and Drug Administration (FDA) for the treatment of erythema
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nodosum leprosum, and its current and potential clinical application have been discussed by Calabrese and Fleischer (2000). The antiangiogenic effects of thalidomide were first documented by D'Amato and colleagues (1994), who demonstrated its inhibitory effects on bFGF-induced corneal neovascularization in a rabbit model. Thalidomide is now being evaluated in the Protocol Ids: E-5398 in various hematologic and solid malignancies, including NSCLC. However, thus far, the results in solid tumors have been disappointing, as documented by Baidas (2000b) and Tseng (2001) and their colleagues.
Curran and Murray (1999) identified matrix metalloproteinases (MMPs) to be a family of enzymes important in tumor invasion and metastases. This family of zinc-dependent endopeptidases was reported by Ellerbroek and Stack (1999) as well as by Nelson and associates (2000) to be responsible for degrading most of the major components of the extracellular matrix, allowing for escape of cells from the primary tumor and metastasizing or migrating to other areas of the body. Expression of MMP1, MMP2, and MMP9, according to Pritchard and co-workers (2001), are among the more common subtypes in NSCLC. Kodate and associates (1997) pointed out that MMP1- or MMP9-expressing tumors are associated with a poorer prognosis than MMP-negative tumors. Most MMP inhibitors target MMP2 and MMP9; more broad-spectrum ones target MMP1, MMP2, and MMP9 (i.e., BMS-275392). Marimastat and BMS-275291 are MMP inhibitors currently being evaluated for NSCLC. Of the two, marimastat is further along in development, with ongoing studies also initiated in other tumors (pancreas, small cell lung, breast) in the investigations of Bramhall (2001), Shepherd (2002), and Wolff (2001) and their co-workers, respectively.
Phase III trials of Prinomastat (AG3340) and BAY12 9566, used alone or in combination with chemotherapy in advanced solid tumors (e.g., lung, prostate, pancreas, brain), have not shown clinical benefit. In advanced NSCLC, preliminary results of a phase III trial reported by Smylie and colleagues (2001) showed that the association between cisplatin and paclitaxel was not enhanced by the addition of Prinomastat (AG3340) in terms of progression-free survival and response rate. The inability of these MMP inhibitors to hinder metastatic disease progression may have been anticipated because MMPs are thought to be important in early disease progression (local invasion and micrometastases) and less important once metastases are present, as noted by Zucker and associates (2000). Effective strategies for use of these agents have not yet become apparent.
GENE THERAPIES
Human gene therapy can be defined as the treatment of any condition through the transfer of genetic material. Although initially targeted at treating inherited disease, in which one gene is defective, most of the current gene therapy trials target acquired diseases, primarily cancer. Strategies of gene therapy to treat cancer may involve the replacement of defective tumor suppressor genes, the introduction of suicide genes, or genetic immunopotentiation. Most of the agents employed to carry out these strategies are currently under phase I investigation. The most widely used system for gene delivery is through the replacement of defective genes using modified viruses (adenoviruses and retroviruses).
Replacement of Tumor Suppressor Genes
The p53 gene has tumor suppressant activity that is mutated in many types of cancer, as discussed by Hollstein (1991) and Levine (1991) and their co-workers. Mutations of p53 were found in 39 of 58 tumor cell lines at the NCI, as recorded in the publication of O'Connor and associates (1997), and these cell lines were resistant to radiation therapy (inability to arrest G1 following irradiation) and most cytotoxic therapy, with the exception of antimitotic agents (e.g., paclitaxel, vincristine). Mutations of p53 have been associated with an increase in angiogenesis; conversely, the introduction of wild-type (normal) p53 is associated with antiangiogenesis. In a study conducted by Van Meir and colleagues (1994), introduction of wild-type p53 gene into glioblastoma cells, a highly neovascularized neoplasm associated with well-documented p53 mutations, induced the secretion of antiangiogenic factors. Further, restoration of wild-type p53 inhibits neovascularization in vivo, as noted in the aforementioned study. In patients with bladder cancer, the occurrence of wild-type p53 gene was also found, in the investigations of Grossfeld and co-workers (1997), to correlate with the expression of thrombospondin 1 (TSP), another naturally occurring antiangiogenic factor. Furthermore, in this study, TSP expression, in turn, was positively correlated with patient survival and inversely correlated with MVD and tumor recurrence.
