Targeted Therapy Using Novel Agents in the Treatment of Non—Small-Cell Lung Cancer

Targeted Therapy Using Novel Agents in the Treatment of Non–Small-Cell Lung Cancer Roy S. Herbst Abstract Patients with advanced non–small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti–epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cβ, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC. Clinical Lung Cancer, Vol. 3, Suppl. 1, S30-S38, 2002

Key words: ZD1839, Angiogenesis inhibitors, IMC-C225, Tyrosine kinase inhibitors, Protein kinase C, Matrix metalloproteinase inhibitors, VEGF inhibitors

Introduction

tained from controlled studies, with 6 first-generation substances classified as active compounds (vindesine, ifosfamide, cisplatin, carboplatin, etoposide, and mitomycin C), which could achieve remission rates between 13%-19%. Usually, the duration of remission was 2-4 months. In the past few years, numerous new, promising chemotherapeutic agents have greatly improved the outlook for the survival of patients with advanced-stage NSCLC. Prominent among these are the taxanes (paclitaxel and docetaxel), the topoisomerase I inhibitors (topotecan and irinotecan), vinorelbine, and gemcitabine.7-11 Most of these agents have been tested in lung cancer against best supportive care. Additionally, these agents have also been tested alone and in combination as first-line and second-line therapy in NSCLC.12-15 An overview of recent key randomized NSCLC trials is provided in Table 1.15-19 The use of newer agents with either cisplatin or carboplatin typically yields a median survival of 8-9 months and a 1-year survival rate of 33%-39%. Recently, the Eastern Cooperative Oncology Group (ECOG) conducted a large multicenter trial to determine which of the newer platinum-based regimens is most effective in treating advanced NSCLC.16 Over 1100 chemonaive patients were randomized to receive either the reference combination of cisplatin/paclitaxel or 1 of the 3 comparator arms: cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel. The median time to progression

Lung cancer currently represents a major cause of morbidity and mortality in developed countries.1 Its incidence is increasing at an alarming rate despite advances in therapy and attempts at prevention through smoking cessation programs, limited advertising, and restricted public smoking.2,3 Approximately 75% of primary lung malignancies are non–small-cell lung cancer (NSCLC), and the overall cure rate for lung cancer patients is only 14%. Treatment options and outcomes for patients with advanced unresectable NSCLC have been issues of controversial discussion. In the 1980s, multiple trials were conducted to evaluate the efficacy of platinum-based therapy versus best supportive care in NSCLC. The results demonstrated a definite survival advantage in favor of platinum therapy.4-6 Since then, most other agents have been tested in NSCLC in the clinical trial setting. In the early 1990s, chemotherapy was based on results obDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX Submitted: Oct. 15, 2001; Revised: Feb. 18, 2002; Accepted: Feb. 22, 2002 Address for correspondence: Roy S. Herbst, MD, PhD, Department of Thoracic/Head and Neck Medical Oncology, UT M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030-4095 Fax: 713-796-8655; e-mail: [email protected]

S30

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

Table 1

Recent Trials for the Treatment of Non–Small-Cell Non Small-Cell Lung Cancer Trial

No. of patients

Kelly et al15 (SWOG)

ORR

1-Year Survival

VC (control)

28%

8.0

36%

TCb

25%

8.0

38%

TC (control)

21%

7.8

31%

GC

22%

8.1

36%

TxC

17%

7.4

31%

TCb

17%

8.1

34%

VC (control)

30%

9.5

37%

GC

30%

9.8

37%

TC

32%

9.9

43%

TC (control)

31%

8.1

36%

GC

36%

8.8

33%

GT

27%

6.9

27%

TCb, arm I* (control)

34%

11.0

NA

TCb, arm II*

37%

7.0†

NA

TCb, arm III*

32%

8.4†

NA

408

Schiller et al16 (ECOG 1594)

Scagliotti et

Median Survival (Months)

Drugs

1155

al17

van Meerbeeck et

607

al18

480

(EORTC)

Belani et al19

403

*Arm I = paclitaxel 100 mg/m2, carboplatin AUC 6; arm II = paclitaxel 100 mg/m2, carboplatin AUC 2; arm III = paclitaxel 150 mg/m2, carboplatin AUC 2 †Significantly different from control Abbreviations: AUC = area under the curve; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organization for Research and Treatment of Cancer; GC = gemcitabine/cisplatin; GT = gemcitabine/paclitaxel; NA = not available; SWOG = Southwest Oncology Group; TC = paclitaxel/cisplatin; TCb = paclitaxel/carboplatin; TxC = docetaxel/cisplatin; VC = vinorelbine/cisplatin

was statistically improved with the cisplatin/gemcitabine combination (4.2 vs. 3.4 months, P = 0.002); however, the results showed no difference between the experimental arms versus the reference arm in survival or objective response rates. Another randomized phase III trial also compared the efficacy of 3 platinum-based regimens in previously untreated advanced NSCLC patients.20 Docetaxel 75 mg/m2 combined with cisplatin 75 mg/m2 every 21 days, or a combination of docetaxel 75 mg/m2 and carboplatin at an area under the curve (AUC) of 6 every 21 days, were compared with the control arm of vinorelbine 25 mg/m2/week combined with cisplatin 100 mg/m2 every 28 days. All 3 arms had comparable toxicity, but the response, median survival, and 1-year survival rates were all slightly improved in the cisplatin/docetaxel arm vs. cisplatin/vinorelbine. No difference was seen between the carboplatin/vinorelbine and the cisplatin/vinorelbine arm (see the European Cancer Conference presentations). Whether this slight superiority of cisplatin/ vinorelbine is clinically significant remains to be seen. Thus, as of today, there is no clear-cut regimen showing superior efficacy in the treatment of advanced NSCLC. There has been modest but real progress in the treatment of NSCLC in the past decade; however, the improvement seems to have reached a plateau. Typically, patients with advanced NSCLC will suffer relapse and eventually die from their disease. Thus, it is becoming clear that, unless alternate paradigms using

newer agents with different modes of action are pursued, any further significant therapeutic advantage may not be obtained.

