Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

BACKGROUND:

Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR‐tyrosine kinase inhibitors (EGFR‐TKI) in patients with nonsmall cell lung cancer (NSCLC).

METHODS:

The authors tested the possibility that nucleotide sequencing may be poorly suited for detection of mutations in tumor samples and found that denaturing high‐performance liquid chromatography (dHPLC) was an efficient and more sensitive method for screening.

RESULTS:

These results suggested that some reports based on standard DNA sequencing techniques may have underestimated mutation rates. In the present report, the authors examined the relationship between the presence and type of EGFR mutations detected by dHPLC and various clinicopathologic features of NSCLC, including response to therapy with EGFR‐TKI. Among 251 patients with advanced disease, 100 individuals received EGFR‐TKI. Those whose tumors harbored a detectable EGFR kinase mutation were much more likely to have a partial response (PR) or stable disease (SD) with EGFR‐TKI therapy than patients whose tumor contained no mutation (80% vs 35%; P = .001). Among the individual genotype subgroups, the frequency of a PR or SD was significantly different between patients with an exon 19 deletion compared with those with no detectable mutation (86% vs 35%; P < .001). Furthermore, patients whose tumors expressed an exon 19 mutant EGFR isoform exhibited a trend toward better EGFR‐TKI response (86% vs 67%; P = .171) and improved survival compared with patients whose tumors expressed an exon 21 mutation.

CONCLUSIONS:

Our findings warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types. Cancer 2010. © 2010 American Cancer Society.     

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.     

Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild‐type nonsmall cell lung cancer treated with EGFR‐tyrosine kinase inhibitors

BACKGROUND:

In patients with nonsmall cell lung cancer (NSCLC), several studies have demonstrated a positive correlation between somatic mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase domain and clinical outcomes with the use of EGFR tyrosine kinase inhibitors (TKIs). However, some patients with wild‐type (WT) EGFR also responded to EGFR TKIs and remained stable. Recently, amphiregulin (AR) has been suggested as a predictive marker for EGFR TKIs in patients with WT EGFR‐positive NSCLC. The objective of the current study was to evaluate the association between AR expression and the efficacy of using EGFR TKIs in the treatment of patients with WT EGFR‐positive NSCLC.

METHODS:

Seventy‐three patients with WT EGFR‐positive NSCLC received treatment with gefitinib or erlotinib between May 2005 and December 2008. AR expression was assessed by immunohistochemistry.

RESULTS:

The clinical response to EGFR TKIs was reassessed for all patients as follows: 16 of 73 patients had a partial response (21.9%), 12 patients had stable disease (16.5%), and 45 patients had progressive disease (61.6%). AR expression was positive in 24 of 40 patients (60%). The ability to achieve disease control did not differ significantly between AR‐positive patients and AR‐negative patients (P = .188). At a median follow‐up of 25.4 months (range, 10.5‐53.3 months), progression‐free survival was 8.1 weeks in AR‐positive patients and 4 weeks in AR‐negative patients (P = .025), and overall survival was significantly longer in AR‐positive patients than in AR‐negative patients (12.2 months vs 4.1 months; P = .001).

CONCLUSIONS:

The current results suggested that patients with WT EGFR‐positive NSCLC who have AR‐positive tumors may benefit clinically from treatment with EGFR TKIs, indicating that AR expression may be a potential marker for the selection of EGFR‐TKI treatment for patients with WT EGFR‐positive NSCLC. Cancer 2011. © 2010 American Cancer Society.     

Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors

BACKGROUND:

Most patients with nonsmall cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The authors investigated the involvement of insulinlike growth factor 1 receptor (IGF‐1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF‐1R TKIs.

METHODS:

Phosphorylated IGF‐1R/insulin receptor (pIGF‐1R/IR) was immunohistochemically evaluated in an NSCLC tissue microarray. The authors analyzed the antitumor effects of an IGF‐1R TKI (PQIP or OSI‐906), either alone or in combination with a small‐molecular inhibitor (PD98059 or U0126) or with siRNA targeting K‐Ras or mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K‐Ras mutations.

