EXPERIENCES WITH ERLOTINIB IN SECOND AND THIRD LINE TREATMENT PATIENTS WITH ADVANCED STAGE IIIB / IV NON-SMALL CELL LUNG CANCER Interim Data Report of TRUST study on patients from Bosnia and Herzegovina

HeadHER/EGFR is known to play a pivotal role in tumorigenesis and is overexpressed in up to  of NSCLCs. Th e study of an Expanded Access Clinical Program of Erlotinib in NSCLC is a phase IV openlabel, non-randomized, multicenter trial in patients with advanced (inoperable stage IIIb/IV) NSCLC who were eligible for treatment with erlotinib but had no access to trial participation. Patients for the study from Bosnia and Herzegovina (B&H) were selected from two Clinical centres (Sarajevo and Banja Luka). Th e aim of study was to evaluated effi cacy and tolerability of erlotinib monotherapy in this setting. All patients who received at least one dose of erlotinib and data were entered in the database as of the CRF cut-off date of th May  were included in analysis of data (n = ). Th is population is defi ned as the Intent to Treat (ITT) population and includes all patients who had at least one dose of erlotinib regardless of whether major protocol violations were incurred. Th e fi ndings are consistent with the results of the randomized, placebo-controlled BR. study. Indicating that erlotinib is an eff ective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed standard chemotherapy. In B&H group of patients DCR was almost , and PFS was approximately , weeks (compared with  and , weeks for erlotinib reported in phase III). Almost three quarter of the patients received erlotinib as their second line of therapy. Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions.  of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).


Introduction
The treatment of advanced non-small cell lung cancer (NSCLC) has evolved substantially over the past decade.Chemotherapy with a platinum based doublet prolongs survival and improves quality of life in patients with good performance status (PS).A number of malignancies are associated with aberrant-or over-expression of the EGFR.EGFR serves as a target for therapeutic intervention in NSCLC and may be a target in several other tumour types, including breast carcinoma, and a variety of squamous cell carcinomas.Erlotinib is an orally active, potent, and highly selective inhibitor of human epidermal growth factor receptor tyrosine-kinase (TK) activity.A large, phase III trial (BR.), fi rst presented at ASCO in , showed that as a single agent, second-or third-line erlotinib ( mg/day) significantly prolonged survival and delayed symptom deterioration in patients with advanced NSCLC ().These results confirm the therapeutic value of HER/EGFR inhibition; HER/EGFR is known to play a pivotal role in tumorigenesis (-) and is overexpressed in up to  of NSCLCs (,).The objective of our work is to evaluate the impact of clinical characteristics on efficacy with erlotinib, among patients with advanced stage IIIB/ IV NSCLC who were eligible for treatment with erlotinib but had no access to trial participation.

Patients and Methods
Phase IV, open-label, single-arm, multi-centre trial in patients with advanced, inoperable, stage IIIB/ IV NSCLC who were eligible for treatment with erlotinib but had no access to trial participation.
Patients ≥ years with histologically or cytologically confi rmed, advanced, unresectable, stage IIIb/IV NSCLC, measurable or non-measurable disease, ECOG PS of -, life expectancy of at least  weeks, received at least one course of standard treatment (chemotherapy or radiotherapy) or are unsuitable for standard treatment (chemotherapy or radiotherapy), had no more than two prior chemotherapy regimens; patients must have recovered from toxicities of any prior therapy ≥- weeks since last dose, patients fully recovered from surgery in < weeks may be considered, having adequate hematologic, renal, and hepatic function, present negative pregnancy test for women of childbearing potential.Any unstable systemic disease, prior therapy with HER/EGFR inhibitor (small molecule or mono-clonal antibody), any other malignancies within  years (except for adequately treated cervical carcinoma or skin cancer), newly diagnosed and/or untreated brain metastases or spinal cord compression, any significant ophthalmologic abnormality.
Patients received oral erlotinib ( mg/day) until unacceptable toxicity or disease progression.Dose interruption or dose reduction (to  mg/day, then  mg/day) was permitted for drug related AEs.
Tumour response was assessed using Response Evaluation Criteria in Solid Tumours (RECIST), as per institutional standards (no less than every  months).For responding patients, confi rmatory evaluation was to be performed  weeks after response determined.Clinical and laboratory assessments were conducted at baseline and every  weeks during the study.AEs were assessed and graded according to v . (NCI-CTC).SAS v.. was used for (statistical) analysis and reporting of the data collected for this study.

Results
All patients who received at least one dose of erlotinib and for whom monitored CRF data were available in these patients was censored at the date of last contact.
The survival analysis is based on  patients.Those who had not died at the time of the data cut-off were censored at the date of last contact (n = ).In this study we followed the date of registration as a fi rst date of survival of patients on erlotinib treatment.Th e data of overall survival are shown in Table  and Figure .
Adverse events (per preferred term) observed during treatment graded using Common Toxicity Criteria (CTCAE v.) of US-NCI (Table ).Th e following safety data were collected: incidence of erlotinib-related rash, Serious Adverse Events (SAEs), Adverse Events (AEs) and unexpected erlotinib-related AEs are not described in population of B&H patients.R a s h :    o f p a t i e n t s e x p e r i e n c e d a rash, of which  were grade  (Table ).The unique reasons were rash ().Withdrawals: Th ere were no patients withdrawing from treatment due to therapy related AE's (Table ).Specifications for ending treatment are shown in Table .

Discussion
Several studies have investigated the eff ect of targeted therapies as monotherapy or in combination with chemotherapy in the second or third line setting.A large phase III study BR. () has reported the benefi t of erlotinib monotherapy in patients with advanced refractory NSCLC who were ineligible for further chemotherapy.Th ere were shown (Table ) the results of comparison the interim effi cacy analysis of global phase IV trial, that refl ect the clinical experience with erlotinib in more than  unselected patients with advanced NSCLC, from  centres in  countries worldwide (), the results of landmark trial BR. (), and interim effi cacy analysis of TRUST patients from Bosnia and Herzegovina.().Almost three quarter of the patients received erlotinib as their second line of therapy; Overall, erlotinib was well tolerated; there were no patients who withdrew due to a treatment-related AE (mainly rash) and there were few dose reductions. of patients experienced an SAE (most commonly gastrointestinal (GI) disorders).

List of Abbreviations
SAEs:  of patients experienced an SAE (Table ), most commonly GI disorders ( patients).Dose reductions:  of patients had dose r e d u c t i o n s d u e t o a n e r l o t i n i b -r e l a t e d event.

TABLE 6 .
Reason for End of TreatmentConclusionTh e results of Interim Data Report of TRUST study on patients from Bosnia and Herzegovina refl ect clinical experience with erlotinib in  unselected patients with advanced NSCLC.Th e fi ndings are consistent with the positive results of the randomized, placebo-controlled BR. study: Indicating that erlotinib is an eff ective option for patients with advanced NSCLC who are unsuitable for, or who have previously failed on, standard chemotherapy.In B&H group of patients DCR was almost , and PFS was approximately , weeks (compared with  and , weeks for erlotinib reported in the phase III setting)