Novel Targeted Therapies Given the rapid advances in the molecular and biological understanding of disease process, carcinogenesis, angiogenesis, and cell growth regulation, it appears logical that many new ideas have emerged for the treatment of cancer. More specifically, with the new understanding of cellular mechanisms and biologic pathways, agents that act on specific targets are being evaluated. A wide spectrum of specific therapies targeting the principal aberrant aspects of malignant cell proliferation and/or cell death are being tested for the treatment of cancer (Table 2). The main categories of novel therapeutics include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. While the conventional chemotherapeutic drugs are known as cytotoxic agents, these new compounds are classified as cytostatic agents because they were not thought to produce tumor response. Recently, however, some of these agents have demonstrated a low but definite single-agent response in some cancers.21,22 The prognosis and choice of therapy for patients with lung cancer is currently based on clinical staging and tumor type. However, the clinical behavior of the tumor cannot be predicted accurately based on this system. For example, even in patients

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

S31

Targeted Therapy in NSCLC Table 2

Biological Agents for Non–Small-Cell Non Small-Cell Lung Cancer

• Receptor-Targeted Therapy (Anti–Epidermal Growth Factor) Trastuzumab IMC-C225 OSI-774 ZD1839 • Signal Transduction/Cell-Cycle Inhibitors Farnesyl transferase inhibitors (SCH66336, R115777) Protein kinase C inhibitors (ISIS 3521) Flavopiridol Retinoids UCN-101 • Angiogenesis Inhibitors Fungal products (TNP-470, endostatin/angiostatin) Anti-VEGF (bevacizumab; LY317615) SU5416/SU6668 Interferon-α/β Marimastat ZD6474 • Gene Therapy Granulocyte macrophage colony-stimulating factor Wild-type p53 Antisense (C-myc, protein kinase C-α) • Vaccines Tumor cells Peptides Dendritic cells Viral vaccines Abbreviation: VEGF = vascular endothelial growth factor

with stage I resectable disease (the earliest possible stage), more than 40% will die within 5 years. Hence, there is an urgent need to uncover and validate new molecular markers to better identify tumor behavior and progression pattern in individual cases. In such a scenario, therapy with biologic agents specifically targeted against a particular tumor can be integrated with surgery, conventional chemotherapy, or radiation therapy at all stages of the disease (Figure 1).

Receptor-Targeted Therapy Human tumors express high levels of growth factors and their receptors. Among the best studied growth factor receptor systems has been the epidermal growth factor receptor (EGFR)

S32

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

family (also known as type I receptor tyrosine kinases or erbB tyrosine kinase receptors). There is increasing evidence that the EGFR is overexpressed in a wide variety of human cancers, including NSCLC.23,24 Furthermore, this occurrence has been associated with a more aggressive clinical behavior and a poor prognosis. Currently, several approaches to EGFR blockade are being explored.25 Those that have shown antitumor activity include anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors, EGFR ligand conjugates, anti-EGFR immunoconjugates, and antisense therapy.26,27 Monoclonal antibodies directed at EGFR inhibit the growth of EGFR-expressing cancer cells.28 The mechanism of action of these antibodies is suggested to comprise the inhibition of tyrosine kinase activity, cell-cycle progression, and angiogenesis; repair after chemotherapy and radiation; and increased apoptosis. Targeting HER2/neu. The EGFR family of receptors includes HER2/neu, or erbB-2, which is overexpressed in a significant subset of breast cancer patients. HER2/neu is also expressed in other epithelial malignancies, such as lung, prostate, and ovarian cancers.29 This receptor has been the target for a new rational therapeutic antibody, trastuzumab (Herceptin®, Genentech, Inc, South San Francisco, CA). Trastuzumab is a humanized version of the murine monoclonal antibody 4D5 that was recently approved for the treatment of advanced breast cancer that overexpresses the HER2/neu oncogene. In preclinical studies with tumor cell lines, trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents.30 Clinical trials in HER2-positive breast cancer patients have demonstrated that the combined use of targeted therapy with trastuzumab, in conjunction with cytotoxic chemotherapy, is associated with improved time to disease progression and overall survival,31 although clearly, the best results are seen in the most overexpressing patients. Clinical trials investigating combination chemotherapy with trastuzumab and a variety of chemotherapeutic agents are already in progress in lung cancer. A phase II study was launched by ECOG to evaluate the combination of carboplatin/paclitaxel/trastuzumab in patients with incurable advanced NSCLC with HER2/neu positivity.32 The results indicate that the combination regimen is feasible, with toxicity no worse than cytotoxic therapy alone, including cardiac toxicity. Trastuzumab was recently evaluated for use in NSCLC.32,33 In a phase II trial, trastuzumab plus either docetaxel or paclitaxel was given to patients with previously untreated advanced NSCLC in whom 23% had a 2+ or 3+ HER2-expressing tumor. The overall response rate to combination therapy was 26%.33 Early analysis of another phase II trial in patients with HER2positive advanced NSCLC who were treated with trastuzumab plus paclitaxel and carboplatin demonstrated that toxicity was no different with combination therapy than with cytotoxic treatment alone.32 At 6 months, 18% of evaluable patients responded, 34% remained on treatment, and 64% were still alive. Projected median survival was 9.2 months. Another phase II trial is ongoing to establish the efficacy of the combination of trastuzumab with cisplatin/gemcitabine in HER2-overexpressing patients with untreated, advanced NSCLC. In spite of the

Roy S. Herbst Figure 1

Potential Treatment Options for Non–Small-Cell Non Small-Cell Lung Cancer: Integration with Current Therapies

Premalignancy

Localized disease

Locally or regionally advanced disease

S (RT)

CT + RT

Biological Agents

Advanced/ metastatic disease

Maintenance Therapy

Abbreviations: CT = chemotherapy; RT = radiation therapy; S = surgery

few HER2-positive patients (17% with enzyme-linked immunosorbent assay ≥ 15 ng/mL, 46% of whom had immunohistochemistry ≥ 1+), preliminary results are encouraging (50% partial response, 42% stable disease, 8% progressive disease), with some patients (33%) still receiving the combination of trastuzumab and chemotherapy.34 Additionally, there is a multinational 2-arm randomized phase II study with one treatment arm of cisplatin and gemcitabine plus trastuzumab and a control arm consisting of cisplatin/gemcitabine alone. This study has completed accrual and the results will soon be available.35 Further evaluation is required to determine the effect of trastuzumab on survival and progression in NSCLC. Anti-EGFR Monoclonal Antibodies. Because HER2/neu overexpression is not as common in lung cancer as in breast cancer24,36 with 2+/3+ overexpression rates of only 10%, the practicality of this target in the treatment of NSCLC is still not clear. Larger phase II and phase III trials will be necessary for a better understanding of the role of trastuzumab in the treatment of patients with advanced NSCLC. IMC-C225 (cetuximab) is a human-murine chimeric monoclonal antibody directed against EGFR.37,38 It has shown impressive activity when combined with radiation by increasing the antitumor effect of radiation therapy.39 It is also active in combination with cytotoxic drugs in many tumor types and may play a role in reversing resistance to chemotherapy. IMCC225 has a synergistic effect with cisplatin in xenograft models and has also demonstrated enhanced activity against pancreatic cancer mouse xenografts in combination with gemcitabine. In a phase I trial, 52 patients with head and neck cancer or NSCLC were treated using IMC-C225 alone or in combination with cisplatin.40 IMC-C225 was well tolerated and showed pharmacologically significant activity in combination with cisplatin. Results from phase I and II trials involving more than 500 patients also showed quite encouraging activity.41-43 The results are particularly promising in advanced colon cancer patients treated with IMC-C225 plus irinotecan,41 in advanced head and neck cancer patients treated with IMC-C225 plus cis-

