Erlotinib in the Treatment of Non-Small Cell Lung Cancer: Current Status and Future Developments

ANTICANCER RESEARCH 30: 1301-1310 (2010)

Review Erlotinib in the Treatment of Non-small Cell Lung Cancer: Current Status and Future Developments

CESARE GRIDELLI, PAOLO MAIONE, MARIA ANNA BARESCHINO, CLORINDA SCHETTINO, PAOLA CLAUDIA SACCO, RITA AMBROSIO, VALENTINA BARBATO, MARZIA FALANGA and ANTONIO ROSSI

Division of Medical Oncology, “S.G. Moscati” Hospital, Avellino, Italy

Abstract. Erlotinib is an orally small molecule inhibiting The epidermal growth factor receptor (EGFR) is one of the tyrosine kinase activity of the epidermal growth factor the most studied targets for cancer therapy. The present receptor (EGFR). Currently, erlotinib, at a standard oral review discusses the role of erlotinib, an anti-EGFR tyrosine daily dose of 150 mg, is licensed for the treatment of kinase inhibitor (TKI), in the treatment of NSCLC. unselected recurrent non-small cell lung cancer (NSCLC) patients, however, it is being investigated in all stages of Epidermal Growth Factor Receptor Pathway NSCLC. Erlotinib is well tolerated, with common toxicities including rash and diarrhoea. The optimization of the The EGFR, also known as ErbB-1/HER1, is the first of four therapeutic impact of erlotinib in NSCLC will be more members of the ErbB family of cell membrane receptors, defined when reliable predictive factors are identified. An which are important mediators in cell growth, differentiation, important step has been made in the molecular and survival (3, 4). The EGFR is known to bind with a high characterization of potentially sensitive NSCLC patients. In affinity to several ligands including EGF, amphiregulin and fact, we have learned that activation, somatic EGFR gene transforming growth factor α (TGFα). NSCLC is mutations within the tyrosine kinase domain, are associated characterized by a generally high expression, about 40-80%, with a high possibility of a long lasting therapeutic response of the EGFR family members of ligands and receptors (5). to erlotinib. The present review discusses the role of erlotinib Two classes of EGFR antagonists have been successfully in the treatment of NSCLC. tested in phase III trials: anti-EGFR monoclonal antibodies (for example cetuximab) and small-molecule EGFR-TKIs Non-small cell lung cancer (NSCLC) accounts for about (for example gefitinib and erlotinib). Both these two small 85% of all lung cancer diagnoses (1). The majority of people molecules are administered orally, daily and inhibit EGFR diagnosed with NSCLC are unsuitable for surgery since most activity by competing with adenosine triphosphate (ATP) for patients have advanced disease at diagnosis. In recent the ATP-binding site localized on the EGFR intracellular decades, conventional treatments (surgery, chemotherapy, domain. The antitumour effects of EGFR inhibition in radiotherapy) have apparently reached a plateau of human cancer models are: inhibition of cancer cell effectiveness in improving the outcomes of NSCLC patients, proliferation with G0/G1 cell cycle arrest and, in some cases, which still remain disappointing, especially in advanced induction of apoptosis; anti-angiogenesis through inhibition stages (2), hence new treatment approaches have been of angiogenic growth factor production; inhibition of developed. invasion and metastases; potentation of antitumour activity of cytotoxic drugs and of radiotherapy (5). Several retrospective and prospective analyses revealed prognostic/predictive clinical and molecular factors related Correspondence to: Cesare Gridelli, MD, Division of Medical to the treatment with EGFR-TKIs, gefitinib and erlotinib (6, Oncology, “S.G. Moscati” Hospital, Contrada Amoretta, 8, 83100 7). In fact, the clinical predictors of response to EGFR-TKIs Avellino, Italy. Tel: + 39 0825203573, Fax: + 39 0825203556, e-mail: [email protected] included female gender, adenocarcinoma histology, Asian ethnicity and particularly a history of never-smoking. The Key Words: NSCLC, erlotinib, EGFR, tyrosine kinase inhibitors, molecular predictors of activity are EGFR overexpression lung cancer, review. detected by immunohistochemistry (IHC), EGFR gene copy

0250-7005/2010 $2.00+.40 1301 ANTICANCER RESEARCH 30: 1301-1310 (2010) number detected by fluorescence in situ hybridization Table I. Clinical and biological prognostic and predictive factors of (FISH), EGFR and Kras mutational status which all seem to EGFR-TKIs in advanced non-small cell lung cancer. influence the outcomes (Table I) (6, 7). EGFR mutations in Factors Role exons 18 through 21 have been reported to be the most important prognostic/predictive molecular factors for Clinical factors* NSCLC and TKI therapy (8, 9). Female gender No absolute prognostic/predictive role The most common toxicity related to treatment with Asian ethnicity No absolute prognostic/predictive role EGFR-TKIs are skin rash and diarrhoea, which are dose- Adenocarcinoma histology No absolute prognostic/predictive role Never smoker status No absolute prognostic/predictive role limiting. The positive relationship between the development of rash and response and/or survival, which has been shown Biological factors in erlotinib clinical trials, makes the occurrence of skin EGFR protein expression No role reactions a potential surrogate marker for anti-EGFR drug EGFR gene copy number No role efficacy (10). EGFR mutations Positive prognostic factor for survival Positive predictive factor for EGFR Early Stage NSCLC TKIs efficacy KRAS mutations Negative prognostic factor for survival Early stages of NSCLC, including stages I-IIIA, are No role as predictive factor for EGFR diagnosed in about 20% of patients. These stages of disease TKI efficacy are amenable to surgery, with 5-year survival rate ranging *Clinical factors in which a higher incidence of EGFR mutations has from 67% (stage I) to 23% (stage IIIA) (11). In patients with been detected; EGFR, epidermal growth factor receptor; TKIs, tyrosine pathological stages, II-IIIA, adjuvant chemotherapy with kinase inhibitors. cisplatin-based regimens is the standard approach, improving the 5-year survival absolute benefit by about 5%. In stage IIIA, radiotherapy is not recommended for routine use due erlotinib or cisplatin plus pemetrexed, or to observation, in to the lack of prospective randomized clinical trial data which the choice of treatment depends on the EGFR evaluating its efficacy (12). mutational status and ERCC-1 (excision repair cross- Erlotinib is being employed in completely resected complementation group 1) expression. The primary endpoint NSCLC patients with the aim to improve the outcome. In is feasibility and the secondary is DFS (14). fact, the RADIANT (Randomized Double-blind Trial In A retrospective review of patients with resected stage I-III Adjuvant NSCLC with Tarceva) study is a phase III trial lung adenocarcinoma harbouring EGFR exon 19 or 21 comparing erlotinib 150 mg daily versus placebo (2:1) in mutations, some of whom received EGFR TKIs stage IB-IIIA NSCLC patients with EGFR-positive tumours postoperatively, was performed. A total of 167 patients were (IHC and/or FISH), following complete surgical resection identified, 53 of whom received either adjuvant erlotinib or and up to 4 cycles of adjuvant chemotherapy. Planned gefitinib. The median DFS was 43 months in the group that accrual is 945 patients and primary endpoint is disease-free received a TKI versus 31 months for the one which did not. survival (DFS). Preliminary data concerning biomarker The 2-year DFS was 88% (77% in non-TKI group). After analysis have been reported. Among the 655 analysed tissue controlling for stage of disease, individuals who received samples, 96% were EGFR IHC-positive and 74% EGFR adjuvant gefitinib or erlotinib had a better DFS (hazard ratio FISH-positive. Of the 476 tissue samples analysed to date for [HR]=0.38, 95% confidence interval [CI], 0.16-0.90) than the mutations, 12% had activating EGFR and 19% had KRAS non-TKI group (p=0.03). The 2-year overall survival (OS) mutations. Preliminary comparisons suggest that EGFR was 95% (86% in the non-TKI group). The median OS was mutation rate increased while KRAS mutation rate decreased not reached (15). These data indicate that the adjuvant use with tumour stage. Once complete, this study will provide a of either gefitinib or erlotinib improves DFS in patients with robust biomarker dataset on which to evaluate predictive and completely resected stage I -III lung adenocarcinomas with prognostic response markers, which may help determine who mutations in EGFR exons 19 and 21, thus justifying a may benefit from treatment with erlotinib in the adjuvant prospective randomized trial in this setting. setting (13). Another ongoing trial, named TASTE (Tailored post- Locally Advanced NSCLC Surgical Therapy in Early stage NSCLC), is a phase II/III randomised study in which patients affected by stage II-IIIA Locally advanced NSCLC stages represent about 25% of new non-squamous NSCLC which have been radically resected diagnoses. This group includes unresectable stages IIIA-IIIB, are randomized either to standard arm, consisting of cisplatin and combinations of chemotherapy and radiotherapy are plus pemetrexed, or to experimental arm, consisting of currently the standard treatment approach for this setting.

