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Primary and Secondary Prevention of Non–Small-Cell Lung Cancer: The SPORE Trials of Lung Cancer Prevention* Fadlo Raja Khuri Abstract The aims of chemoprevention in lung cancer are to prevent the appearance of disease (primary prevention) and to stop or reverse the progression of premalignant lesions (secondary prevention). Until recently, there was little hope that these goals could be attained. However, the results achieved with tamoxifen in the prevention of breast cancer, and the emergence of new therapies specifically targeted to molecules involved in the pathogenesis of lung cancer have set the stage for investigation of these agents for chemoprevention of lung cancer. Two of these new molecular targeted agents are gefitinib, an inhibitor of epidermal growth factor receptor–tyrosine kinase activity, and tipifarnib (R115777, Zarnestra®), an inhibitor of the farnesyltransferase enzyme, which is required for the proper localization and function of the ras oncogene. Tumor responses and disease stabilization have been achieved with both agents in clinical trials. In the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)–1 and IDEAL-2 phase II trials, gefitinib was demonstrated to be effective for disease control in patients with advanced non–small-cell lung cancer. The SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention (STOP) are 2 parallel studies that will investigate the potential effectiveness of gefitinib and tipifarnib in preventing the appearance and progression of premalignant lesions in former or current smokers with a history of smoking-related cancer. These trials should provide information not only about the potential role of gefitinib and tipifarnib in lung cancer chemoprevention, but also about the molecular changes that underlie tumorigenesis and that may serve as markers of disease progression. The STOP trial objectives are to evaluate the effect of gefitinib and tipifarnib on histologic and biologic parameters in patients with evidence of sputum atypia, to evaluate various parameters as potential predictors of the effectiveness of these agents, and to evaluate the tolerability of these agents over a 6-month course of treatment. Histologic response, defined as prevention of appearance or progression of premalignant lesions, is the primary endpoint of these trials. New targeted molecular therapies such as gefitinib and tipifarnib may offer the opportunity to make chemoprevention a viable treatment modality in lung cancer as well as in other human solid tumors. Clinical Lung Cancer, Vol. 5, Suppl. 1, S36-S40, 2003

Key words: Chemoprevention, EGFR, Farnesyltransferase inhibitors, Gefitinib, Ras, Tipifarnib

Introduction

(NSCLC) are frequently caused by aberrant intracellular signaling, which in turn leads to abnormal cell growth, differentiation, apoptosis, or angiogenesis. Several key signaling molecules such as epidermal growth factor receptor (EGFR) and K-ras have been identified as potential mediators of tumor cell growth when mutated, overexpressed, or dysregulated. For example, overexpression of EGFR and mutated K-ras have been frequently observed in lung cancer.5-7 Recent advances in the understanding of the pathogenesis of lung cancer have led to the development of new therapies targeted to tumor-specific molecular alterations. It is hoped that these new agents will improve the outcomes for lung cancer treatment. Increased knowledge of the molecular processes underlying carcinogenesis has resulted in new approaches for cancer prevention. The antiestrogen tamoxifen has shown considerable success in reducing the incidence of breast cancer in high-risk patients, and encouraging results have been obtained with 13-cis-retinoic acid in clinical trials in preventing the development of cancers of the

Despite considerable effort over the past several years toward improving treatment for patients with lung cancer, the prognosis for those who suffer from this disease remains grim. Even among patients diagnosed at the earliest stages, one third will die within 5 years.1 Patients who have undergone surgical resection of lung tumors frequently experience relapse with advanced disease as occult metastases become clinically evident or as a result of their increased risk for developing new primary lung tumors.2-4 Solid tumors including non–small-cell lung cancer *These chemotherapy trials have been closed prior to completion. Emory University, Winship Cancer Institute, Atlanta, GA Submitted: May 1, 2003; Revised: Jul 17, 2003; Accepted: Jul 21, 2003 Address for correspondence: Fadlo R. Khuri, MD, Winship Cancer Institute, 1365-C Clifton Road NE, Suite 3094, Atlanta, GA 30322 Fax: 404-778-5016; e-mail: fadlo_khuri@emoryhealthcare.org