Loss or mutation of p53, a tumor suppressor gene, is a very common genetic abnormality in NSCLC patients and has been reported by Carbone and Minna (1992) and by Nemunaitis and associates (2000) to occur in as many as 90% of patients with advanced NSCLC. Abnormalities in p53 may result in genetic instability favoring an accumulation of mutations, alterations in the apoptotic and proliferation processes, and reduced sensitivity to radiation therapy and chemotherapy. Phase 1 studies conducted by Nguyen (1996), Roth (1996), Nemunaitis (2000), and Albelda (2000) and their colleagues of adenovirus- or retrovirus-mediated reintroduction of wild-type p53 into lung cancer cells with deleted or mutant p53 have demonstrated an increased apoptosis and sensitivity to chemotherapy. In the seminal p53-based gene therapy study conducted by Roth and colleagues (1996), nine patients with NSCLC were given a direct intratumoral injection of wild-type p53; tumors were excised at biopsy before and after gene therapy. In six of seven evaluable patents, an increase in apoptosis was
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observed, as measured by the TUNEL assay. Objective responses were detected in four of seven patients. A bystander effect also was observed, whereby cells transduced with p53 had an effect on the nontransduced cells.
Nemunaitis and associates (2000) have suggested that when used in combination with chemotherapy in NSCLC patients, introduction of wild-type p53 adenovirus increased apoptotic cells and improved chemosensitivity. Recently, however, Schuler and co-workers (2001), in a phase II trial of adenovirus-mediated wild-type p53 (SCH 58500) transfer in patients receiving chemotherapy for NSCLC, reported no difference in response rate of lesions in patients treated with p53 gene therapy compared with those receiving chemotherapy alone (52% versus 48%). Use of wild-type p53 gene therapy does not appear to have additional benefit in patients receiving first-line chemotherapy.
However, when used in combination with radiation therapy (60 Gy) in 19 patients with NSCLC who were not candidates for surgery or chemoradiation therapy, intratumoral delivery of adenoviral p53 (RPR/INGN 201) resulted in DNA transduction and induction of proapoptotic and p53-regulated genes. Further, Swisher and co-workers (2001) reported that 12 of 15 evaluable patients underwent biopsies that demonstrated absence of tumor at 3 months. Adverse effects most frequently encountered were fever, which was transient or self-limiting, and pain at the injection site.
Replacement of other tumor suppressor genes (e.g., Rb) and introduction of combination of tumor suppressor genes (e.g., p16INK4 and wild-type p53) also have been shown by Lukas (1995) and Xu (1996) and their associates to exhibit an apoptotic tumor-regressing effect and, in the case of combination therapy, a synergistic one. Despite these data, gene therapy use is still limited because it must be delivered to the local tumor site (i.e., injection at specific tumor site), and most patients with NSCLC have distant metastases that are often difficult to access with local injection. Systemic strategies are under development with a phase I trial underway at the M. D. Anderson Cancer Center. In this project, patients with advanced NCSLC receive adenoviral p53 in a Chol-Fus 1 liposomal complex administered intravenously (C. Lu, personal communication, 2003).
Suicide Gene Therapy
Suicide gene therapy has been discussed by Roth and Cristiano (1997) and by Singhal and Kaiser (1998) and is an approach whereby there is a delivery of a gene encoding an enzyme that catalyses the conversion of a normally nontoxic prodrug administered systemically into a toxic substance. An example is the herpes simplex virus thymidine kinase (HSV-tk) gene. The enzyme HSV-tk converts the normally nontoxic nucleoside analogue ganciclovir into a toxic compound. Studies in glioma models also demonstrated what appears to be a bystander effect. Currently, a phase 1 trial of adenoviral vector delivery of HSV-tk followed by intravenous ganciclovir is under way in NSCLC patients.