platin or radiation,42 and in advanced pancreatic cancer patients treated with IMC-C225 plus gemcitabine.43 It is notable that responses were seen in cisplatin-refractory patients whose tumors have rarely responded to any agent.44 Recently, the effects of IMC-C225 were investigated on several NSCLC cell lines with high, moderate, and low EGFR expression, with IMC-C225 administered alone, and combined with radiation and cytotoxic agents (cisplatin, paclitaxel) in vitro. IMC-C225 alone was found to inhibit growth on high EGFR-expressing NSCLC cells.45 Combinations of IMC-C225 with radiation or chemotherapy have shown synergy/additive effects in high/moderate EGFR-expressing NSCLC cells.46-49 Animal experiments with H157 xenografts have shown enhanced tumor growth inhibition with IMC-C225/radiation compared with radiation or IMC-C225 alone.50 If animal data remain promising, evaluation of IMC-C225 with radiation therapy and/or chemotherapy is warranted in clinical trials for NSCLC. At present, 3 phase II trials are in progress evaluating the activity of IMC-C225 in combination with carboplatin/gemcitabine or carboplatin/paclitaxel as front-line therapy, and with docetaxel as second-line therapy. Tyrosine Kinase Inhibitors. Because EGFR tyrosine kinase is the key component of the signaling pathway, the inhibition of its activity appears to be a rational approach in NSCLC treatment. OSI-774 is an EGFR tyrosine kinase inhibitor that is being assessed for antitumor properties. Preclinical studies with OSI-774 have revealed potent and selective inhibition of EGFR autophosphorylation and cell proliferation in vitro and in mouse xenograft models. Recently, in a phase II trial, OSI-774 was used in patients with advanced EGFR-expressing NSCLC.51 The results showed that OSI-774 as daily oral therapy is well tolerated. It has significant antitumor activity in patients with advanced NSCLC after failing platinum-based combination chemotherapy, with response rates > 10% in a second/third-line setting, and an astounding 1-year survival rate of 48% in the refractory setting. Two phase III studies are ongoing in stage IV NSCLC that compare standard chemotherapy with chemotherapy along with OSI-774. The two standard baseline chemotherapy regimens being tested in these studies are cisplatin/gemcitabine, or carboplatin with or without paclitaxel. ZD1839 (Iressa®, AstraZeneca Pharmaceuticals, LP, Somerville, NJ) is a novel, low molecular-weight inhibitor of tyrosine kinase. Preclinical studies in vitro have shown it to be a potent and selective inhibitor of EGFR tyrosine kinase52 at concentrations that do not affect other kinases tested. ZD1839 has also prevented autophosphorylation of EGFR in a number of tumor cell lines in culture. This results in dysregulated growth, differentiation, and delayed cell-cycle progression.53 Similar to trastuzumab, ZD1839 has demonstrated synergy with cytotoxic agents. Preliminary results of early clinical trials suggest that ZD1839 has promising antitumor activity in a variety of tumor types, particularly in NSCLC.21,22,54 In a phase I trial assessing the efficacy of ZD1839, durable tumor regressions were noted in patients with NSCLC who were heavily pretreated. Pooled data from various studies have also shown that treatment with

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

S33

Targeted Therapy in NSCLC ZD1839 leads to objective responses and improvement in disease-related symptoms in about 10% of patients. Approximately one third of NSCLC patients treated with ZD1839 have had stable disease for ≥ 3 months.21,22,55 ZD1839 is being evaluated in two multicenter, multinational, randomized, doubleblind, placebo-controlled phase III trials. More than 1000 chemonaive patients with advanced NSCLC will receive ZD1839 (250 mg or 500 mg oral daily) or placebo in combination with the standard treatments of gemcitabine/cisplatin or carboplatin/paclitaxel. The main objective is improvement in overall survival and, at present, the patient enrollment is complete. Two phase II trials are evaluating the effectiveness of ZD1839 as monotherapy in NSCLC patients whose disease has progressed despite having received 2 or 3 lines of chemotherapy.53 The primary endpoints are objective response rate and disease-related symptom improvement, while the third-line study also has quality-of-life improvement as a primary objective. The results of these trials will greatly enhance our understanding of the significance of ZD1839 in the treatment for NSCLC. The standard toxicities of EGFR inhibitors are quite mild. Dose-limiting toxicity for the oral drugs was a watery diarrhea at the highest doses.21,56 Skin rash is also a common toxic manifestation.

transplanted with a variety of human tumors, including breast, prostate, large-cell lung, and small-cell lung carcinomas, and melanomas. Additive effects of LY900003 were observed.62 Recently a phase I/II trial of LY900003 was conducted in NSCLC.63 Carboplatin and paclitaxel were administered at standard doses (carboplatin AUC = 6 and paclitaxel 175 mg/m2) along with LY900003 as a 2-week continuous infusion at 2 mg/kg/day. In the phase I portion of the study, 18 patients (12 with NSCLC) showed no dose-limiting toxicity at the dose levels given. There was no evidence of pharmacokinetic interactions between LY900003 and either carboplatin or paclitaxel. In the phase II portion of this study, 42% of the 48 patients with advanced NSCLC had partial or complete responses and only 17% progressed during treatment. The median survival was 15.9 months, time to progression was 6.6 months, and 1-year survival was 75%. A phase III study comparing carboplatin and paclitaxel with and without LY900003 is in progress. LY317615 is an inhibitor of the PKC-β. In cell culture and in the rat corneal micropocket assay, this compound was found to be a potent inhibitor of vascular endothelial growth factor (VEGF)-stimulated angiogenesis.64 This novel targeted agent is currently being evaluated in phase I human trials.