1302 Gridelli et al: Erlotinib in NSCLC (Review)

Concomitant chemo-radiotherapy, although associated with paclitaxel with or without erlotinib 150 mg daily. Median OS increased acute toxicity, has been demonstrated to be the for patients treated with erlotinib was 10.6 versus 10.5 better strategy over sequential chemoradiotherapy and it is to months for placebo (HR 0.99; p=0.95, 95% CI, 0.86-1.16), be considered a standard approach in patients with good OR was similar for both the erlotinib and the placebo arm performance status (PS) (16). The locally advanced disease (21.5% versus 19.3%, respectively; p=0.36), time-to- includes several and high heterogeneous stages, as progression (TTP) was 5.1 months for erlotinib and 4.9 demonstrated by the 5-year survival rate, which ranges from months for placebo (HR 0.937; p=0.36). Patients who were 3 to 13% (11). Notwithstanding the progresses reported in the reported as never smokers (72 erlotinib; 44 placebo) treatment of locally advanced NSCLC obtained by combining experienced improved OS in the erlotinib arm (22.5 versus chemotherapy with radiotherapy, treatment outcomes in this 10.1 months for placebo; HR 0.49, 95% CI, 0.28-0.85; clinical setting are still to be considered disappointing. p=0.01). The median TTP in never smokers was also Data concerning only a few cases involving the improved by the administration of erlotinib, being 6.0 versus introduction of erlotinib in the multimodality treatment of 4.3 months for the placebo arm (HR 0.50) (20). locally advanced NSCLC are available, most of which report In the TRIBUTE trial, among erlotinib-treated patients, only preliminary results. The only study reporting final EGFR mutations were associated with improved OR (53% results is a phase I study aimed to determine the maximum- versus 18% for the placebo arm; p<0.05) and there was a tolerated dose (MTD) of erlotinib administered with two trend toward an erlotinib benefit on TTP (12.5 versus 6.6 for standard chemoradiotherapy regimens (17). placebo group; p=0.092), but it did not improve OS (p=0.96) A randomised phase II feasibility trial evaluated the addition (21). As a result, this analysis revealed that EGFR mutations of erlotinib to radiotherapy in patients with unresectable stage may be a positive prognostic factor for OS in advanced I-IIIA NSCLC not suitable for chemotherapy. Preliminary NSCLC patients treated with chemotherapy with or without results on 23 evaluable patients (10 receiving radiotherapy and erlotinib, and may predict greater likelihood of response to 13 radiotherapy plus erlotinib) showed that the addition of erlotinib. In the TALENT (Tarceva Lung Cancer erlotinib did not appear to increase in-field toxicities, thus Investigation Trial) study 1,172 patients were randomised improving the control of disease (18). (586 per each arm) to receive cisplatin plus gemcitabine, Another interesting trial investigated the combination of with or without erlotinib 150 mg daily. In this trial there was erlotinib and bevacizumab, an antivascular endothelial also no statistically significant difference in any outcome, growth factor (VEGF) monoclonal antibody, in combination with median OS of 43 versus 44.1 weeks for the erlotinib with chemo-radiotherapy in stage III NSCLC. The primary and the placebo groups, respectively (HR 1.06). The endpoint was progression-free survival (PFS) at 1 year. All subgroup analyses were performed on a very small number histologies were studied including squamous cell carcinoma. of patients, and only those who had never smoked had an Overall response rate (OR) following treatment in the 31 increased OS reported; no other subgroups were found more evaluable patients was 68.2% (95% CI, 45-86%). The PFS likely to benefit from treatment (22). at 1 year was 58% (95% CI, 34-76%), with a promising The effect of smoking was examined in the TRIBUTE estimated 1-year survival of 79% (19). trial. Despite a lack of benefit in the overall patient population, when the analysis was confined to those who had Metastatic Stage NSCLC never smoked, erlotinib seemed to provide an OS benefit (median OS of 10 and 22.5 months, for smokers and never- It is estimated that about 50% of all patients are at metastatic smokers, respectively; p=0.01) (20). In the TALENT study, stage at the time of diagnosis of their disease. Chemotherapy smoking history was collected retrospectively, and was is the cornerstone for the treatment of metastatic NSCLC, available for a small number of patients. Median OS in while radiotherapy has only a palliative role. Unfortunately never-smokers (n=10) was 11.4 months with placebo, but the prognosis is very poor, with a 5-year survival < 1% (11). was not reached with erlotinib (n=8). Median PFS was Erlotinib has been investigated in metastatic NSCLC as first-, longer with erlotinib (7.9 months) than with placebo (5.4 second- and third-line therapy and as maintenance treatment. months; HR 0.195; p=0.02) (23). Table II summarizes the results of phase III trials First-line therapy. Erlotinib in combination with employing erlotinib plus chemotherapy as first-line treatment chemotherapy for the first-line treatment of NSCLC has been of advanced NSCLC. evaluated in two large multicentre randomised placebo- Overall, there was no clinical benefit in either trial, and controlled clinical trials. In the TRIBUTE (Tarceva currently concurrent use of erlotinib with chemotherapy is Responses in Conjunction with Paclitaxel and Carboplatin) not recommended in the first-line treatment of NSCLC. study, 1,059 patients with untreated advanced stage IIIB/IV However, erlotinib has been investigated in conjunction with NSCLC were randomised to receive carboplatin plus chemotherapy but with a different combination method. A

1303 ANTICANCER RESEARCH 30: 1301-1310 (2010)

Table II. Phase III randomized trials with erlotinib plus concurrent chemotherapy in first-line treatment for advanced non-small cell lung cancer patients.