RESULTS:

pIGF‐1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant K‐Ras, and wild‐type (WT) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF‐1R TKIs exhibited significant antitumor activity in NSCLC cells with WT EGFR and WT K‐Ras but not in those with mutations in these genes. Introduction of mutant K‐Ras attenuated the effects of IGF‐1R TKIs on NSCLC cells expressing WT K‐Ras. Conversely, inactivation of MEK restored sensitivity to IGF‐TKIs in cells carrying mutant K‐Ras.

CONCLUSIONS:

The mutation status of both EGFR and K‐Ras could be a predictive marker of response to IGF‐1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF‐1R TKIs. Cancer 2012. © 2012 American Cancer Society.     

非小细胞肺癌EGFR不同突变状态的脑转移发生特点及治疗

目的 有研究显示,表皮生长因子受体(epidermal growth factor receptor,EGFR)的突变状态,与非小细胞肺癌(non-small cell lung cancer,NSCLC)脑转移存在相关性.本研究进一步探讨EGFR不同突变状态的NSCLC患者,脑转移发生的特点以及相应的治疗.方法 选取2009-04-01-2014-12-01中国人民解放军火箭军总医院肿瘤科病理确诊断的231例NSCLC患者的临床资料,进行回顾性研究.并应用实时定量PCR方法,检测上述患者的EGFR突变状态.利用x2检验比较EGFR不同突变状态的患者,脑转移特点的差异.Kaplan-Meier法进行生存分析.结果 EGFR检测结果示野生型119例,18、19、20、21号外显子及19/21双突变的分别有3例、58例、5例、42例和4例.19号外显子突变患者的脑转移发生率(55.2％)显著高于野生型患者(41.2％),P=0.04.伴21号外显子突变＞3个脑转移病灶患者(47.6％)的比例显著高于野生型患者(28.6％),P＜0.01.此外,伴21号外显子突变患者的中位脑转移年龄(63岁)也显著高于野生型患者(52岁),P=0.02.对于伴有EGFR突变的脑转移患者,脑转移后接受过酪氨酸激酶抑制剂(tyro-sine kinase inhibitors,TKIs)的患者,其中位脑转移后生存期显著长于接受常规化疗的患者(未达到vs 9个月),P=0.01.结论 伴EGFR特定位点突变的患者有更高的脑转移发生率、脑转移数目及脑转移时年龄.TKIs可改善伴EG-FR突变脑转移患者的预后.     

Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer

BACKGROUND:

The discovery of distinct subsets of nonsmall cell lung cancer (NSCLC) characterized by activation of driver oncogenes has greatly affected personalized therapy. It is hypothesized that the dominant oncogene in NSCLC would be associated with distinct patterns of metastatic spread in NSCLC at the time of diagnosis.

METHODS:

A total of 209 consecutive patients with stage IV nonsquamous NSCLC with an EGFR (epidermal growth factor receptor) mutation (N = 39), KRAS (v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog) mutation (N = 49), ALK (anaplastic lymphoma receptor tyrosine kinase) gene rearrangement (N = 41), or wild‐type for all 3 (triple negative, N = 80) were included. The percentage of patients with metastatic disease at a given site was compared between each molecular cohort (EGFR, KRAS, or ALK) and the triple negative cohort.

RESULTS:

ALK gene rearrangement was significantly associated with pericardial disease (odds ratio [OR] = 4.61; 95% confidence interval [CI] = 1.30, 16.37; P = .02) and pleural disease (OR = 4.80; 95% CI = 2.10, 10.97; P < .001). Patients with ALK gene rearrangements (OR = 5.50; 95% CI = 1.76, 17.18; P = .003) and patients with EGFR mutations (OR = 5.17; 95% CI = 1.63, 16.43; P = .006) were predisposed to liver metastasis compared to the triple negative cohort. No molecular cohort had a predisposition to pulmonary nodules, or adrenal, bone, or brain metastasis compared to the triple negative cohort. The mean number of metastatic disease sites in patients within the ALK rearranged cohort was significantly greater than that of the triple negative cohort (mean = 3.6 sites vs 2.5 sites, P < .0001).

CONCLUSIONS:

The results support the hypothesis that the dominant molecular oncogenes in NSCLC are associated with different biological behaviors manifesting as distinct patterns of metastatic spread at the time of diagnosis. Cancer 2012. © 2012 American Cancer Society.     