Angiogenesis Inhibitors Signal Transduction Inhibitors Farnesyl Transferase Inhibitors. Farnesyl transferase inhibitors interfere with posttranslational C-terminal modification of many essential proteins, including Ras, Rho, and most cellular G-proteins, and disrupt signal transduction pathways.57 Among such compounds, SCH66336 and R115777 have shown promising results in preclinical experiments, and these are now being tested for the treatment of NSCLC. In two phase I trials where SCH66336 was used in combination with paclitaxel or gemcitabine in patients with solid tumors, including 14 patients with NSCLC, results were encouraging.58 Enhancement of activity was seen when paclitaxel was used in combination with SCH66336, and disease stability was seen with the gemcitabine/ SCH66336 combination. Similarly, phase I trials using R115777 in combination with cytotoxic drugs have been carried out.57,59 Phase II studies using farnesyl transferase inhibitors will add credence to the use of such compounds in therapy. Protein Kinase C Inhibitors. Protein kinase C (PKC) is a group of isozymes that plays an important role in the signal transduction process.60 It is an attractive target in cancer therapy because it is overexpressed in a variety of cancers. Nonspecific inhibitors of PKC have demonstrated antitumor activity. Antisense oligonucleotides against PKC can inhibit mRNA, protein synthesis, and the growth of tumors in vitro and in vivo. LY900003 (formerly known as ISIS 3521) is a 20-mer phosphorothioate oligodeoxynucleotide directed against human PKC-α. LY900003 was found to inhibit the growth of 3 different human tumor cell lines grown in nude mice: bladder (T-24), human lung carcinoma (A549), and colon carcinoma (Colo 205).61 Studies combining LY900003 with the chemotherapeutic agents cisplatin, mitomycin-C, vinblastine, estramustine, and doxorubicin were performed in nude mice that had been

S34

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

Active angiogenesis is critical to the expansion of the majority of solid tumors. Most solid tumors increase in mass through the proliferation of both malignant and stromal cells, resulting in formation of increased tumor vasculature. Certain cellular agents and factors are known to enhance angiogenesis. Therefore, angiogenesis appears to be an attractive target to control and reverse tumor growth.65,66 Several inhibitors of angiogenesis have antitumorigenic properties and have been included in many clinical trials. Some such antiangiogenic agents used in clinical trials for NSCLC include interferons (interferon-α, polyethylene glycol-interferon), fungal products such as TNP470, and endostatin/angiostatin.59,67 TNP-470 is a synthetic analogue of fumagillin that has antiangiogenic activity. Preclinical studies have demonstrated additive/synergistic effects between TNP-470 and cytotoxic drugs. In a phase I study, TNP470 showed moderate toxicity and encouraging activity when administered in combination with paclitaxel.67 Matrix Metalloproteinase Inhibitors. Matrix metalloproteinase (MMP) inhibitors are yet another class of antiangiogenic agents that is being investigated for the control of tumor growth.68,69 MMPs are a family of proteolytic enzymes that are important in tumor progression, angiogenesis, and metastasis.70 This family of zinc-dependent endopeptidases is responsible for degrading most of the major components of the extracellular matrix, allowing for the escape of cells from the primary tumor and metastasizing/migrating to other areas of the body.71,72 A positive correlation has been shown between overexpression of MMPs and the development of metastases. Expression of MMP1, MMP2, and MMP9 are among the more common subtypes in NSCLC.73 MMP1- or MMP9-expressing tumors are associated with a poorer prognosis than MMP-negative tumors.74 Several MMP inhibitors, such as AG3340 (Prinomastat®,

Roy S. Herbst Agouron Pharmaceuticals, Inc, La Jolla, CA), marimastat, BMS-275291, and COL-3, are being tested in vivo and in vitro for potential use in the treatment of cancer. Most MMP inhibitors target MMP2 and MMP9; more broad-spectrum inhibitors target MMP1, MMP2, and MMP9 (ie, BMS-275392). Some of these have demonstrated antitumor activity as single agents and in combination with chemotherapy in preclinical murine models and solid tumors.75-79 Phase III trials of AG3340 and BAY12-9566, another MMP, used alone or in combination with chemotherapy in advanced solid tumors (eg, lung, prostate, pancreas, brain), were recently reported and have not shown any clinical benefit. Marimastat and BMS-275291 are currently being evaluated for NSCLC. Of the two, marimastat is further along in development, with ongoing studies also initiated in other tumors (small-cell lung, breast, pancreas).80-82 Preliminary results of a phase III study in advanced NSCLC showed that the association between cisplatin and paclitaxel was not enhanced by the addition of AG3340 in terms of progression-free survival and response rate. A recent phase III study investigated AG3340 in combination with paclitaxel and carboplatin in chemonaive patients with advanced NSCLC. The treatment was well tolerated and the efficacy was comparable in all arms, indicating no extra clinical benefit of adding AG3340.83 The inability of these MMP inhibitors to hinder metastatic disease progression might 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.84 It appears that these agents may not be as promising as once believed. Recombinant Human Endostatin. Recombinant human endostatin (rhE) induces epithelial cell apoptosis and tumor regression in preclinical models. In an ongoing study, rhE is being administered to patients with solid tumors to determine the biologically effective dose and to look for evidence of cell apoptosis. The initial results suggest that rhE is safe and exhibits antitumor activity.85-87 Angiostatin. Angiostatin, a potent inhibitor of angiogenesis, is known to induce endothelial cell apoptosis and tumor regression and suppresses metastatic spread in mice. The first phase I clinical trial assessing the safety and pharmacokinetics of recombinant human angiostatin (rhA) has already begun. Initial results have shown rhA to be safe, with no dose-limiting toxicity so far. Treated patients have experienced no hemorrhagic or thrombotic events.88 Vascular Endothelial Growth Factor Inhibitors. The combination of certain antiangiogenic agents with standard therapies appears to be synergistic.89 Vascular endothelial growth factor is one of the most frequently present angiogenic factors in cancer patients.65,90 In a randomized clinical trial of carboplatin and paclitaxel, with or without recombinant human monoclonal antibody to VEGF, patients treated with the VEGF antibody regimen showed increased time to progression compared to that of the cytotoxic combination.91 The combination of VEGF antibody with carboplatin and paclitaxel may also prolong survival in nonsquamous NSCLC.92 A major drawback of this therapy, however, is evidence of an increased incidence of hemorrhage,