Trial Treatment No. of patients OR (%) TTP (months) OS (months)

TRIBUTE, 2005 (20) CBDCA + PAC + Placebo vs. 533 19.3 10.5 4.9 CBDCA + PAC + Erlotinib 526 21.5 10.6 5.1 TALENT, 2007 (22) CDDP + GEM + Placebo vs. 586 29.9 24.6* 44.1* CDDP + GEM + Erlotinib 586 31.5 23.7* 43*

*Weeks; OR=response rate; TTP=time-to-progression; OS=overall survival; CBDCA=carboplatin; PAC=paclitaxel; CDDP=cisplatin; GEM=gemcitabine.

Table III. Phase III randomized trials with erlotinib as maintenance therapy for advanced non-small cell lung cancer patients.

Trial Treatment No. of patients OR (%) PFS (months) OS (months)

SATURN, 2009 (34) Placebo vs. 451 5 HR 0.71 HR 0.81 Erlotinib 438 12 HR 0.71 HR 0.81 ATLAS, 2009 (38, 39) Bevacizumab + Placebo vs. 373 NR 3.75 NR Bevacizumab + Erlotinib 370 NR 4.76 NR

OR=Response rate; PFS=progression-free survival; OS=overall survival; HR=hazard ratio; NR=not reported.

Table IV. Phase III randomized trials with erlotinib in recurrent advanced non-small cell lung cancer.

Trial Treatment No. of patients OR (%) PFS (months) OS (months)

BR.21, 2005 (40) Placebo vs. 243 <1 2.2 4.7 Erlotinib 488 8.9 1.8 6.7 BeTa Lung, 2008 (46) Erlotinib + Placebo vs. 317 6.2 1.7 9.2 Erlotinib + Bevacizumab 319 12.6 3.4 9.3

OR=Response rate; PFS=progression-free survival; OS=overall survival.

phase II randomised trial evaluated whether sequential weeks; 95% CI, 42.7-75.1 weeks; p<0.0001). The addition administration of erlotinib and chemotherapy improves of erlotinib to chemotherapy was well tolerated, with no clinical outcomes versus chemotherapy alone in unselected, increase in hematological toxicity (23). Thus, this method of chemotherapy-naive patients with advanced NSCLC. A total combining erlotinib and chemotherapy should be further of 154 patients were randomly assigned to either receive investigated. erlotinib, 150 mg daily, or placebo on days 15 to 28 of a 4- Several phase II trials investigating erlotinib as a single- week cycle that included gemcitabine and either cisplatin or agent in the first-line setting in unselected NSCLC patients carboplatin. The nonprogression rate at 8 weeks, primary have been performed, reporting OR and OS values endpoint, was 80.3% in the gemcitabine plus platinum- comparable with those expected after conventional erlotinib arm (n=76) and 76.9% in the chemotherapy-placebo chemotherapy (10, 24, 25). arm (n=78). At 16 weeks, the nonprogression rate was 64.5% Based on these results, our group launched the Italian- versus 53.8%, respectively. The OR was 35.5% versus Canadian trial TORCH (Tarceva or Chemotherapy), a phase 24.4%, median PFS was 29.4 versus 23.4 weeks (HR, 0.47; III randomized multicenter study based on a non-inferiority p=0.0002), respectively. There was no significant difference OS comparison between an experimental strategy including in OS with 74.1 weeks for the erlotinib arm and 75.7 weeks first-line erlotinib followed at progression by chemotherapy for the placebo arm (HR1.09, 95% CI, 0.70-1.69; p=0.42). with cisplatin and gemcitabine, or the inverse sequence as Of interest is the fact that regardless of the treatment standard arm. This trial will allow the relationship between received, never smokers (median not reached; 95% CI, 85.7 molecular predictors, such as EGFR and KRAS mutational weeks) had longer OS than ever smokers (median, 57.9 status, and erlotinib treatment response to be studied. The aim