Retracted: Genistein enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitors and inhibits nuclear factor kappa B in nonsmall cell lung cancer cell lines

BACKGROUND:

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) have shown modest clinical benefit in patients with relapsed nonsmall cell lung cancer (NSCLC). Down‐regulation of Akt appears to correlate with the antitumor activity of EGFR‐TKIs. Akt activates nuclear factor kappa B (NF‐κB), which transcribes genes important for cell survival, invasion, and metastasis. The authors hypothesized that genistein, through the inhibition of NF‐κB, could enhance the activity of EGFR‐TKIs in NSCLCs.

METHODS:

Three NSCLC cell lines with various EGFR mutation status and sensitivities to EGFR‐TKIs were selected: H3255 (L858R), H1650 (del E746‐A750), and H1781 (wild‐type EGFR). Cells were treated with erlotinib, gefitinib, genistein, or the combination of each of the EGFR‐TKIs with genistein. Cell survival and apoptosis were assessed, and expression levels of EGFR, pAkt, cyclooxygenase‐2 (COX‐2), E‐cadherin, prostaglandin E₂ (PGE₂), and NF‐κB were measured.

RESULTS:

Both EGFR‐TKIs demonstrated growth inhibition and apoptosis in each of the cell lines, but H1650 and H1781 were much less sensitive. Genistein demonstrated some antitumor activity in all cell lines, but enhanced growth inhibition and apoptosis when combined with the EGFR‐TKIs in each of the cell lines. Both combinations down‐regulated NF‐κB significantly more than either agent alone in H3255. In addition, the combinations reduced the expression of EGFR, pAkt, COX‐2, and PGE_2, consistent with inactivation of NF‐κB.

CONCLUSIONS:

The authors concluded that genistein enhances the antitumor effects of EGFR‐TKIs in 3 separate NSCLC cell lines. This enhanced activity is in part because of greater reduction in the DNA‐binding activity of NF‐κB when EGFR‐TKIs were combined with genistein. Cancer 2009. © 2009 American Cancer Society.     

KRAS mutation status in primary nonsmall cell lung cancer and matched metastases

BACKGROUND:

The objective of this study was to determine whether the mutation status of the v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) differed between primary tumors and matched distant metastases in nonsmall cell lung cancer (NSCLC).

METHODS:

Patients who underwent resection for both primary NSCLC and matched distant metastases were included in the study. KRAS and EGFR mutation status were assessed by polymerase chain reaction (PCR) amplification and direct sequencing on both primary tumors and metastases. For KRAS analysis, mutant‐enriched PCR (ME‐PCR) was performed in case of discordance between a primary tumor and its matched metastasis.

RESULTS:

Twenty‐one patients were included. No EGFR mutations were detected. KRAS mutations were detected in 6 patients (28%). In all patients, the mutations identified by direct sequencing were discordant between the primary tumor and the matched metastasis. The use of ME‐PCR allowed a resolution of the discordance in 3 of the 6 cases by demonstrating the presence of low levels of mutant KRAS in lesions that were negative by direct sequencing.

CONCLUSIONS:

Highly sensitive tools are required to identify biomarkers. The KRAS mutation status mostly was concordant between primary tumors and matched distant metastases. In a few patients, KRAS mutation status differed between different tumor sites. Cancer 2010. © 2010 American Cancer Society.     

表皮生长因子受体突变:gefitinib和erlotinib治疗非小细胞肺癌的靶点研究进展

Gefitinib和erlotinib是表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)类药物,是目前治疗非小细胞肺癌(NSCLC)的热点,已在多个临床试验中证实,东亚人群、女性、无吸烟史和腺癌患者有效,进一步的研究揭示癌症病人EGFR酪氨酸激酶区突变与对EGFR-TKI的敏感性密切相关。这些突变包括框架缺失、点突变等多种类型。本文综述了EGFR突变的研究现状和进展。     

Comparative analyses of overall survival in patients with anaplastic lymphoma kinase-positive and matched wild-type advanced nonsmall cell lung cancer

BACKGROUND:

The purpose of this study was to investigate the overall survival (OS) of patients with advanced ALK‐positive nonsmall cell lung cancer (NSCLC) who were managed in the pre‐ALK inhibitor era and to compare their survival with that of a matched case cohort of ALK wild‐type (WT) patients.