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head and neck.8,9 Some of the same novel molecular-targeted agents that are being investigated as cancer therapy also have the potential for use as chemopreventive agents, based on their effectiveness in controlling tumor growth in clinical trials. The farnesyltransferase inhibitor (FTI) tipifarnib (R115777, Zarnestra®) blocks the activity of ras, which requires farnesylation for proper localization to the plasma membrane and subsequent activation.10 Gefitinib specifically inhibits the activity of the EGFR–tyrosine kinase (EGFR-TK) by blocking the intracellular adenosine triphosphate binding site.11 In normal tissue, EGFR-TK and Ras function in multiple important signaling pathways that affect cellular processes such as proliferation, apoptosis, and differentiation (Figure 1). When dysregulated, these molecules play key roles in processes such as metastasis, invasion, and angiogenesis, which are hallmarks of malignant tumors.

Figure 1

Signaling Pathways Mediated by EGFR and Ras that Lead to Proliferation or Apoptosis TKI

EGFR

Apoptotic Pathway

Proliferative Pathway P

P

Ras

PI3K

Raf

Akt

ERK

FTI

MEKK Rho–B SEK1

Clinical Trial Results Gefitinib and tipifarnib have shown activity against NSCLC in phase I clinical trials, both as single agents and in combination with chemotherapy.12-18 In phase I trials of tipifarnib, dose-limiting toxicities (DLTs) consisted of myelosuppression (especially with prolonged use), confusion, fatigue, and gastrointestinal toxicities.13,15,19 The recommended dose for prolonged administration of tipifarnib is 300 mg twice daily. In phase I trials of gefitinib, DLTs included reversible diarrhea and rash at daily doses of 700-800 mg.12,20 Gefitinib has been found to be effective and well tolerated as single-agent therapy for advanced, previously treated NSCLC in 2 large, randomized trials.21,22 The most common adverse events in clinical trials of gefitinib were rash and diarrhea, and both were generally mild and reversible.

Lung Cancer Chemoprevention: The STOP Trials Two trials are planned to investigate gefitinib and tipifarnib for the prevention of lung cancer in individuals at high risk. The Lung Cancer Biomarkers Chemoprevention Consortium (LCBCC) is a multicenter organization that is sponsoring the SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention (STOP). Former or current smokers with a history of cancer are enrolled in 1 of 2 parallel phase IIB trials: STOP-FTI, a study of tipifarnib versus placebo; and STOP-TKI (TK inhibitor), a study of the EGFR-TK inhibitor gefitinib versus placebo. There are 15 LCBCC participating centers in the United States and Canada.

Trial Objectives and Design Trial objectives for STOP are 3-fold: (1) to evaluate the effectiveness of tipifarnib or gefitinib in modulating the histologic response and biologic parameters of airway epithelia, (2) to assess intermediate serologic and tissue markers as preliminary predictors of the efficacy of tipifarnib or gefitinib, and (3) to evaluate the tolerability of these compounds when administered as daily treatment for 6 months. The primary efficacy endpoint of each study is the change in histologic score after 6 months of treatment. A secondary efficacy endpoint is the Ki67 labeling index, a marker of cellular proliferation.23 The study design of the 2 STOP trials is shown in Figure 2. Approximately 150 patients with a previously diagnosed and fully treated early-stage, smoking-related malignancy (lung, bladder, or esophageal) will be registered. Patients will be stratified by their smoking status (current vs. former smoker) and by the type of prior tumor, and then randomized at a 2:1 ratio to the treatment or placebo arm, respectively. Treatment with gefitinib will consist of a once-