1304 Gridelli et al: Erlotinib in NSCLC (Review) of the TORCH study is to evaluate, in a randomised fashion, presence of the L858R mutation as compared with the which is the most appropriate and cost-effective sequential absence of the mutation (p=0.02). Grade 3 skin toxicity was approach for erlotinib and chemotherapy in an unselected recorded in 16 patients (7.4%) and grade 3 diarrhoea in 8 advanced NSCLC (26). patients (3.7%) (32). These results confirmed those reported, On the other hand, phase II trials have investigated mainly retrospectively, concerning the role of EGFR erlotinib in patients selected for prognostic/predictive clinical mutations in the treatment with EGFR-TKIs; patients and molecular factors. In fact, erlotinib has been administered harbouring sensitising EGFR mutations should be considered as first-line therapy, within phase II trials, in patients having for first-line erlotinib or gefitinib. A phase III trial comparing at least one of the clinical factors predictive of EGFR-TKI erlotinib with platinum-based chemotherapy in NSCLC activity, i.e. in adenocarcinoma and bronchioloalveolar patients harbouring EGFR mutations in Western countries as carcinoma (27), never-smokers (28), female gender (29), and first-line therapy is ongoing (14). Asians (30). Overall, the results reported better outcomes in respect to those reported in the unselected patient population. Maintenance treatment. Maintenance treatment is the However, analysing where possible the molecular factors, in prolongation of treatment duration with the administration of most of the responsive patients, EGFR mutations were additional drugs at the end of a defined number of initial detected, which as stated before are represented mainly in chemotherapy cycles, after achieving tumour control in an patients with the reported clinical characteristics (8, 9). individual patient (33). A retrospective analysis combined data from 223 patients The phase III trial named SATURN (Sequential Tarceva who were included in five trials in predominantly Western in Unresectable Lung Cancer) was a randomized clinical populations to assess the impact of EGFR and KRAS study set up to determine whether erlotinib is effective as mutations on first-line therapy with an EGFR-TKIs, erlotinib maintenance therapy in advanced NSCLC. A total of 889 or gefitinib. Clinical versus molecular predictors of patients with no evidence of disease progression after 4 sensitivity were compared. Sensitising EGFR mutations were cycles of chemotherapy were randomised to receive either associated with a 67% OR, TTP of 11.8 months, and OS of erlotinib 150 mg/day or placebo until progression or 23.9 months. Exon 19 deletions were associated with longer unacceptable toxicity. The primary endpoint was PFS in all median TTP and OS compared with L858R mutations. This patients and the co-primary endpoint was PFS in EGFR IHC- means that not only is the presence of EGFR mutations positive patients. PFS was significantly prolonged with important but also the type of mutation, which could be the erlotinib versus placebo in all patients (HR 0.71, 95% CI, strongest predictive factor of EGFR-TKI activity. Wild-type 0.62-0.82; p=0.000003) and in EGFR IHC-positive patients EGFR was associated with poorer outcomes (OR, 3%; TTP, (HR 0.69, 95% CI, 0.58-0.82; p=0.00002). All biomarker 3.2 months) irrespective of KRAS status. No difference in subgroups showed a PFS benefit with erlotinib, including outcome was seen between patients harbouring KRAS patients whose tumours had wild-type EGFR (HR 0.78, 95% transition versus transversion mutations. EGFR genotype was CI, 0.63-0.96; p=0.0285). In particular, the EGFR mutation more effective than clinical characteristics at selecting status (exon 19 deletions and/or L858R) was associated with appropriate patients for consideration of first-line therapy a marked improvement in PFS with erlotinib therapy (HR with an EGFR-TKI (31). 0.10, 95% CI, 0.04-0.25; p<0.0001). KRAS mutation status Recently, a prospective large phase II trial reported very was a prognostic factor but did not affect the clinical benefit interesting results about the use of erlotinib in advanced seen with erlotinib. Median OS was statistically significantly NSCLC patients harbouring EGFR mutations. In this trial, the superior for all the population in the erlotinib arm (HR 0.81). feasibility of large-scale screening for EGFR mutations in It was superior both in patients with non-squamous histology such patients was evaluated by analysing the association (HR 0.79) and patients with EGFR wild-type (HR 0.77, 95% between the mutations and the outcome of the erlotinib CI, 0.61-0.97; p=0.0243). Median OS was not reached in treatment. The patients screened for EGFR mutations were patients with EGFR mutations (HR 0.83) and there was a 2,105 and only 350 (16.6%) harboured them. Mutations were 67% of these patients, randomized in the placebo arm, who more frequent in women (69.7%), in patients who had never received a second-line EGFR-TKIs. OR was 12% with smoked (66.6%), and in those with adenocarcinomas (80.9%) erlotinib versus 5% with placebo. The disease control rate (p<0.001 for all comparisons). The mutations were deletions (complete response + partial response + stable disease > 12 in exon 19 (62.2%) and L858R (37.8%). Median PFS and OS weeks) was 40.8% with erlotinib versus 27.4% with placebo for 217 patients (113 as first-line and 104 as second- or third- (p<0.0001). Quality of life (QoL) was similar in both arms. line therapy) who received erlotinib were 14 and 27 months, Erlotinib significantly extended time to pain (HR 0.61; respectively. The adjusted HR for the duration of PFS were p=0.008) and time to analgesic use (HR 0.66; p=0.0199). 1.92 for the presence of the L858R mutation, as compared Erlotinib was well tolerated: the majority of treatment-related with a deletion in exon 19 (p=0.02); and 1.68 for the adverse events were grade 1/2. Overall, the SATURN study

1305 ANTICANCER RESEARCH 30: 1301-1310 (2010) met its primary and co-primary endpoints with high regimen (50% of patients) or with two chemotherapy statistical significance. The survival benefit was particularly regimens (50% of patients). Almost all patients received large in patients with adenocarcinoma histology and was not platinum-based chemotherapy. The OR was 8.9% in the driven by the EGFR mutation-positive subgroup, with a erlotinib arm and less than 1% in the placebo group significant improvement in survival also observed in the (p<0.001). PFS was 2.2 and 1.8 months, respectively (HR EFGR wild-type group (34, 35). 0.61; p<0.001). The median OS was 6.7 months for those in A functional relationship between the EGFR signalling the erlotinib regimen compared with 4.7 months in the pathway and the VEGF pathway exists (36), suggesting that placebo arm (HR 0.7, 95% CI, 0.58-0.85; p<0.001). Based a dual blockade of these targets may produce additive and/or on these results, erlotinib was licensed for the treatment of synergistic antitumor effects. On this rational basis, several chemotherapy-resistant advanced NSCLC patients. QoL preclinical studies have evaluated the activity of combined evaluation, defined as the time for a clinically significant anti-EGFR and anti-VEGF drugs (37). deterioration to occur in three common lung cancer Based on these data, the combination of erlotinb and symptoms, showed that patients receiving erlotinib had a bevacizumab has been studied as maintenance treatment. In significantly longer median deterioration-time for all three fact, the ATLAS trial, a global, multicentre, randomised, symptoms: 4.9 versus 3.7 months for cough (p=0.04); 4.7 double-blind, placebo-controlled study, involved 743 patients versus 2.9 months for dyspnoea (p=0.04); and 2.8 versus 1.9 with advanced NSCLC who were treated with 4 cycles of months for pain (p=0.03) (41). chemotherapy (various platinum-containing doublets) and Several retrospective analyses were performed in the bevacizumab. Patients who did not progress were then BR.21 study. In this trial, clinical predictors of response randomized to maintenance therapy with bevacizumab alone included female gender, adenocarcinoma, Asian ethnicity and or bevacizumab plus erlotinib until progression. The main a history of never-smoking, even though erlotinib had a endpoint was PFS. Grade 3 to 4 adverse events were significant effect on OS in all subgroups of patients (42). In observed in 44.1% of patients enrolled in the bevacizumab fact, the ORs were more frequent in women (14% versus 6%, plus erlotinib arm and 30.4% of patients in the bevacizumab p=0.0065), in patients with adenocarcinoma as compared to only arm. The treatment was well tolerated in both arms. The other histotypes (14% versus 4.1%, p<0.0001), and in Data Monitoring Committee recommended stopping the trial patients without smoking history (25% versus 4%, at the second planned interim efficacy analysis because it had p<0.0001). Despite the fact that male smokers with met the primary endpoint. The results showed a significant squamous cell carcinoma have been considered non-ideal increase in median PFS from 3.75 months for bevacizumab candidates for treatment with erlotinib, in this group, the alone to 4.76 months for bevacizumab plus erlotinib (HR median OS improved significantly among patients receiving 0.722, 95% CI, 0.592-0.881; p=0.0012) (38). At the time of erlotinib (n=100) compared with patients with similar this report, the OS data are still not mature. In addition for characteristics in the placebo arm (n=57) (p=0.016). This this trial, a prospective analysis of the prognostic/predictive difference resulted in a median OS of 5.5 months in the value of several biomarkers was performed. PFS results erlotinib arm compared with 3.4 months in the placebo arm suggested that EGFR FISH-positive (HR 0.66, 95% CI, 0.39- (42). Overall, 197 specimens were analysed for EGFR gene 1.13), EGFR mutated (HR 0.93, 95% CI, 0.55-1.56), and mutations which were most commonly identified in exon 19 KRAS wild-type (HR 0.67, 95% CI, 0.49-0.91) patients could and 21. A total of 45 EGFR mutations were identified in derive the greatest improvement with bevacizumab plus 23% of the analysed samples. Twenty-one mutations were erlotinib (39). either deletions in exon 19 or a mutation in exon 21 L858R, Overall, taking into account the results of these two trials, whereas 24 were novel mutations. Patients who had a erlotinib could be indicated as a potential drug for use as mutation had a higher OR, although this was not statistically maintenance first-line therapy (Table III). significant. There was no significant difference in OS benefit observed in the erlotinib group as compared with the placebo Recurrent NSCLC group in patients with exon 19 deletion or exon 21 L858R mutation (p=0.39), nor in patients with novel mutations Two randomized phase III trials investigated erlotinib in (p=0.41) (43). Moreover in this trial, high levels of EGFR recurrent NSCLC patients (Table IV). The registrative BR.21 protein expression were associated with OR and OS in a study in which erlotinib was compared with placebo in stage retrospective subset analysis. In fact, EGFR-IHC positive III/IV NSCLC patients who had failed first- or second-line patients treated with erlotinib had a significantly superior OS chemotherapy (40). A total of 731 patients were randomized compared with placebo treated patients (HR 0.68; p=0.02) in a 2:1 ratio to receive either erlotinib at 150 mg/day or (43). In the same trial, 159 tumours were analysed for EGFR placebo. These patients had a metastatic NSCLC which had gene copy by FISH and 61 (38%) were positive. ORs were previously been treated with one standard chemotherapy 5% for EGFR FISH-negative and 21% for FISH-positive

