INTRODUCTION. Key words: Gefitinib, EGFR-tyrosine kinase inhibitors, Non Small Cell Lung Cancer

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1 Gefitinib (Iressa) in Non Small Cell Lung Cancer at Kuwait Cancer Control Centre Experience, Kuwait, with Focus on Future Use of EGFR- Tyrosine Kinase Inhibitors Vinay Vyas, Al-Awadi Shafika, Jarslov N, Delvadiya MD, Muralidharan KC Department of Medical Oncology, Kuwait Cancer Control Centre, Kuwait INTRODUCTION Lung cancer is the leading cause of cancer-related mortality in both men and women, 1 with 1.2 million new cases diagnosed every year and 1 million deaths recorded worldwide in Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. The majority of NSCLC patients present with advanced disease at diagnosis, and a large portion of those diagnosed with early-stage disease eventually recur, experiencing metastatic disease. For advanced disease, palliation and the patients quality of life are still the primary goals of therapy, with total cure remaining elusive. Although chemotherapy has recently produced promising results as neoadjuvant and adjuvant strategies for early-stage patients, 3, 4 and some progress has been made in the treatment of locally advanced Key words: Gefitinib, EGFR-tyrosine kinase inhibitors, Non Small Cell Lung Cancer and advanced disease, 5, 6 treatment outcomes for NSCLC patients must still be considered disappointing. Thus, clinical research of new treatment strategies is warranted. Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. Targeted therapies are designed to interfere with specific aberrant biological pathways involved in tumorigenesis. A large amount of preclinical in vivo and in vitro data has been gathered on the antitumor properties of a number of new biological agents, both as single agents and combined with other conventional treatment modalities, such as chemotherapy and radiotherapy. Consequently, several targeted agents have been introduced into clinical trials in NSCLC, with many phase I and phase II studies already completed and some phase III study results being recently made available. Molecular targeted therapies, such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), provide a different mechanism of action from chemotherapy and can be much more specific in their approach to cancer treatment The first generation of clinical trials of targeted agents in NSCLC treatment has Correspondence to: Dr. Vinay Vyas, Senior Registrar, Department of medical oncology, Kuwait cancer control centre, Kuwait vinay25vyas@hotmail.com 53

2 Vinay Vyas been concluded, and some conclusions can now be drawn. To date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease, and negative results are more commonly reported than positive ones. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, gefitinib and erlotinib, two epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), represent a further chance for tumor control and symptom palliation for a subset of patients otherwise eligible only for supportive care Moreover, disappointing results should not be considered definitive, and important lessons can be learned from this first generation of clinical trials, which should be considered only the first step in clinical research in this field. In fact, one of the main reasons for the relative failure of the first generation of clinical trials of targeted therapy in lung cancer is that there is multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events, and blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidence of synergistic antitumor activity achievable by combining targeted agents that block multiple signaling pathways has recently been emerging. 11, 12 Clinical trials of multitargeted therapy may represent the second generation of studies in this field, and some of these are already ongoing. With the recent changes in FDA directions limiting gefitinib use to patients currently or previously benefiting from this agent and restricting new access to patients enrolled in a clinical study conducted under an investigational new drug application. 13 This prompted us to review our data. METHOD Retrospective data review of 7 patients who took gefitinib as a part of international expanded access programme at our centre was made.there were 4(57%) females and 3(43%) males. All of them received 250 mg/d of gefitinib until treatment failure, or disease progression. Outcomes analyzed included clinical response and adverse events. RESULTS Nonsmokers were 3(43%) and smokers were 4(57%). Six patients (86%) belonged to stage IV and one (14%) was stage III. According to the ECOG performance score 3(43%) patients were PS I, 2(28.5%) were PS II and 2(28.5%) were PS III. Predominant histology was adenocarcinoma in 6(86%) patients and was not specified in 1(14%) patient. Gefitinib was used after 3 previous lines of chemotherapy in one patient and after 2 lines of chemotherapy in all other patients Median duration of Gefitinib received was15 months ranging from 3 months to 38 months.most common adverse effect of the drug was skin rash which was seen in all patients, followed by diarrhea in two patients.subjective response was noted in 5(71%) patients in form of better control of cough dyspnea and weight gain in 2(29%) other patients it didn t help. Objective response was noted in form of 3(43%) partial responses 2(28.5%) stable diseases, in rest of the 2(28.5%) patients progressive disease was noted. Two patients continue to receive Gefitinib with favourable partial response, one patient changed over to chemotherapy after progression on gefitinib and remaining four died of progressive disease. DISCUSSION Gefitinib and erlotinib are two orally available EGFR-TKIs. Two large, phase II trials have been conducted on gefitinib monotherapy in patients with advanced NSCLC that was not controlled after one or more chemotherapy regimens. In those two studies, named Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2, gefitinib was demonstrated to be active (with overall response rates in the range of 10% 20%), to improve disease symptoms in about 40% of patients, and to be well tolerated. 