which may limit the use of the effective doses of the antibody to VEGF. Inhibition of VEGF activity can also occur through inhibition of the VEGF-receptor tyrosine kinase by small-molecule compounds. SU5416 (Sugen, Inc, South San Francisco, CA; Pharmacia Corp, Peapack, NJ), a VEGF-receptor tyrosine kinase inhibitor, has shown in vitro activity against VEGF-stimulated proliferation of human endothelial cells. Additionally, in vivo, the agent inhibited the growth and metastasis of lung, colon, breast, and prostate cancers, as well as melanoma, glioma, and sarcoma xenografts.93-95 These agents are in early development; no clinical studies have formally evaluated their use in the treatment of NSCLC. In a phase I dose-ranging trial, SU5416 (4.4-190 mg/m2) was administered intravenously (I.V.) 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.96 A phase Ib/IIa trial of SU5416 showed an improvement in disease-related symptoms in patients with acquired immunodeficiency syndrome–associated Kaposi’s sarcoma. SU5416 also has been evaluated in combination with cytotoxic agents. Twenty-eight patients with untreated metastatic colorectal cancer received SU5416 at either 85 mg/m2 I.V. or 145 mg/m2 I.V. twice weekly with 5-fluorouracil (5-FU)/leucovorin (LV) on either the Roswell Park or Mayo Clinic regimen. Toxicities experienced were common to 5-FU/LV therapy. Six patients had objective tumor responses, whereas 9 patients experienced stable disease.97 In an ongoing randomized phase III trial, SU5416 is being evaluated with irinotecan in patients with advanced colorectal cancer. SU6668 (Sugen/Pharmacia) competitively inhibits several angiogenic receptor tyrosine kinases: Flk-1/KDR, platelet-derived growth factor receptor, and fibroblast growth factor receptor. Further, SU6668 inhibits the growth of various human tumor xenografts in athymic mice. The most marked inhibitory effect is on the A431 human epidermoid tumor.98 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, such as Colo-205 and SF767T. The delay in response may be partially explained by greater sensitivity of A431 vasculature to SU6668. Phase I experience in 68 patients with various advanced tumors demonstrated that SU6668 is well tolerated at a wide range of dose levels (100-2400 mg/m2/day), and only mild-to-moderate side effects, including nausea, diarrhea, fatigue, and dyspnea occurred.99 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 a minor decline in tumor markers and softening of palpable tumors in several patients. Ongoing studies are being conducted to identify patients most likely to respond to SU6668 therapy and to find markers of response. Antibodies to VEGF inhibited the growth of subcutaneous human xenografts in the nude mouse.100 Further, antibodies to

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

S35

Targeted Therapy in NSCLC Figure 2

Combinations of Chemotherapy and Biologic Therapy: A New Paradigm for the 21st Century Systemic Therapy

Local Therapy Surgery

Conclusion

Chemotherapy Chemotherapy + Biologic Therapy

Biologic Therapy

Radiation

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

The development of newer agents specifically targeting different aspects and processes of malignant cells offers a wide range of agents that has significantly contributed to the arsenal in the battle Brain against NSCLC. Inherent in the search for more effective biological agents is the need to identify additional targets and to determine whether the Liver target is important in NSCLC and whether screening for overexpression is necessary. To better judge Bone and choose which molecules to pursue, the mechanism of action of the biological agent should be better defined, and preclinical models and surrogate markers of activity should be identified for use in phase I trials. Maximization of the therapeutic effect will require a combination of agents aimed at biological pathways more specific for the tumor cells than normal cells and, therefore, potentially less toxic. Most of the novel biologic agents will be combined with existing cytotoxic drugs to enhance and focus their activity (Figure 2). Nearly all the available information on targeted therapy is derived from phase I and II studies. Larger phase III studies incorporating the latest generation of effective cytotoxic agents with the novel targeted therapies must be conducted before the benefit of these agents can be widely accepted. Biologic therapies represent a new paradigm for NSCLC, involving less toxic targeted therapy, combined with other treatment modalities such as chemotherapy, radiotherapy, or surgery. Once the activity of the drugs is confirmed, chemotherapy and biologic therapy will likely be combined. In the case of local therapy, surgery and/or radiation therapy can be administered. However, if local therapy is not possible, or if the disease recurs, the proposed new approach will be to combine chemotherapy with biologic agents. It is hoped that this synergistic regimen will kill tumor cells more effectively. Finally, any chemotherapeutic intervention should be followed by maintenance therapy with a biologic agent to maintain tumor dormancy and/or prevent metastasis to the brain, liver, and bone, among other sites. Because most cancer patients die from metastatic disease, it is this disease process that must be prevented.

Lungs Eradicate micrometastases

Signal transduction (new molecular target)

Angiogenic therapy (new cellular target)

VEGF reduced human tumor growth and hepatic metastases in a dose- and time-dependent manner and reduced the number of VEGF receptors in mice.101 A humanized version of the murine antibody (muMAb) to VEGF has been developed that inhibits endothelial cell proliferation in vitro and in vivo, and reduces tumor growth in vivo.102 Early clinical studies of recombinant humanized monoclonal antibody to VEGF (bevacizumab, Avastin, Genentech, Inc) produced undetectable serum concentrations of VEGF.103 In a subsequent phase Ib trial, no pharmacologic interactions were observed between bevacizumab and cytotoxic agents, including doxorubicin, carboplatin/paclitaxel, or 5-FU/LV. Notable toxicities possibly related to drug were diarrhea (with 5-FU), thrombocytopenia (with carboplatin and paclitaxel), and leukopenia.104 In a phase II study, bevacizumab (7.5 or 15 mg/kg) was evaluated in combination with carboplatin/paclitaxel compared to control (carboplatin/paclitaxel alone) in 99 patients with stage IIIB or IV NSCLC.91 Response rates with the antibody were approximately 10% higher, and the time to tumor progression was prolonged by approximately 3 months (4.5-7.5 months) in the high-dose antibody group. However, a development warranting concern was that 6 patients developed severe hemoptysis, 4 cases of which were fatal. In an evaluation of potential risk factors, it was found that squamous histology and bevacizumab treatment were the only factors associated with hemoptysis. After much deliberation, this drug entered phase III studies in NSCLC in patients with non–squamous cell histology. Recent subset reanalysis of these data suggest that the addition of bevacizumab to carboplatin/paclitaxel may prolong survival in patients with non–squamous cell NSCLC without excess toxicity-related deaths.92 Objective response rates (32% vs. 12%) and time to progression (30 weeks vs. 17 weeks) were higher in patients in the bevacizumab arm compared with control in the non–squamous cell patients from this randomized phase II trial. However, given the small number of patients enrolled, no meaningful comparison of efficacy endpoints can be made in this study. The Eastern Cooperative Oncology Group is currently evaluating the effect of adding 15 mg/kg bevacizumab to carboplatin/pa-