MAPK

Intermediates

jnk/SAPK

c-myc c-Jun

Apoptosis Ki67

Nucleus

Abbreviations: EGFR = epidermal growth factor receptor; ERK = extracellular signal–regulated kinase; FTI = farnesyltransferase inhibitor; MAPK = mitogenactivated protein kinase; MEKK = mitogen-activated protein kinase kinase; P = phosphate; PI3K = phosphatidylinositol-3 kinase; SAPK = stress-activated protein kinase; SEK1 = stress-activated protein/extracellular signal–regulated kinase 1; TKI = tyrosine kinase inhibitor

daily 250-mg dose.24,25 Treatment with tipifarnib will consist of twice-daily doses of 300 mg for 3 of 4 weeks. After 6 months of treatment, patients will be reassessed by bronchoscopy. Patients with progressive disease who are in the placebo group will be allowed to cross over to the study drug, and those in the treatment arm will be allowed to cross over to the parallel study. Although the trials will be conducted separately, they will be centrally randomized, with the 2 placebo groups being combined for analysis. This sharing of control populations minimizes the overall population size required. Different investigational centers will maintain responsibility for tissue distribution, tracking, and/or biomarker assessment. The patient population accrued for these trials will consist of 50% current smokers and 50% former smokers with a > 30 pack-year history. Eligible patients must be disease-free from previous smoking-related cancers for ≥ 1 year after stage I NSCLC or stage I/II squamous cell carcinoma of the head and neck or for ≥ 3 years after limited-stage small-cell lung cancer, stage I or III bladder cancer, or stage I/II esophageal cancer. The primary objective is to evaluate effectiveness by changes in histology and biomarkers; therefore, enrolled patients are required to have evidence of abnormal cytology in the sputum. In such patients, the chance of having moderate to severe dysplasia is approximately 60%.26 Even among people with an apparently normal histology and prior malignancy who have not smoked for 1 year, 67% have genetic abnormalities in their airways.27 Women, elderly patients, and minority patients will be actively recruited to participate in the trial. Because only 42% of patients with lung cancer and 22% of patients with laryngeal cancer are women, it is expected that the majority of patients in the study will be men.

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Targeted Therapies in Primary and Secondary Prevention of NSCLC Figure 2 Study Design of the 2 STOP Trials

•Bronchoscopy •Randomization •Stratification - Smoking - Tumor type

R A N D O M I Z E

Gefitinib 250 mg/day or Tipifarnib 300 mg twice daily for 3 of 4 weeks for 6 months

Improvement or SD Repeat bronchoscopy at 6 months

Placebo

PD

Off drug

PD on Gefitinib or Tipifarnib PD on placebo

Repeat bronchoscopy at 12 months

Unblind Off drug

Crossover to Gefitinib or Tipifarnib

In each trial, approximately 150 patients will be randomized: 100 to the study drug and 50 to placebo. All are required to have had a previous early-stage, smoking-related malignancy (airway, digestive, or bladder), and evidence of sputum atypia. Abbreviations: PD = progressive disease; SD = stable disease; STOP = SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention

The ethnic distribution of the enrolled patients is expected to reflect the population of each institution’s surrounding local community. It is estimated that, of approximately 5000 patients screened, approximately 800 will have positive sputum cytology and 240 will be randomized and evaluable. Trial accrual is projected to require 34 years, and treatment and follow-up are estimated at 1-2 years.

Tissue Samples Bronchoscopy samples will be obtained by endobronchial biopsy, bronchial washing, or bronchoalveolar lavage. Endobronchial biopsy specimens will be obtained from 6 predetermined sites (Figure 3) as well as from any suspicious sites. On follow-up bronchoscopy, biopsy samples will be obtained from any sites with a histology of mild or greater-than-mild dysplasia. Between 6 and 12 biopsies will be routinely performed on each patient. More than 12 sites will be sampled only if it is clinically indicated. Depending on patient tolerance and operator discretion, bronchoalveolar lavage will be carried out after the endobronchial biopsies are completed. The decision of whether to use UV fluorescence bronchoscopy (light imaging fluorescence endoscope [LIFE]) in addition to white-light bronchoscopy (WLB) will be made by individual institutions. Several studies have found improved detection and localization of premalignant lesions with LIFE compared with WLB;26,28,29 however, other data suggest that LIFE does not offer a significant advantage.30