7, 8 On the basis of these clinical trials, gefitinib was licensed for the third-line treatment of platinum- and docetaxel-refractory advanced NSCLC in several countries, including Japan, Australia,and the U.S. However, recently, Thatcher et al. 9 reported on a phase III trial named Iressa Survival Evaluation in Lung Cancer (ISEL), which compared gefitinib with best supportive care in patients with advanced NSCLC who had received one or two prior chemotherapy regimens. In 1,692 patients (ISEL is the largest study conducted in the refractory advanced NSCLC population), a difference between gefitinib and placebo was reported, although this did not reach statistical significance in the overall or adenocarcinoma histology populations. Preplanned subgroup analyses suggested a survival benefit in patients of Asian origin and in patients who never smoked. Specifically, at a median follow-up of 7 months, the median survival times were 5.6 months versus 5.1 months (hazard ratio [HR], 0.89; 95% confidence interval [CI], ; p =.11), in the overall population, and 6.3 months versus 5.4 months, in patients with adenocarcinoma histology (HR, 0.83; 95% CI, ; p =.07), for gefitinib and placebo, respectively. As stated before, preplanned subgroup analyses indicated statistically different survival outcomes in smokers compared with never-smokers and in patients of Asian versus non- Asian origin. In patients of Asian origin, gefitinib-treated patients survived longer than placebo-treated patients (HR, 0.66; 95% CI, ; p =.01; median survival, 9.5 months 54

3 Gefitinib (Iressa) in Non Small Cell Lung Cancer at Kuwait Cancer Control Centre... vs. 5.5 months, respectively). A similar result was seen in never-smokers, where gefitinib-treated patients survived longer than placebo-treated patients (HR, 0.67; 95% CI, ; p =.01; median survival, 8.9 months vs. 6.1 months, respectively). A statistically significant higher response rate was observed for gefitinib-treated patients compared with placebo-treated patients. Although our experience is very small to derive any statistical significance, but good subjective and objective responses were observed in our patients who were having similar characteristics as of other good responders in major international trials. Iressa was able to control progression of disease for 15 months in our cohort which is also comparable to that in major trials. In one of our patient it could control the disease for 4yrs. Multilevel cross-stimulation exists among the targets of the new biological anticancer agents. Molecular pathways involved in survival and replication of cancer cells are very complex and interfering with only single steps in these pathways may often be an insufficient therapeutic approach (fig 1). An example of this complexity is what happens with EGFR signaling pathways. 14 Several ligands can bind to EGFR, including EGF and transforming growth factor alpha (TGF-α). After the ligand binds to the receptor, the receptor dimerizes either as a homodimer or as heterodimer with other members of the EGFR family and undergoes autophosphorylation at specific tyrosine residues with in the intracellular domain. These autophosphorylation events in turn activate downstream signaling pathways, including the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3' kinase (PI3K)/Akt pathway. Activation of Ras initiates a multistep phosphorylation cascade that leads to the activation of MAPKs. The MAPKs extracellular signal regulated kinase ERK1 and ERK2 subsequently regulate gene transcription and have been linked to cell proliferation, survival, and transformation in laboratory studies. Akt also plays a critical role in controlling the balance between cell survival and apoptosis. Phosphorylation of Akt is required for its activation; once activated, Akt inactivates proapoptotic proteins, including the Bcl-2 family member Bad and caspase-9, and cell cycle regulatory molecules. This brief description makes intuitive sense because blocking only one molecular target allows others to act as salvage or escape mechanisms for cancer cells. Predictive Markers of Sensitivity to HER-1/EGFR TKIs - Identifying predictive markers of clinical response to therapy may provide an opportunity to better select patient subsets appropriate for specific treatment. Emerging data suggest possible links between certain patient characteristics and better outcome to treatment with the HER-1/EGFR TKI gefitinib for NSCLC. These characteristics include patients with no prior or current smoking (having smoked fewer Figure 1. Complexity of signal transduction molecular pathways targeted by new anticancer therapies. Abbreviations: CDK, cyclin dependent kinase; EGFR, epidermal growth factor receptor; ERK, extra cellular signal regulated kinase; hsp-90, heat shock protein- 90; IGFR, insulin-like growth factor; MEK, mitogen-activated protein kinase (MAPK)/ERK kinase; mtor, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; and PI3K, phosphatidylinositol 3¹ kinase. 55