1306 Gridelli et al: Erlotinib in NSCLC (Review) patients (p=0.02). Significant OS benefit from the erlotinib of treatment after disease progression showed that most therapy was observed for patients with EGFR FISH patients in the erlotinib plus placebo arm received post- positivity (HR=0.43; p=0.004) but not for patients with protocol therapies including bevacizumab-containing EGFR FISH negativity (HR=0.80; p=0.35). In multivariate regimens. This may explain why the significant PFS benefit analysis, only EGFR FISH-positive status was prognostic for observed did not translate into an OS benefit. poorer OS (p=0.025) and predictive of differential OS A phase IV trial, the TRUST study, employing erlotinib, benefit from erlotinib (p=0.005). An exploratory analysis of mainly as second- or third-line treatment, in advanced KRAS mutations status in the BR.21 trial was conducted in NSCLC patients was performed worldwide. The results 206 patients; 30 (14.6%) specimens had missense mutations reporting the general practice use of erlotinib were in codon 12 or 13 (22 on the erlotinib arm and 8 on the superimposable with those reported by trial BR.21, placebo arm). For all 206 patients with known KRAS confirming the drug efficacy and safety in an extended subset genotype, the HR in the erlotinib was 0.77 (95% CI 0.57- of patients closer to clinical practice (47-49). 1.06, p=0.06). Significant OS benefit from the erlotinib therapy was observed for the 176 patients with wild-type Mechanisms of Resistance to Erlotinib KRAS with HR of 0.69. In contrast, the HR for the 30 patients with mutant KRAS was 1.67, with an interaction p- Unfortunately patients who initially benefited from the value of 0.09. ORs were 5% (1/20) in KRAS-mutant patients, erlotinib therapy at a certain point of their illness and 10.2% (10/98) in KRAS wild-type patients. In patients experienced a progression of their disease. Over time with identified KRAS genotype, the multivariate Cox (median of 6-12 months), most of the developed tumours regression model showed that KRAS mutations were strongly acquired resistance to EGFR-TKIs. The most important associated with shorter OS (HR 1.63) (44). mechanisms of resistance to EGFR-TKIs are: activation of Cigarette smoking induces CYP1A1/1A2 and is EGFR-independent and tumour-induced angiogenesis, hypothesized to alter erlotinib pharmacokinetics. Cohorts of activation of alternative TK receptors which bypass the NSCLC patients currently smoking ≥10 cigarettes per day for EGFR pathway, independent or constitutive activation of ≥1 year received escalating doses of erlotinib for 14 days intracellular molecular effectors downstream to EGFR, and until dose-limiting toxicity (DLT). A separate cohort of EGFR gene mutations or loss of the target. This means that patients was then randomly assigned to erlotinib at either in addition to primary resistance to anti-EGFR therapies, MTD or 150 mg daily, with pharmacokinetics assessed at day resistance eventually develops in most NSCLC patients who 14. DLT was observed in two out of five patients at 350 mg initially respond to gefitinib or erlotinib and in which (acneiform dermatitis and fatigue). Thirty-five patients were sensitising EGFR mutations harbour, leading to disease randomly assigned to 150 mg or 300 mg of erlotinib. progression during treatment. In these cases, acquired Common adverse events (all grades) were: skin toxicity (150 resistance to EGFR inhibitors was shown to be associated mg, 29%; 300 mg, 67%), diarrhoea (150 mg, 18%; 300 mg, with the occurrence of an additional EGFR gene mutation 50%), and fatigue (150 mg, 12%; 300 mg, 17%). This trial (50, 51). The most studied of such EGFR mutations occurs reported that the MTD of erlotinib in NSCLC patients who in exon 20 at position 790 in the kinase domain of the EGFR smoked was 300 mg. Steady-state trough plasma gene, leading to a substitution of methionine for threonine, concentrations and incidence of rash and diarrhoea in which would change the conformation of the receptor and smokers at 300 mg were similar to those in former or never block the binding of gefinitib or erlotinib to the active site, smokers receiving 150 mg in previous studies. Further studies creating resistance to these EGFR-TKIs (51). The secondary should investigate this erlotinib dose in current smokers (45). T790M mutation occurs in 50% of patients with mutated Another phase III randomized trial, the BeTa Lung study, EGFR with TKI resistance, and in vitro, this mutation evaluated the combination of erlotinib and bevacizumab negates the hypersensitivity of activating EGFR mutations. versus erlotinib plus placebo in 636 patients with advanced Sensitive detection methods have identified a proportion of NSCLC who progressed during or after first-line therapy. TKI-naive tumours that carry T790M, and these resistant Median OS was 9.3 months for the bevacizumab plus clones may be selected after exposure to gefitinib or erlotinib arm and 9.2 months in the erlotinib plus placebo erlotinib. Other secondary resistance mutations (D761Y, group (HR 0.97). Median PFS was 3.4 months and 1.7 L747S, T854A) seem to be rare. It is possible that other months, respectively (HR 0.62). OR was 12.6% and 6.2%, kinases, such as insulin-like growth factor-1 receptor (IGF- respectively (p=0.006). The safety profile was consistent 1R) might also be selected to bypass EGFR pathways in with those known for each drug (46). The study showed no resistant tumours. The growing preclinical data in EGFR- statistically significant difference in OS between the two mutated NSCLC with acquired resistance to gefitinib or arms (primary endpoint), with a doubled time of PFS erlotinib has increased the number of clinical trials testing favouring the combination arm. Analysis of subsequent lines novel EGFR inhibitors that in vitro inhibit T790M (neratinib,