the proapoptotic death-associated protein kinase.32,40,41,43 The state of methylation of a particular promoter can be determined through methylation-specific polymerase chain reaction assays. Proliferation, Apoptosis, and Cell Cycle Markers. A variety of markers that are specific for proliferating cells or for different points within the cell cycle will be evaluated. The nuclear antigen Ki67 is present only in proliferating cells, and is often used to determine cell proliferation rates.23 The molecules cyclin B and p53, or the CDK inhibitor p27, play key roles in driving cell cycle progression. Apoptotic cells will be identified with terminal deoxynucleotidyl transferase biotin–deoxyuridine triphosphate nick-end labeling, which labels fragmented DNA. The fragile histidine triad (FHIT) gene is a putative tumor suppressor that may be involved in cell cycle regulation or apoptosis. Alteration of the FHIT gene by a variety of mechanisms (mutation, deletion, hypermethylation) has been found in many cancers.33,34 Minichromosome maintenance 2 is a protein that is essential for replication and is expressed only in replicating cells. This protein has been found to be an independent predictive factor in NSCLC.35 Figure 3 Planned Biopsy Sites in the STOP Trials

Right

Left

Biologic Markers of Response The STOP trials will evaluate changes in a variety of biologic parameters in response to treatment with gefitinib or tipifarnib. These changes represent biomarkers of carcinogenesis that could serve as intermediate endpoints in chemoprevention trials. In addition, parameters that are specific to the signaling pathways affected by treatment with gefitinib or tipifarnib may be useful as predictors of the efficacy of these agents.31 Some of these biomarkers are described in further detail later in this article. Table 1 provides a comprehensive list of biomarkers to be evaluated in the STOP trials.23,32-41 Methylation. Methylation of CpG sites that lie within a promoter region inhibits gene expression by blocking transcription factor binding and by altering the structure of chromatin.42 A variety of genes have been found to be methylated in lung cancer, including retinoblastoma, E-cadherin, the cell-cycle inhibitor p16, and

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Main RUL Carina Orifice LUL Orifice RML Orifice RB 9/10

LB 9/10

Any additional site that appears suspicious on bronchoscopy may have a biopsy performed on it. Abbreviations: LB = left bronchiole; LUL = left upper lobe; RB = right bronchiole; RML = right middle lobe; RUL = right upper lobe; STOP = SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention


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Fadlo Raja Khuri Table 1

Biomarkers to Be Evaluated in the STOP Trials22,31-40

Biomarker

Akt Cyclin B DNA-J2

Function

Normal

Cell cycle

2

Reserve cell hyperplasia

Heat-shock protein

3

Metaplasia

4

Mild dysplasia

5

Moderate dysplasia

6

Severe dysplasia

7

Carcinoma in situ

8

Invasive cancer

ERK1

Activated in EGFR/Ras signaling

FHIT

Tumor suppression

FTase and GGTase

Enzymes that regulate localization of ras family GTPases to the plasma membrane

HER2

Increased expression in tumorigenic lesions

Ki67

Proliferation A downstream marker of EGFR signaling

MCM2

Proliferation

Mean vessel density

Angiogenesis

Methylation APC

Activated in EGFR/Ras signaling Gene silencing Differentiation

DAP kinase

Proapoptotic; promoter hypermethylation observed in NSCLC

E-cadherin

Differentiation, cell adhesiveness, invasion, metastasis

MGMT

DNA repair

p16

Inhibits CDKs

RAR-β

Differentiation

Ras-F1

Ras effector homologue

p27

Cyclin-dependent kinase inhibition Marker of EGFR pathway inhibition and growth arrest Keratinocyte maturation

p53

Tumor suppression

PI3K Raf Rap1A and R-ras

Histology

1

EGFR

MEK1

Score

Bronchial Biopsy Grading Used in the STOP Trials

Activated in receptor tyrosine kinase signaling

Increased expression in tumorigenic lesions

MAPK

Table 2

Activated in EGFR/Ras signaling Activated by Ras localized to plasma membrane Ras family GTPases