S36

clitaxel therapy in patients with advanced non– squamous cell NSCLC.105

References 001. Greenlee RT, Murray T, Bolden S, et al. Cancer statistics, 2000. CA Cancer J Clin 2000; 50:7-33. 002. Henderson BE, Ross RK, Pike MC. Toward the primary prevention of cancer. Science 1991; 254:1131-1138. 003. Cancer Facts and Figures, 2001. American Cancer Society. New York: 2001. 004. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer-report of a Canadian multicenter randomized trial. J Clin Oncol 1988; 6:633-641. 005. Ganz PA, Figlin RA, Haskell CM, et al. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer. Does chemotherapy make a difference? Cancer 1989; 63:1271-1278. 006. Cartei G, Cartei F, Cantone A, et al. Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer. J Natl Cancer Inst 1993; 85:794-800. 007. Johnson D. Treatment strategies for metastatic non–small-cell lung cancer. Clin Lung Cancer 1999; 1:34-41.

Roy S. Herbst 008. Roszkowski K, Pluzanska A, Krzakowski M, et al. A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC). Lung Cancer 2000; 27:145-157. 009. Ranson M, Davidson N, Nicolson M, et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000; 92:1074-1080. 010. Anderson H, Cottier B, Nicolson M, et al. Phase III study of gemcitabine (Gemzar) vs. best supportive care (BSC) in advanced non-small-cell lung cancer (NSCLC). Lung Cancer 1997; 18:9 (Abstract #24). 011. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 1999; 91:66-72. 012. Crino L, Mosconi AM, Scagliotti G, et al. Gemcitabine as second-line treatment for advanced non-small-cell lung cancer: A phase II trial. J Clin Oncol 1999; 17:20812085. 013. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18:2095-2103. 014. Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-smallcell lung cancer. J Clin Oncol 2000; 18:122-130. 015. Kelly K, Crowley J, Bunn PA, Jr., et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19:3210-3218. 016. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92-98. 017. Scagliotti G, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing thre platinum-based doublets in advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2001; 20:308a (Abstract #1287). 018. van Meerbeeck J, Smit E, Lianes P, et al. A EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20:308a (Abstract #1228). 019. Belani C, Barstis J, Perry M, et al. Phase II multicenter randomized trial of weekly paclitaxel (P) administered in combination with carboplatin (C) followed by maintenance vs. observation for patients (pts) with advanced & metastatic non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20:323a (Abstract #1287). 020. Rodriguez J, Pawel J, Pluzanska A, et al. A multicenter, randomized phase III study of docetaxel + cisplatin (DC) and docetaxel + carboplatin (DCB) vs. vinorelbine + cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 2001; 20:314a (Abstract #1252). 021. Baselga J, Herbst R, LoRusso P, et al. Continuous administration of AD1839 (Iressa), a novel oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in patients with five selected tumor types: evidence of activity and good tolerability. Proc Am Soc Clin Oncol 2000; 19:177a (Abstract #686). 022. Herbst R, Khuri FR, Fossella FV, et al. ZD1839 (IRESSATM) in non–small-cell lung cancer. Clin Lung Cancer 2001; 3:27-32. 023. Fontanini G, Vignati S, Bigini D, et al. Epidermal growth factor receptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer 1995; 31A:178-183. 024. Rusch V, Klimstra D, Venkatraman E, et al. Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clin Cancer Res 1997; 3:515-522. 025. Herbst RS, Kim ES, Harari PM. IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody, for treatment of head and neck cancer. Expert Opin Biol Ther 2001; 1:719-732. 026. Meric JB, Faivre S, Monnerat C, et al. Zd 1839 "Iressa". Bull Cancer 2000; 87:873876. 027. Nemunaitis J, Holmlund JT, Kraynak M, et al. Phase I evaluation of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C-alpha, in patients with advanced cancer. J Clin Oncol 1999; 17:3586-3595. 028. Mendelsohn J. The epidermal growth factor receptor as a target for cancer therapy. Endocr Relat Cancer 2001; 8:3-9. 029. Kumar R, Mandal M, Vadlamudi R. New insights into anti-HER-2 receptor monoclonal antibody research. Semin Oncol 2000; 27:84-100. 030. Pegram MD, Lopez A, Konecny G, et al. Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 2000; 27:21-25; 92-100. 031. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783-792. 032. Langer C, Adak S, Thor A, et al. Phase II Eastern Cooperative Oncology Group (ECOG) pilot study of paclitaxel (P), carboplatin (C), and trastuzumab (T) in HER2/neu (+) advanced non-small cell lung cancer (NSCLC): early analysis of E2598. Proc Am Soc Clin Oncol 2001; 20:315a (Abstract #1257). 033. Krug L, Miller V, Crapanzano J, et al. Randomized phase II trial of trastuzumab (Tras) plus either weekly docetaxel (Doc) or paclitaxel (Pac) in previously untreated advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20:333a (Abstract #1328). 034. Zinner R, Glisson B, Pisters K, et al. Cisplatin and gemcitabine combined with herceptin in patients (pts) with HER2 overexpressing, untreated, advanced, non-small-

035. 036. 037. 038. 039. 040. 041. 042.

043.

044.

045. 046. 047. 048. 049.

050. 051.

052.

053. 054.

055.

056. 057. 058. 059.