1307 ANTICANCER RESEARCH 30: 1301-1310 (2010)

XL647, BIBW 2992, and PF-00299804), MET, or IGF-1R 6 Rossi A, Galetta D and Gridelli C: Biological prognostic and inhibitors in combination with EGFR TKIs, and heat-shock predictive factors in lung cancer. Oncology 77(Suppl 1): 90-96, protein 90 inhibitors (52). As already discussed, KRAS 2009. mutations were described to be associated with resistance to 7 John T, Liu G and Tsao MS: Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy EGFR TKIs in NSCLC (44). Ongoing preclinical and number, protein expression and other biomarkers of EGFR for clinical research in EGFR-mutated NSCLC has the potential the prediction of response to tyrosine kinase inhibitors. to significantly improve the outcomes of patients with these Oncogene 28(Suppl 1): S14-S23, 2009. somatic mutations. 8 Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T and Mitsudomi T: Mutations of the epidermal growth factor receptor Conclusion gene in lung cancer: biological and clinical implications. Cancer Res 64: 8919-8923, 2004. A series of studies are planned to contribute to our 9 Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, Fong KM, Lee H, Toyooka S, Shimizu N, Fujisawa T, Feng Z, understanding of the role of erlotinib in NSCLC treatment. In Roth JA, Herz J, Minna JD and Gazdar AF: Clinical and biological our opinion, major areas of clinical research are: the features associated with epidermal growth factor receptor gene assessment of erlotinib in the adjuvant treatment, in mutations in lung cancers. J Natl Cancer Inst 97: 339-346, 2005. combination with chemotherapy and/or radiotherapy in 10 Kolesar J, Brahmer J, Lee J, Guaglianone P, Patel J, Keppen M, locally advanced disease, in the first-line therapy of advanced Hidalgo M, Carbone D and Schiller J: Final results of ECOG disease in patients harbouring activating EGFR mutations, 3503: a pilot study to determine if downstream markers of EGFR and in combination and/or sequence with cytotoxic treatments linked signalling pathways predict response to erlotinib (OSI- 774) in the first-line treatment of patients with advanced non- and/or other molecular target agents. Another development small cell lung cancer (NSCLC). J Clin Oncol 25(18S): 406s could be multitargeted inhibition, combining the blockade of (abstr 7588), 2007. angiogenesis, ras/raf/ERK and EGFR. In this context, an 11 Mountain C: Revisions in the international system for staging interesting multitargeted agent with a low toxicity profile is lung cancer. Chest 111: 1710-1717, 1997. sorafenib. A phase II, randomized, multicenter clinical trial 12 Pisters KMW, Evans WK, Azzoli CG, Kris MG, Smith CA, investigating if the combinations of erlotinib and sorafenib or Desch CE, Sommerfield MR, Brouwers MC, Darling G, Ellis gemcitabine plus sorafenib could be active and tolerated in PM, Gaspar LE, Pass HI, Spigel DR, Strawn JR, Ung YC and Shepherd FA: Cancer Care Ontario and American Society of elderly or PS 2 NSCLC patients has completed the accrual, Clinical Oncology adjuvant chemotherapy and adjuvant radiation and the results are expected in the first part of 2010 (53). therapy for stages I-IIIA resectable non-small-cell lung cancer However, the optimization of the therapeutic impact of guideline. J Clin Oncol 25: 5506-5518, 2007. erlotinib in NSCLC will be more defined when more reliable 13 Richardson F, Richardson K, Sennello G, Young D, Orlov S, predictive factors are identified. To date, EGFR gene Pápai-Székely Z, Keshavjee S, Kim J, Cerfolio R and Shepherd mutations are associated with a higher possibility of a long FA: Biomarker analysis from completely resected NSCLC lasting therapeutic response and efficacy to erlotinib. patients enrolled in an adjuvant erlotinib clinical trial (RADIANT). J Clin Oncol 27(15S): 387s (abstr 7520), 2009. 14 http://www.cancer.gov/ (accessed on November 22, 2009). References 15 Janjing YY, Park BJ, Kris MG, Miller VA, Riely GJ, Zheng J, Dycoco JP, Shen R and Azzoli CG: Impact on disease-free survival 1 Govindan R, Page N, Morgensztern D, Read W, Tierney R, of adjuvant erlotinib or gefitinib in patients with resected lung Vlaiotis A, Spitznagel EL and Piccirillo J: Changing adenocarcinomas that harbor epidermal growth factor receptor epidemiology of small-cell lung cancer in the United States (EGFR) mutations. J Clin Oncol 27(15S): 387s (abstr 7523), 2009. over the last 30 years: analysis of the Surveillance, 16 Guida C, Maione P, Rossi A, Bareschino M, Schettino C, Epidemiologic, and End Results database. J Clin Oncol 24: Barzaghi D, Elmo M and Gridelli C: Combined chemo- 4539-4544, 2006. radiotherapy for locally advanced non-small cell lung cancer: 2 Breathnach OS, Freidlin B, Conley B, Green MR, Johnson DH, current status and future development. Crit Rev Oncol Hematol Gandara DR, O’Connel M, Shepherd FA and Johnson BE: 68: 222-232, 2008. Twenty-two years of phase III trials for patients with advanced 17 Choong NW, Mauer AM, Haraf DJ, Lester E, Hoffman PC, non-small-cell lung cancer: Sobering results. J Clin Oncol 19: Kozloff M, Lin S, Dancey JE, Szeto L, Grushko T, Olopade OI, 1734 –1742, 2001. Salgia R and Vokes EE: Phase I trial of erlotinib-based 3 Perez-Soler R: HER1/EGFR targeting: refining the strategy. multimodality therapy for inoperable stage III non-small cell Oncologist 9: 58-67, 2004. lung cancer. J Thorac Oncol 3: 1003-1011, 2008. 4 Mass RD: The HER receptor family: A rich target for therapeutic 18 Martinez E, Martinez M, Casas F, Vinolas N, Minguez J, Paredes development. Int J Radiat Oncol Biol Phys 58: 932-940, 2004. A, Perez Casa AM, Domine M, de la Torre A and Valcarcel F: 5 Kurie JM, Shin HJ, Lee JS, Morice RC, Ro JY, Lippman SM, Feasibility and tolerability of the addition of erlotinib to 3D Hittelman WN, Yu R, Lee JJ and Hong WK: Increased epidermal thoracic (RT) in patients (P) with unresectable NSCLC: A growth factor receptor expression in metaplastic bronchial prospective randomized phase II study. Ann Oncol 19(Suppl 8): epithelium. Clin Cancer Res 2: 1787-1793, 1996. viii100 (abstr. 263P), 2008.