STAT3

Keratinocyte maturation

TGF-α

Expression associated with tumorigenic lesions

TUNEL

Apoptosis

Abbreviations: APC = adenomatous polyposis coli; CDK = cyclin-dependent kinase; DAP = death-associated protein; EGFR = epidermal growth factor receptor; ERK1 = extracellular signal–related kinase 1; FHIT = fragile histidine triad; FTase = farnesyltransferase; GGTase = geranyl geranyl transferase; GTPase = guanosine triphosphate; MAPK = mitogen-activated protein kinase; MCM2 = minichromosome maintenance 2; MEK1 = mitogen-activated protein kinase kinase 1; MGMT = O(6)-methylguanine-DNA-methyltransferase; NSCLC = non–small-cell lung cancer; PI3K = phosphatidylinositol-3 kinase; RAR = retinoic acid receptor; STAT3 = signal-transducing activator of transcription 3; STOP = SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention; TGFα = transforming growth factor–α; TUNEL = terminal deoxynucleotidyl transferase biotin–deoxyuridine triphosphate nick-end labeling

Abbreviation: STOP = SPORE (Specialized Program of Research Excellence) Trials of Lung Cancer Prevention

Angiogenesis. Blood supply is necessary for the continued growth and survival of tumors beyond a certain size. Both EGFR and ras have been implicated in tumor-associated angiogenesis. Mutated ras is associated with increased expression of vascular endothelial growth factor (VEGF). Enhanced EGFRTK activity can also lead to increased production of the angiogenesis factors VEGF and interleukin-8 (IL-8) by tumor cells.36 Inhibitors of EGFR-TK, including gefitinib, can block EGFRinduced upregulation of VEGF and IL-8 in tumor cells.37,38 In the STOP trials, angiogenesis will be assessed by determining mean vessel density in the biopsy specimens. Target-Specific Efficacy. The effectiveness of treatment with gefitinib or tipifarnib in inhibiting signal transduction through their respective targets (EGFR-TK or farnesylated ras) will be evaluated by examining the expression and activation of downstream effector molecules. For example, mitogen-activated protein kinase kinase 1, extracellular signal–regulated kinase 1, and Raf are key players in ras-mediated signal transduction (Figure 1).39 The serine/threonine kinase Akt and phosphatidylinositol-3 kinase are major downstream targets of growth factor receptor TKs.

Specimen Requirements and Histology Sputum will be collected following nebulization because atypia is more likely to be observed in induced versus standard collected sputum. To be considered satisfactory, samples should contain numerous histiocytes in most fields with a magnification of 40×. Samples in which histiocytes are few in number and present in < 50% of fields at a magnification of 40× will be considered less than optimal, whereas samples with rare or absent histiocytes will be considered unsatisfactory. Because inflammation can mask true sputum atypia, samples should ideally exhibit mild to insignificant inflammation, with < 5% of cells obscured. The cytologic diagnosis will be in 1 of 3 categories: mild, moderate, or severe atypia. In addition to sputum samples, patients are required to give blood and urine samples at the time of enrollment, as well as to fill out an epidemiologic questionnaire and consent form. Specimens from each patient will include ≥ 2 well-prepared and definitive sputum samples in Saccomanno fixative, biopsy specimens from suspicious and normal sites, bronchial wash, and possibly