cell lung cancer (NSCLC); a phase II trial. Proc Am Soc Clin Oncol 2001; 20:328a (Abstract #1307). Zinner R, Kim J, Herbst R. Trastuzumab enters non-small cell lung cancer clinical trials. Her2 in Oncol 2000; 1:2-11. Fontanini G, Vignati S, Lucchi M, et al. Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression. Br J Cancer 1997; 75:1295-1301. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995; 1:1311-1318. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 19:6550-6565. Robert F, Ezekiel MP, Spencer SA, et al. Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 2001; 19:3234-3243. Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 2000; 18:904-914. Saltz L, Rubin M, Hochester H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT11) is active in CPT-11 refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 2001; 20:3a (Abstract #7). Hong W, Arquette M, Nabell L, et al. Efficacy and safety of the anti-epidermal growth factor antibody (EGFR) IMC-C225, in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 2001; 20:224a (Abstract #895). Abbruzzese J, Rosenberg A, Xiong Q, et al. Phase II study of anti-epidermal growth factor receptor (EGFR) antibody cetuximab (IMC-C225) incombination with gemcitabine in patients with advanced pancreatic cancer. Proc Am Soc Clin Oncol 2001; 20:130a (Abstract #518). Herbst R, Arquette M, Nabell L, et al. Efficacy and safety of the anti-epidermal growth factor antibody (EGFR) IMC-C225, in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy, 2001 AACR-NCI-EORTC International Conference, Miami Beach, FL, October 29-November 2, 2001. Mendelsohn J. Epidermal growth factor receptor inhibition by a monoclonal antibody as anticancer therapy. Clin Cancer Res 1997; 3:2703-2707. Fan Z, Baselga J, Masui H, et al. Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 1993; 53:4637-4642. Prewett M, Rockwell P, Rose C, et al. Anti-tumor and cell cycle responses in KB cells treated with a chimeric anti-EFGR monoclonal antibody in combination with cisplatin. Int J Oncol 1996; 9:217-224. Wen X, Li C, Wu Q-P, et al. Potentiation of antitumor activity of PG-TXL with antiEGFR monoclonal antibody C225 in MDA-MB-468 human breast cancer xenograft. Proc Am Soc Clin Oncol 2000; 41:323 (Abstract #2052). Prewett M, Rockwell P, Rose C, et al. Altered cell cycle distribution and cyclin-CDK protein expression in A431 epidermoid carcinoma cells treated with doxorubicin and a chimeric monoclonal antibody to the epidermal growth factor receptor. Molecular & Cellular Differentiation 1996; 4:167-186. Harari PM, Huang SM. Modulation of molecular targets to enhance radiation. Clin Cancer Res 2000; 6:323-325. Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced, EGFR-expressing, nonsmall cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20:310a (Abstract #1235). Barker AJ, Gibson KH, Grundy W, et al. Studies leading to the identification of ZD1839 (IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001; 11:1911-1914. Baselga J, Averbuch SD. ZD1839 ('Iressa') as an anticancer agent. Drugs 2000; 60 (Suppl 1):33-42. Miller V, Johnson D, Heelan R, et al. A pilot trial demonstrates the safety of ZD1839 ('Iressa'), an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI), in combination with carboplatin (C) and paclitaxel (P) in previously untreated advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20:326a (Abstract #1301). Kris M, Herbst R, Rischin D, et al. Objective regressions in non-small cell lung cancer patients treated in phase I trials of oral ZD1839 IRESSA: a selective tyrosine kinase inhibitor that blocks the epidermal growth factor receptor (EGFR). Lung Cancer 2000; 29 (suppl 1):71 (Abstract #230). Hidalgo M, Siu LL, Nemunaitis J, et al. Phase I and pharmacologic study of OSI774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001; 19:3267-3279. Patnik A, Eckhardt S, Itzbicka E, et al. A phase I and pharmacokinetic (PK) study of the farnesyltransferase inhibitor, R115777 in combination with gemcitabine (gem). Proc Am Soc Clin Oncol 2000; 19:2a (Abstract #5A). Khuri F, Glisson B, Meyers M, et al. Phase I study of farnesyl transferase inhibitor (FTI) SCH66336 with paclitaxel in solid tumors: dose finding, pharmacokinetics, efficacy/safety. Proc Am Soc Clin Oncol 2000; 19:205a (Abstract #799). Khuri FR, Herbst RS, Fossella FV. Emerging therapies in non-small-cell lung cancer. Ann Oncol 2001; 12:739-744.

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

S37

Targeted Therapy in NSCLC 060. Goekjian PG, Jirousek MR. Protein kinase C in the treatment of disease: signal transduction pathways, inhibitors, and agents in development. Curr Med Chem 1999; 6:877-903. 061. Dean N, McKay R, Miraglia L, et al. Inhibition of growth of human tumor cell lines in nude mice by an antisense of oligonucleotide inhibitor of protein kinase C-alpha expression. Cancer Res 1996; 56:3499-3507. 062. Geiger T, Muller M, Dean NM, et al. Antitumor activity of a PKC-alpha antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted into nude mice. Anticancer Drug Des 1998; 13:3545. 063. Yuen AR, Halsey J, Fisher GA, et al. Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer. Clin Cancer Res 1999; 5:3357-3363. 064. Teicher BA, Alvarez E, Menon K, et al. Antiangiogenic effects of a protein kinase Cbeta selective small molecule. Cancer Chemotherap Pharmacol 2002; 49:69-77. 065. Pluda JM. Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies. Semin Oncol 1997; 24:203-218. 066. Herbst RS, Fidler IJ. Angiogenesis and lung cancer: potential for therapy. Clin Cancer Res 2000; 6:4604-4606. 067. Herbst R, Tran H, Madden T, et al. Phase I study of the angiogenesis inhibitor TNP470 (T) in combination with paclitaxel (P) in patients with solid tumors. Proc Am Soc Clin Oncol 2000; 19:182a (Abstract #707). 068. Michael M, Babic B, Tsao M, et al. Prognostic significance of metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in patients with small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 1998; 17:563a (Abstract #2161). 069. Sahasrabudhe D, Kudrick F, Zotalis G, et al. Matrix metalloprotease-3 (MMP-3) expression as a prognostic factor in soft tissue sarcoma. Proc Am Soc Clin Oncol 2000; 19:553a (Abstract #2179). 070. Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 1999; 189:300-308. 071. Ellerbroek SM, Stack MS. Membrane associated matrix metalloproteinases in metastasis. Bioessays 1999; 21:940-949. 072. Nelson AR, Fingleton B, Rothenberg ML, et al. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 2000; 18:1135-1149. 073. Pritchard SC, Nicolson MC, Lloret C, et al. Expression of matrix metalloproteinases 1, 2, 9 and their tissue inhibitors in stage II non-small cell lung cancer: implications for MMP inhibition therapy. Oncol Rep 2001; 8:421-424. 074. Kodate M, Kasai T, Hashimoto H, et al. Expression of matrix metalloproteinase (gelatinase) in T1 adenocarcinoma of the lung. Pathol Int 1997; 47:461-469. 075. Gupta E, Huang M, Mao Y, et al. Pharmacokinetic (PK) evaluation of BMS-275291, a matrix metalloproteinase (MMP) inhibitor, in cancer patients. Proc Am Soc Clin Oncol 2001; 20:76a (Abstract #301). 076. Munoz-Mateu M, de'Grafenried L, Eckhardt S, et al. Pharmacodynamic studies of Col-3, a novel matrix metalloproteinase inhibitor, in patients with advanced cancer. Proc Am Soc Clin Oncol 2001; 20:76a (Abstract #302). 077. Carmichael J, Ledermann J, Woll R, et al. Phase IB study of concurrent administration of marimastat and gemcitabine in non-resectable pancreatic cancer. Proc Am Soc Clin Oncol 1998; 17:232a (Abstract #888). 078. Pithavala Y, Shalinsky D, Wilding G, et al. Comparison of preclinical efficacy and associated plasma concentrations of AG3340, a matrix metalloprotease (MMP) inhibitor, with plasma concentrations achieved clinically. Proc Am Soc Clin Oncol 1999; 18:223a (Abstract #860). 079. Collier M, Shepherd F, Ahmann F, et al. A novel approach to studying the efficacy of AG3340, a selective inhibitor of matrix metalloproteases (MMPs). Proc Am Soc Clin Oncol 1999; 18:482a (Abstract #1861). 080. Bramhall SR, Rosemurgy A, Brown PD, et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001; 19:3447-3455. 081. Shepherd F, Giaccone G, Debruyne C, et al. Randomized double-blind placebo-controlled trial of marimastat in patients with small cell lung cancer (SCLC) following response to first-line chemotherapy: a NCIC-CTG and EORTG Study, 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, 2001. 082. Wolff A, Krishnamurthi S, Sparano J, et al. A pharmacokinetic (PK) and pharmacodynamic study of doxorubicin and docetaxel combinations plus marimastat (AT/M) in metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 2001; 20:98a (Abstract #388). 083. Smylie M, Mercier R, Aboulafia D, et al. Phase III study of the matrix metalloprotease (MMP) inhibitor prinomastat in patients having advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20:307a (Abstract #1226).