Genetic Immunopotentiation
Genetic immunopotentiation, as noted by Albelda (1997), involves the following immunology-based gene therapy strategies: (a) stimulation of T-cell activity through the introduction of cytokine genes into tumor cells; (b) transduction of tumor cells with genes that either augment class I major histocompatibility complex presentation or provide costimulatory signals to enhance T-cell proliferation; or (c) active vaccination with tumor-specific genes. Phase I trials of immunopotentiation therapies in NSCLC have met with discordant results. Preliminary results of interleukin-2 gene (rAd-IL2) therapy show no dose-limiting toxicities; however, no antitumor effects were observed in the phase I study reported by Escudier and co-workers (2001). Vaccination with lethally irradiated autologous NSCLC cells engineered by gene transfer to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF) (GVAX) appears to be well tolerated and may enhance antitumor immunity according to the study of Salgia and colleagues (2000). Nemunaitis and associates (2001) showed in preliminary results of a multicenter phase I and II trial that GM-CSF gene-modified NSCLC vaccines (GVAX) is feasible and immunologic, and clinical antitumor activity has been demonstrated in subjects with advanced NSCLC.
Antisense Gene Therapy
Antisense oligodeoxynucleotides target a complementary mRNA sequence and, by doing so, are incorporated and hinder oncogene transcription, translation, and expression. Several oligonucleotides have been evaluated in NSCLC, including those that target H-Ras, c-raf-1, or PKC oncogenes.
ISIS 2503 is a 20-mer phosphorothioate antisense oligodeoxynucleotide that selectively reduces the expression of H-Ras mRNA. A recent phase II trial reported by Dang and coinvestigators (2001) evaluated the use of ISIS 2503 in 24 patients with advanced NSCLC (stages IIIB or IV) who were given ISIS 2503 (6 mg/kg per day). Patients were evaluated for response or progression after six cycles. Seven of 20 evaluable patients (39%) had stable disease; 13 progressed within the first three cycles. Two patients maintained stable disease for six cycles, and 1 had stable disease for nine cycles. Most common toxicities included grade 1 to 2 chills (10 patients), grade 1 to 2 fever (9 patients), and thrombocytopenia (8 patients). The authors concluded that ISIS 2503 is well tolerated and may have an effect on delaying disease progression in some patients with NSCLC. Further studies are ongoing.
ISIS 3521, an antisense inhibitor of PKC- (an important enzyme involved in signal transduction), has been evaluated in a phase I and II trial by Yuen and associates (2001) with carboplatin and paclitaxel in the treatment of 53 patients
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with advanced NSCLC. In the initial dose-ranging phase, no dose-limiting toxicities were observed at the highest dose (ISIS 3521, 2.0 mg/kg per day) when used with carboplatin and paclitaxel. In the expanded phase, patients received the combination therapy for an average of four cycles. Median overall survival was 15.9 months, and median time to progression was 6.6 months. Commonly experienced toxicities included neutropenia grade 3 to 4 (30 patients) and thrombocytopenia grade 3 to 4 (13 patients). Among the 48 evaluable patients, 42% had a partial or complete response, and only 17% progressed while receiving treatment. A phase III study is being conducted to evaluate the addition of ISIS 3521 on survival in NSCLC compared with chemotherapy (carboplatin and paclitaxel) alone and unfortunately did not show any prolongation of survival, as noted by Lynch and associates (2003).
Novel Approaches to Delivery of Gene Therapies
Administration of gene therapy is challenging. In addition to the approaches discussed, potential therapies, as suggested by Wickham and colleagues (1997a), include the oral or buccal administration of bispecific antibodies that bind to both alpha(v) integrin and viral vectors, leading to enhanced gene transfection of endothelial cells involved in angiogenesis. Clark and Brugge (1995) have noted that alpha(v) integrin is a cell surface receptor involved in mediating cell adhesion to, and migration on, the extracellular matrix; it appears to play an important role in tumor growth and metastasis. Alpha(v) integrins, as pointed by Koukoulis and colleagues (1997), are common in squamous cell carcinoma, adenocarcinoma, and large cell carcinoma of the lung. Ideally situated, the acinar and ductal cells of salivary glands also express alpha(v) integrin, as demonstrated by Delporte and co-workers (1997), making them excellent candidates for adenoviral transfection through buccal administration for delivering gene therapy. Modifying the fiber coat of the viral vector by incorporating the RGD sequence (a high-affinity peptide ligand), the binding region of alpha(v) improves transfection, as shown by McDonald (1999) and Wickham (1997b) and their associates. Further, use of cationic-charged liposomes, as noted by Qiu and coinvestigators (1998), can increase gene transfection of cells that do not express alpha(v) integrin and may be effective, according to Smythe and colleagues (1997), for NSCLC that does not express alpha(v) integrin.