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Targeted Therapies in Primary and Secondary Prevention of NSCLC bronchoalveolar lavage fluid. Bronchoscopic biopsy tissue will be embedded in paraffin and sectioned at 6 µm. Tissue sections will be collected on serial slides, and every fourth and fifth slide will be left unstained for future analysis. Each sample will be stained with hematoxylin and eosin or by immunohistochemistry. The University of Colorado will be responsible for the central, blinded review of histologic response using their grading system (Table 2). Scores range through progressive degrees of dysplasia, from 1 (normal) to 8 (invasive cancer). The 3 criteria that will be used to grade histologic response to treatment are (1) the average score of all bronchial biopsies; (2) the dysplasia index, or the percentage of biopsies with dysplasia (a 10% decrease is considered significant improvement); and (3) the worst score (decrease of ≥ 1 score is considered to be significant improvement). Improvement in ≥ 2 of 3 criteria is considered a response. Disease is considered stable if ≥ 2 of 3 criteria are unchanged, 2 of 3 criteria are improved but the third is worse, 2 of 3 criteria are worse but the third is improved, or if 1 criterion shows improvement, 1 worsens, and 1 remains unchanged. Finally, worsening of ≥ 2 of 3 criteria is considered disease progression.

Considerations for Data Analysis These trials will be powered to assess both histologic response and the Ki67 proliferation index. In evaluating disease progression, histology will be considered the primary criterion, followed by the Ki67 index. Due to the relatively small population sizes in these trials, data analyses will present a number of statistical challenges, including evaluation of primary and secondary endpoints and model checking and validation. Multivariate analysis will be required to integrate clinical, epidemiologic, biomarker, and genomic data. It may be necessary to adapt and develop statistical models for optimal analysis of the complex data.

Conclusion It is hoped that the results from these trials will provide a compelling rationale for larger trials by cooperative oncology groups.

Acknowledgements Dr. Khuri has received research grant support from AstraZeneca, Johnson & Johnson, and Schering Plough.

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Kennedy TC, Lam S, Hirsch FR. Review of recent advances in fluorescence bronchoscopy in early localization of central airway lung cancer. Oncologist 2001; 6:257-262. 30. Kurie JM, Lee JS, Morice RC, et al. Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia in current and former smokers. J Natl Cancer Inst 1998; 90:991-995. 31. Papadimitrakopoulou VA, Hong WK. Biomolecular markers as intermediate end points in chemoprevention trials of upper aerodigestive tract cancer. Int J Cancer 2000; 88:852855. 32. Belinsky SA, Palmisano WA, Gilliland FD, et al. Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. Cancer Res 2002; 62:2370-2377. 33. Ingvarsson S. FHIT alterations in breast cancer. Semin Cancer Biol 2001; 11:361-366. 34. Tseng JE, Kemp BL, Khuri FR, et al. Loss of Fhit is frequent in stage I non-small-cell lung cancer and in the lungs of chronic smokers. Cancer Res 1999; 59:4798-4803. 35. Ramnath N, Hernandez FJ, Tan DF, et al. MCM2 is an independent predictor of survival in patients with non-small-cell lung cancer. J Clin Oncol 2001; 19:4259-4266. 36. Rak J, Yu JL, Klement G, et al. Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Invest Dermatol Symp Proc 2000; 5:24-33. 37. Bancroft CC, Chen Z, Yeh J, et al. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-kappaB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer 2002; 99:538-548. 38. Hirata A, Ogawa S, Kometani T, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002; 62:2554-2560. 39. Sebolt-Leopold JS. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene 2000; 19:6594-6599. 40. Ng MH. Death associated protein kinase: from regulation of apoptosis to tumor suppressive functions and B cell malignancies. Apoptosis 2002; 7:261-270. 41. Zochbauer-Muller S, Fong KM, Virmani AK, et al. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 2001; 61:249-255. 42. Eng C, Herman JG, Baylin SB. A bird's eye view of global methylation. Nat Genet 2000; 24:101-102. 43. Tang X, Khuri FR, Lee JJ, et al. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst 2000; 92:1511-1516.

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