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19 Socinski MA, Stinchcombe TE, Halle JS, Moore DT, Petty WJ, 29 Jackman DM, Cioffredi L, Lindeman NI, Morse LK, Lucca J, Blackstock AW, Gettinger SN, Decker RH, Khandani AH and Weckstein D, Huberman MS, Lynch TJ, Johnson BE and Janne Morris DE: Incorporation of bevacizumab (B) and erlotinib (Er) PA: Phase II trial of erlotinib in chemotherapy-naive women with induction (Ind) and concurrent (Conc) carboplatin with advanced pulmonary adenocarcinoma. J Clin Oncol (Cb)/paclitaxel (P) and 74 Gy of thoracic radiotherapy in stage 27(15S): 423s (abstr 8065), 2009. III non-small cell lung cancer (NSCLC). J Clin Oncol 27(18S): 30 Mok TS, Zhou C, Kim S, Wu Y and Perng R: Efficacy and 389s (abstr 7528), 2009. safety of erlotinib in >1200 East/South-East (E/SE) Asian 20 Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, patients (pts) with advanced non-small-cell lung cancer Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson (NSCLC). J Clin Oncol 26(15S): 706s (abstr 19001), 2008. DH and Miller VA: TRIBUTE: a phase III trial of erlotinib 31 Jackman DM, Miller VA, Cioffredi LA, Yeap BY, Janne PA, hydrochloride (OSI-774) combined with carboplatin and Riely GJ, Ruiz MG, Giaccone G, Sequist LV and Johnson BE: paclitaxel chemotherapy in advanced non-small-cell lung cancer. Impact of epidermal growth factor receptor and KRAS mutations J Clin Oncol 23: 5892-5899, 2005. on clinical outcomes in previously untreated non-small cell lung 21 Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens cancer patients: results of an online tumor registry of clinical SL, Herbst RS, Ince WL, Janne PA, Januario T, Johnson DH, trials. Clin Cancer Res 15: 5267-5273, 2009. Klein P, Miller VA, Ostland MA, Ramies DA, Sebisanovic D, 32 Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Stinson JA, Zhang YR, Seshagiri S and Hillan KJ: Mutations in Majern M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, the epidermal growth factor receptor and in KRAS are predictive Massuti B, Gonzales-Larriba JL, Paz-Ares L, Bover I, Garcia- and prognostic indicators in patients with non-small-cell lung Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero cancer treated with chemotherapy alone and in combination with R, Sanchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina erlotinib J Clin Oncol 23: 5900-5909, 2005. MA, Sanchez JJ and Taron M: Screening for epidermal growth 22 Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, factor receptor mutations in lung cancer. N Engl J Med 361: 958- De Rosa F, Milanowski J, Karnicka-Mlodkowski H, Pesek M, 967, 2009. Serwatowski P, Ramlau R, Janaskova T, Vansteenkiste J, Strausz 33 Gridelli C, Maione P, Rossi A, Ferrara ML, Bareschino MA, J, Manikhas GM and von Pawel J: Phase III study of erlotinib Schettino C, Sacco PC and Ciardiello F: Potential treatment in combination with cisplatin and gemcitabine in advanced non- options after first-line chemotherapy for advanced NSCLC: small-cell lung cancer: the Tarceva Lung Cancer Investigation maintenance treatment or early-second line? Oncologist 14: 137- Trial. J Clin Oncol 25: 1545-1552, 2007. 147, 2009. 23 Mok TS, Wu YL, Yu CJ, Zhou C, Chen YM, Zhang L, Ignacio J, 34 Cappuzzo F, Coudert B, Wierzbicki R, Park K, Custers F, Liao M, Srimuninnimit V, Boyer MJ, Chua-Tan M, Sriuranpong Curbera GA, Giaccone G, Hilbe W, Klingelschmitt G and V, Sudovo AW, Jin K, Johnston M, Chui W and Lee JS: Ciuleanu TE: Overall survival analyses from the SATURN phase Randomized, placebo-controlled, phase II study of sequential III placebo-controlled study of erlotinib as first-line maintenance erlotinib and chemotherapy as first-line treatment for advanced therapy in advanced non-small-cell lung cancer (NSCLC). Eur J non-small-cell lung cancer. J Clin Oncol 27: 5080-5087, 2009. Cancer Supplements 7(3): 12 (abstr 22LBA), 2009. 24 Giaccone G, Gallegos Ruiz M, Le Chevalier T, Thatcher N, Smit 35 Brugger W, Kim JH, Hansen O, Sullivan R, White S, Lee JS, E, Rodriguez JA, Janne P, Oulid-Aissa D and Soria JC: Erlotinib Schlegel M, Noe J, Nagelmeier I and Cappuzzo F: Biomarker for frontline treatment of advanced non-small cell lung cancer: a analyses from SATURN, a phase III placebo-controlled study of phase II study. Clin Cancer Res 12: 6049-6055, 2006. erlotinib as first-line maintenance therapy for advanced NSCLC. 25 Akerley W, Boucher KM, Bentz JS, Arbogast K and Walters T: Eur J Cancer Supplements 7(2): 559 (abstr P-9176), 2009. A phase II study of erlotinib as initial treatment for patients with 36 Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, stage IIIB-IV non-small cell lung cancer. J Thorac Oncol 4: 214- Jackson JA, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, 219, 2009. Graham GA, Hughes GD, Thomas AP, Stokes ESE, Curry B, 26 Gridelli C, Butts C, Ciardiello F, Feld R, Gallo C and Perrone Richmond GHP, Wadsworth PF, Bigley AL and Hennequin LF: F: An international, multicenter, randomized phase III study of ZD6474 inhibits vascular endothelial growth factor signaling, first-line erlotinib followed by second-line cisplatin/gemcitabine angiogenesis, and tumor growth following oral administration. versus first-line cisplatin/gemcitabine followed by second-line Cancer Res 62: 4645-4655, 2002. erlotinib in advanced non-small-cell lung cancer: treatment 37 Ciardiello F, Bianco R, Damiano V, Fontanini G, Caputo R, rationale and protocol dynamics of the TORCH trial. Clin Lung Pomatico G, De Placido S, Bianco AR, Mendelsohn J and Cancer 9: 235-238, 2008. Tortora G: Antiangiogenic and antitumor activity of anti- 27 Miller VA, Riely GJ, Zakowski MF, Li AR, Patel JD, Heelan RT, epidermal growth factor receptor C225 monoclonal antibody in Kris MG, Sandler AB, Carbone DP, Tsao A, Herbst RS, Heller combination with vascular endothelial growth factor antisense G, Ladanvi M, Pao W and Johnson DH: Molecular characteristics oligonucleotide in human GEO colon cancer cells. Clin Cancer of bronchioloalveolar carcinoma and adenocarcinoma, bronchio- Res 6: 3739-3747, 2000. loalveolar carcinoma subtype, predict response to erlotinib. J Clin 38 Miller VA, O’Connor P, Soh C and Kabbinavar F: A randomized, Oncol 26: 1472-1478, 2008. double-blind, placebo-controlled, phase IIIb trial (ATLAS) 28 Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C and Lee comparing bevacizumab (B) therapy with or without erlotinib JS: Epidermal growth factor receptor tyrosine kinase inhibitors (E) after completion of chemotherapy with B for first-line as a first-line therapy for never-smokers with adenocarcinoma of treatment of locally advanced, recurrent, or metastatic non-small the lung having asymptomatic synchronous brain metastasis. cell lung cancer (NSCLC). J Clin Oncol 27(18S): 799s (abstr Lung Cancer 65: 351-354, 2009. LBA8002), 2009.