THE RAS FAMILY
Farnesyl Transferase Inhibitors
Prendergast and Oliff (2000) have shown that farnesyl transferase inhibitors (FTIs) block the conversion of the biologically inactive rasp21 protooncogene (referred to as ras) located in the cytoplasm to the active form attached to the inner surface of the plasma cell membrane. There are three types of ras in human cells: the H-ras, K-ras, and N-ras. Among these, mutations in K-ras are the most common in human malignancies. Ras mutations occur in about 30% of NSCLC cases, as described by Zachos and Spandidos (1997), particularly in adenocarcinomas.
Ras Function
Ras is a key intermediate protein, as noted by Boguski and McCormick (1993) and Lowy and Willumsen (1993), that belongs to an extended family of guanosine triphosphatases (GTPases) involved in regulating signal transduction pathways between upstream receptor tyrosine kinases and downstream protein kinases. Downstream cellular effects of ras-mediated pathways are multiple on growth, differentiation, apoptosis, cytoskeletal organization, and membrane trafficking. Mutations in ras genes produce oncogenic cellular transformation and spontaneous formation of cancer in animals and are associated with malignant tumor status, as noted by Sinn (1987), Mangues (1990), and Chin (1999) and their associates as well as by Shirasawa (1993).
Ras Structure and Metabolism
Rowinsky and colleagues (1999) have recorded that ras is composed of 188 or 189 amino acids with high-sequence homology: the first 86 amino acids are homologous, the next 78 have 79% homology, and the last 25 amino acids are variable. The carboxyl terminus has a particular sequence, referred to as the CA1A2X box, whereby C is a cysteine residue, A1 and A2 are aliphatic amino acids (e.g., valine, leucine, or isoleucine), and X is either serine or methionine.
Ras proteins undergo a number of enzymatic modifications at the CA1A2X box to become active, as noted by Boguski and McCormick (1993). Prenylation, a lipid modification of the cysteine residue occurring through protein farnesyl transferase (FTase) or geranylgeranyltransferases (GGTase I and II) is the first critical step. This is followed by proteolytic cleavage and methylesterification of the isoprenylated cysteine residue. Of these reactions, farnesylation is critical; the other two are nonessential. GGTase appears critical if farnesyl transferase is inhibited; the route of prenylation (FTase or GGTase) appears to be dictated by the CA1A2X sequence on the target protein according to the investigations of Lerner (1997) and Whyte (1997) and their co-workers. Because farnesylation is integral for ras activity, the inhibition of such a reaction is a novel strategy in developing anticancer agents.
Farnesyl transferase inhibitors (FTIs) that have been identified by Rowinsky and colleagues (1999) include farnesyl diphosphate (FDP) analogues that compete with the substrate FDP for FTase, CA1A2X peptidomimetics that
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compete with the CA1A2X portion for ras or FTase, or a hybrid of the two (FDP analogues plus peptidomimetics). These inhibitors were initially identified by in vitro screening of random libraries and natural products.
Preclinical Studies with Farnesyl Transferase Inhibitors
In vitro studies by Sun and associates (1999) demonstrate a dose-dependent effect of FTIs on farnesylation of ras cells in H-ras tumor cells. However, these agents are less effective against K-ras mutations, a more common ras mutation in human cancers. Sepp-Lorenzino and colleagues (1995) showed that in addition to inhibiting K-ras, FTase inhibition also inhibited mutant p53 and wild-type ras. Similarly, L-739,749 demonstrated activity against xenografts, with mutations in K-ras and p53. These results indicate that FTase inhibition may have other effects in addition to those on ras mutations. Several ongoing studies are being conducted to evaluate this effect.
In vivo testing of FTIs (L-744832 and SCH-66336) by Prendergast and Oliff (2000) and Rowinsky and associates (1999) showed a dramatic regression of tumors in mice. Moreover, other FTIs (R115777, POH) tested by Lerner and co-workers (1997) were found to inhibit colon tumor angiogenesis and to delay tumor onset. Interestingly, FTIs appear to act on a variety of tumor types, including NSCLC.