S38

Clinical Lung Cancer Vol 3 • Suppl 1 March 2002

084. Zucker S, Cao J, Chen WT. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 2000; 19:6642-6650. 085. Herbst R, Tran H, Mullani N, et al. Phase I clinical trial of recombinant human endostain (rHE) in patients (pts) with solid tumors: pharmacokinetic (PK), safety and efficacy analysis using surrogate endpoints of tissue and radiologic response. Proc Am Soc Clin Oncol 2001; 20:3a (Abstract #9). 086. Eder J, Clark J, Supko J, et al. A phase I pharmacokinetic and pharmacodynamic trial of recombinant human endostain. Proc Am Soc Clin Oncol 2001; 20:70a (Abstract #275). 087. Thomas J, Schiller J, Lee F, et al. A phase I pharmacokinetic and pharmacodynamic study of recombinant human endostain. Proc Am Soc Clin Oncol 2001; 20:70a (Abstract #276). 088. DeMoraes E, Fogler W, Grant D, et al. Recombinant human angiostain (rhA): a phase I clinical trial assessing safety, pharmacokinetics (PK) and pharmacodynamics (PD). Proc Am Soc Clin Oncol 2001; 20:3a (Abstract #10). 089. Teicher BA. A systems approach to cancer therapy. (Antioncogenics + standard cytotoxics-->mechanism(s) of interaction). Cancer Metastasis Rev 1996; 15:247-272. 090. Ellis LM, Takahashi Y, Liu W, et al. Vascular endothelial growth factor in human colon cancer: biology and therapeutic implications. Oncologist 2000; 5 (suppl 1):1115. 091. DeVore R, Fehrenbacher L, Herbst R, et al. A randomized phase II trial comparing rhumab VEGF (recombinant humanized monoclonal antibody to vascular endothelial cell growth factor) plus carboplatin/paclitaxel (CP) to CP alone in patients with stage IIIB/IV NSCLC. Proc Am Soc Clin Oncol 2000; 19:485a (Abstract #1896). 092. Johnson D, DeVore R, Kabbinavar F, et al. Carboplatin (C) + paclitaxel (T) + rhuMab-VEGF (AVF) may prolong survival in advance non-squamous cell lung cancer. Proc Am Soc Clin Oncol 2001; 20:315a (Abstract #1256). 093. Mendel DB, Schreck RE, West DC, et al. The angiogenesis inhibitor SU5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin Cancer Res 2000; 6:4848-4858. 094. Rosen L, Kabbinavar F, Rosen P, et al. Phase I trial of SU5416, a novel angiogenesis inhibitor in patients with advanced malignancies. Proc Am Soc Clin Oncol 1998; 17:218a (Abstract #843). 095. Vajkoczy P, Thurnher A, Hirth KP, et al. Measuring VEGF-Flk-1 activity and consequences of VEGF-Flk-1 targeting in vivo using intravital microscopy: clinical applications. Oncologist 2000; 5 (suppl 1):16-19. 096. Cropp G, Hannah A. SU5416, a molecularly targeted novel anti-angiogenesis drug: clinical pharmacokinetics and safety review. Clin Cancer Res 2000; 6 (suppl 11):95 (Abstract #262). 097. Rosen P, Amado R, Hecht J, et al. A phase I/II study of SU5416 in combination with 5-FU/leucovorin in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2000; 19:3a (Abstract #5D). 098. Laird A, Carver J, Smith K, et al. SU6668, a broad spectrum angiogenesis inhibitor, induces apoptosis of microvessels in established A431 tumor xenografts, resulting in tumor destruction. Clin Cancer Res 2000; 6 (suppl 1):4152-4160. 099. Rosen L, Rosen P, Kabbinavar F, et al. Phase I experience with SU6668, a novel multiple receptor tyrosine kinase inhibitor in patients with advanced malignancies. Proc Am Soc Clin Oncol 2001; 20:97a (Abstract #383). 100. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362:841-844. 101. Warren RS, Yuan H, Matli MR, et al. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995; 95:1789-1797. 102. Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997; 57:4593-4599. 103. Margolin K, Gordon MS, Talpaz M, et al. Phase Ib trial of intravenous (i.v.) recombinant humanized monoclonal antibody (MAb) to vascular endothelial growth factor (rhuMAbVEGF) in combination with chemotherapy (ChRx) in patients (pts) with advanced cancer (CA): pharmacologic and longterm safety data. Proc Am Soc Clin Oncol 1999; 18:435a (Abstract #1678). 104. Margolin K, Gordon MS, Holmgren E, et al. Phase Ib trial of intravenous recombinant humanized monoclonal antibody to vascular endothelial growth factor in combination with chemotherapy in patients with advanced cancer: pharmacologic and long-term safety data. J Clin Oncol 2001; 19:851-856. 105. Phase II/III randomized study of paclitaxel and carboplatin with or without bevacizumab in patients with advanced, metastatic, or recurrent non-squamous cell nonsmall cell lung cancer. Protocol IDs: E-4599, CTSU. Vol. 2002. Available at: http://www.cancer.gov/search/clinical_trials.