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39 Johnson B, Miller V, Amler L, Stern H, Soh C, O’Connor P and 47 Wu Y, Zhang L, Siu-Kie Au L, Cheng A, Park K, Kim H, Kabbinavar F: Biomarker evaluation in the randomized, double- Srimuninnimit V, Sriuranpong V, Lin M and Kuo H: Safety of blind, placebo-controlled, Phase IIIb ATLAS Trial, comparing erlotinib in TRUST, a phase IV trial in patients with advanced bevacizumab (B) therapy with or without erlotinib (E), after non-small cell lung cancer (NSCLC): initial results from the completion of chemotherapy with B for the treatment of locally- East/South East (E/SE) Asian subgroup. J Clin Oncol 25(18S): advance. Eur J Cancer Supplements 7(3): 5 (abstr 8LBA), 2009. 685s (abstr 18018), 2007. 40 Shepherd FA, Perira JR, Ciuleanu T, Tan EH, Hirsh V, 48 Schneider CP, Heigener D, Schott-von-Romer K, Gutz S, Laack Thongprasert S, Campos D, MaoleeKoonpiroj S, Smylie M, E, Digel W, Guschall WR, Franke A, Bodenstein H, Schmidtgen Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston C and Reck M: Epidermal growth factor receptor-related tumor D, Bezjak A, Clark G, Santabarbara P and Seymour L: Erlotinib markers and clinical outcomes with erlotinib in non-small cell in previously treated non-small-cell lung cancer. N Engl J Med lung cancer: an analysis of patients from german centers in the 353: 123-132, 2005. TRUST study. J Thorac Oncol 3: 1446-1453, 2008. 41 Bezjak A, Tu D, Seymour L, Clark G, Trajkovic A, Zukin M, 49 Tiseo M, Gridelli C, Cascinu S, Crinò L, Piantedosi FV, Grossi Ayoub J, Lago S, de Albuquerque Ribeiro R, Gerogianni A, F, Brandes AA, Labianca R, Siena S, Amoroso D, Belvedere O, Cyjon A, Noble J, Laberge F, Chan RT, Fenton D, von Pawel J, Valentino B, Bearz A, Venturino P and Ardizzoni A: An Reck M and Shepherd FA: Symptom Improvement in Lung expanded access program of erlotinib (Tarceva) in patients with Cancer Patients Treated With Erlotinib: Quality of Life Analysis advanced non-small cell lung cancer (NSCLC): data report from of the National Cancer Institute of Canada Clinical Trials Group Italy. Lung Cancer 64: 199-206, 2009. Study BR.21. J Clin Oncol 24: 3831-3837, 2006. 50 Pao W, Miller WA, Politi KA, Riely GJ, Somwar R, Zakowski 42 Clark GM, Zborowski DM, Sanatabarbara P, Ding K, Whitehead MF, Kris MG and Varmus H: Acquired resistance of lung M, Seymour L and Shepherd FA: Smoking history and adenocarcinomas to gefitinib or erlotinib is associated with a epidermal growth factor receptor expression as predictors of second mutation in the EGFR kinase domain. PLoS Med 2: e73, survival benefit from erlotinib for patients with non-small-cell 2005. lung cancer in the National Cancer Institute of Canada Clinical 51 Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Trials Group study BR.21. Clin Lung Cancer 7: 389-394, 2006. Meyerson M, Johnson BE, Eck MJ, Tenen DG and Halmos B: 43 Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Karnel-Reid S, Squire EGFR mutation and resistance of non-small-cell lung cancer to J, Lorimer I, Zhang T, Liu N, Daneshmand M, Marrano P, da gefitinib. N Engl J Med 352: 786-792, 2005. Cunha Santos G, Lagarde A, Richardson F, Seymour L, 52 Nguyen KS, Kobayashi S and Costa DB: Acquired resistance to Whitehead M, Ding K, Pater J and Shepherd FA: Erlotinib in epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer: molecular and clinical predictors of outcome. non-small-cell lung cancers dependent on the epidermal growth N Engl J Med 353: 133-144, 2005. factor receptor pathway. Clin Lung Cancer 10: 281-289, 2009. 44 Zhu CQ, da Cunha Santos G, Ding K, Sakurada A, Cutz JC, Liu 53 Gridelli C, Rossi A, Mongillo F, Bareschino M, Maione P and N, Zhang T, Marrano P, Whitehead M, Squire JA, Kamel-Reid Ciardiello F: A randomized phase II study of sorafenib/ S, Seymour L, Shepherd FA and Tsao MS: Role of KRAS and gemcitabine or sorafenib/erlotinib for advanced non-small-cell EGFR as biomarkers of response to erlotinib in National Cancer lung cancer in elderly patients or patients with a performance Institute of Canada Clinical Trials Group Study BR.21. J Clin status of 2: treatment rationale and protocol dynamics. Clin Oncol 26: 4268-4275, 2008. Lung Cancer 8: 396-398, 2007. 45 Hughes AN, O’Brien ME, Petty WJ, Chick JB, Rankin E, Woll PJ, Dunlop D, Nicolson M, Boinpally R, Wolf J and Price A: Overcoming CYP1A1/1A2-mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol 27: 1220-1226, 2009. 46 Hainsworth J and Herbst R: A phase III, multicenter, placebo- controlled, double-blind, randomizaed clinical trial to evaluate the efficacy of bevacizumab (AVASTIN®) incombination with erlotinib (TARCEVA®) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). J Thorac Oncol Received December 22, 2009 3(Suppl 4): S302 (abstr 189). Accepted March 2, 2010

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