Clinical Studies with Farnesyl Transferase Inhibitors
These in vitro and in vivo findings led to clinical trials with FTI. To date, at least six agents have been evaluated in phase I clinical trials: R115777; L-778,123; L-744,832; BMS-214662; SCH66336; and FTI-277. Hurwitz and associates (2000) have pointed out that the accumulation of unfarnesylated prelamin A in buccal mucosa cells serves, as a dose-dependent surrogate marker for FTI. One of us (MSK) and colleagues (2002) demonstrated inhibition of tumor farnesylation in head and neck cancer patients treated preoperatively with SCH66336, for 1 to 2 weeks. Clinical phase I trials reported by Sebti and Hamilton (2000), as well as by Hurwitz (2000) and Piccart-Gebhardt (2001) and their colleagues, in various tumors show that FTIs (SCH66336; R115777; L-778,123) promote a reduction in solid tumors and have low toxicity in normal cells. Several patients with advanced NSCLC reported by Adjei (2000), Hahn (2000), Nakagawa (2001), and Kim (2001) and their associates responded to FTI therapy (1 PR in SCH66336; 1 PR in R115777; and 2 PR in 778,123). Nakagawa (2001) and Kim (2001) and their associates noted that dose-limiting toxicities with FTIs are generally mild and consist of fatigue, fever, anorexia, nausea and vomiting, diarrhea, and increased alkaline phosphatase. Moderate myelosuppression has been observed by Hurwitz and associates (2000) with other FTIs (e.g., SCH66336). Ophthalmologic effects (because several proteins involved in retinal signal transduction are farnesylated), such as visual defects, also have been reported in some phase I FTI trials (e.g., R115777) by Zujewski (2000) and Adjei (2000) and their colleagues.
Phase I and II trials are underway that combine FTIs with chemotherapy or radiation therapy. Preclinical studies by Bernhard (1998), Moasser (1998), Liu (1998), and Shi (2000) and their co-workers suggest that combination of FTIs with chemotherapy or radiation therapy may have synergistic effects on tumor growth inhibition. Further, combination with angiogenesis inhibitors may be useful because a number of angiogenic factors (e.g., VEGF, FGF) bind tyrosine kinase receptors that also use the ras pathway for signal transduction. FTIs appear to have great potential for use in NSCLC because of the frequency of ras mutations observed in NSCLC, the generally mild toxicity profile of FTIs, and the potential for additive effects with chemotherapy and radiation therapy.
NEW ISSUES FOR CANCER TRIALS
The development of new agents into useful therapies requires modifications in preclinical and clinical methods. High-throughput screening methods should be perfected to evaluate a large number of drug candidates quickly. However, it is not always possible to extrapolate data from in vitro to in vivo studies, or from animal models to human disease. For example, angiostatin in combination with radiation therapy reduced growth of four different tumor types without increasing toxicity in vitro but failed in vivo as reported by Mauceri and associates (1998). The converse has also occurred: trastuzumab was successful against human gastric carcinoma in a mouse xenograft in vivo but failed in vitro, as noted by Tokuda and colleagues (1996). These examples demonstrate some of the limitations of preclinical studies.
Molecular markers may serve as biologic surrogates of clinical outcome and may prove useful in monitoring a patient's progress as suggested by D'Amico (1999), Fehm (1998), Mehta (1998), Nemunaitis (1998), Kern (1994), and Krainer (1997) and heir colleagues. Graziano and co-workers (1998) noted that changes in expression of regulatory molecules may be more useful as an end point than maximum tolerable dose when determining dose schedules and may reduce toxic adverse effects.
Development of new cytotoxic drugs and the identification of new regulatory molecules will continue. On average, the research and development process takes 10 years. In other words, the search for new effective agents can take twice as long as the 5-year survival period typically used to establish a disease-free state.
CONCLUSION: A NEW PARADIGM FOR CANCER THERAPY
Lung cancer is the most common cause of cancer death in the United States. As reviewed in this chapter, a new paradigm
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shift is occurring with the development of therapies directed against specific biologic pathways involved in malignancies. These agents are developed against specific genes, receptors, and molecules involved in the development and maintenance of the malignant phenotype, and hence are expected to have a higher therapeutic index. Overall, these compounds appear to be less toxic than standard chemotherapy.
Combining these targeted compounds may have major implications in transforming a progressive disease to a chronic illness. Combining targeted molecules with traditional cytotoxic therapies may result in lower doses of the latter and, hence, reduced toxicity. This will of course necessitate better diagnostic and prognostic tests to identify critical targets for any given tumor. The validation of these diagnostic studies will be necessary for the success of this approach. Randomized studies are underway. It is anticipated that targeted therapies will play an important future role, along with cytotoxic and radiation therapy, in the management of lung cancer.
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