4 Vinay Vyas than 100 cigarettes in a lifetime), female gender, having adenocarcinoma and/or bronchioalveolar histology, and Asian ethnicity. 7, 15, 16 The reasons behind the higher efficacy of HER-1/EGFR TKIs are not entirely clear, though the higher prevalence of HER-1/EGFR mutations in these subsets could be a possible explanation. A relationship between HER-1/EGFR over expression and response to HER-1/EGFR-targeted agents remains to be firmly established, as results have been contradictory. The link between HER-1/EGFR expression and response was absent in two phase II trials of single-agent gefitinib in advanced, refractory NSCLC (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL]1 and IDEAL2). 17 Amplification of the HER-1/EGFR gene has recently been linked to a higher likelihood of response and extended survival with HER-1/EGFR TKI. Data from the Southwest Oncology Group (SWOG) 0126 studies have shown a longer median survival duration for patients whose tumors had either gene amplification or high gene copy numbers. 18 However, these observations have yet to be confirmed in prospective trials and should not form the basis of decision making in routine care. Studies have also explored possible correlations between expression of HER-1/EGFR downstream signaling components, phosphorylated mitogen activated protein kinase (pmapk) and phosphorylated protein kinase B (pakt), but the results are also contradictory Recent findings suggest that potentially predictive patient characteristics may be indicative of somatic mutations in the HER-1/EGFR TK domain. The mutations generally occur on exons 19 and 21 and are usually amino acid deletions or substitutions. 22, 23 They appear more common in adenocarcinomas, tumors from never smokers, and women. 23, 24, 25 Their incidence also appears higher in Japanese and Asian patients than in whites. 23, 26 It has also been suggested that acquired resistance to gefitinib is associated with a second mutation in the HER- 1/EGFR TK domain at position Retrospective analysis of clinical data shows that many patients who respond to treatment with gefitinib have HER- 1/EGFR mutations. 18, 22-23, 28 Most studies examined the relationship between mutation and response to therapy. However, prolonged survival is arguably the more important outcome with these agents and assessing the relationship between any predictive marker and survival is essential. Recent data with gefitinib in patients with NSCLC recurring after surgery show survival was significantly longer in patients with mutations; gefitinib was effective in 83% of patients with mutations compared with 10% of patients without them. However, tumor progression was also observed in a small minority of patients harboring mutations. 25 Another study with gefitinib in NSCLC demonstrated partial response rates of 64.7% in patients with HER-1/EGFR mutations compared with 13.7% in patients without mutations, and patients with HER-1/EGFR mutations (including responders and nonresponders) had a significantly longer time to progression (21.7 vs. 1.8 months) and overall survival time (30.5 vs. 6.6 months). 29 Considered together, current data indicate the potential for patient selection based on both clinical and molecular determinants of targeted therapy. They suggest certain patient subsets may be extremely sensitive to HER-1/ EGFRtargeted agents, and could potentially benefit from these as frontline therapy. Studies are already under way to evaluate the efficacy of erlotinib first line in enriched patient subsets. However, available data on predictive markers are retrospective and based on small numbers of patients, and should therefore be interpreted with caution. The variable results observed, and differing conclusions drawn by experts in labs and cooperative groups from around the world, underscore the challenges of applying such predictive marker data in clinical practice, and the need for further research. CONCLUSION Oral gefitinib was well tolerated and effective in this group of patients with otherwise limited choices. A larger study with newer EGFR-TKI is required to identify select population of patient who are going to benefit from these targeted therapies. That s why we need molecular analysis in our lung cancer population. The Diverse ethnicity of Kuwait population can provides best materials for study by cdna arrays and proteomic technology, as gene expression profiles in the tumor are being used to identify molecular signatures of prognosis. It is mandatory to identify an EGFR- dependent signature. Although fresh tumor tissue would be ideal, new technologies such as quantitative analysis of gene expression in paraffin embedded tissue may also be useful to identify correlates of response to EGFR kinase inhibitors from formalin fixed tissue samples. 30 REFERENCES 1 Jemal A, Murray T, Samuels A et al. Cancer Statistics, CA Cancer J Clin 2003;53: Parkin DM, Bray F, Ferlay J et al. Estimating the world cancer burden: Globocan Int J Cancer 2001;94: Depierre A, Milleron B, Moro-Sibilot D et al. 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