METHODS:

Data from 1166 patients who had stage IIIB/IV NSCLC with nonsquamous histology were collected from the NSCLC database of Seoul National University Hospital between 2003 and 2009. ALK fluorescence in situ hybridization (FISH) was used to analyze 262 patients who either had the WT epidermal growth factor receptor (EGFR) or were nonresponders to previous EGFR tyrosine kinase inhibitor (TKI) therapy. Overall survival (OS) was compared between 3 groups: 1) ALK‐positive patients, 2) EGFR mutation‐positive patients, and 3) ALK‐WT/EGFR‐WT patients. Progression‐free survival (PFS) after first‐line chemotherapy and EGFR TKIs also was analyzed.

RESULTS:

Twenty‐three patients were ALK‐positive according to FISH analysis and did not receive ALK inhibitors during follow‐up. The median OS for ALK‐positive patients, EGFR mutation‐positive patients, and WT/WT patients was 12.2 months, 29.6 months, and 19.3 months, respectively (vs EGFR mutation‐positive patients, P = .001; vs WT/WT, P = .127). The PFS after first‐line chemotherapy for the 3 groups was not different. However, the PFS for patients who received EGFR TKIs was shorter in ALK‐positive patients compared with the other 2 groups (vs EGFR mutation‐positive patients, P < .001; vs WT/WT, P < .021).

CONCLUSIONS:

In the pre‐ALK inhibitor era, ALK‐positive patients experienced the shortest survival, although it did not differ statistically from that of WT/WT patients. Although their responses to platinum‐based chemotherapy were not different from comparator groups, ALK‐positive patients were even more resistant to EGFR TKI treatment than WT/WT patients. Cancer 2012;3579–3586. © 2011 American Cancer Society.     

EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer

A small subset of patients with nonsmall cell lung cancer (NSCLC) harbors mutations in the epidermal growth factor receptor (EGFR) that predict unique sensitivity to EGFR tyrosine kinase inhibitors (TKIs). The characteristics and behavior of brain metastases (BMs) in these patients have not been well described. The longitudinal records of all NSCLC patients who underwent EGFR mutation screening at our center from August 2004 to November 2008 were reviewed for eligibility, and 93 patients were identified who developed BM during the course of their disease. Survival was estimated using the Kaplan–Meier method and the log-rank test. Multivariable predictors were assessed via the Cox proportional hazards model. Among the 93 patients with BM, 41 (44%) had mutations in EGFR, including 13 exon 19 deletions and 12 L858R mutations. Eighty-three percent of patients with BM were treated initially with whole brain radiation, either alone (53%) or in combination with craniotomy for neurosurgical resection (22%) or stereotactic radiosurgery (8%). Median survival from the time of BM was 11.7 months and was longer for patients with an EGFR mutation (14.5 vs 7.6 months, P = .09). On multivariable analysis, EGFR mutation (HR: 0.50, 95% CI: 0.30–0.82), age (HR: 1.03, 95% CI: 1.00–1.05), and active extracranial disease (HR: 3.30, 95% CI: 1.70–6.41) were independently associated with survival. In NSCLC patients with BM, EGFR mutation status is associated with improved survival, independent of age, functional status, extracranial disease status, and number of BMs.     

EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer

BACKGROUND:

Somatic mutations in the epidermal growth factor receptor (EGFR) are present in ～10% of nonsmall cell lung cancers, and higher in never‐smokers, women, and Asians. Small in‐frame deletions in exon 19 (～45%) and L858R mutation in exon 21 (～40%) predict response to treatment with tyrosine kinase inhibitors, whereas some others herald resistance. Direct sequencing of tumor DNA detects all EGFR mutations, but is limited by interference from nonmalignant cells within the samples. Concern over such interference has discouraged testing cytologic samples, but the adequacy of cytologic specimens for EGFR sequencing has not been studied.

METHODS:

EGFR sequencing of surgical and cytologic specimens at Brigham and Women's Hospital over the past 2 years was reviewed. Of 239 specimens, 227 (95%) were surgical, and 12 (5%) were cytologic (fine needle aspirations, pleural fluids, bronchial washings, and bronchoalveolar lavages).

RESULTS:

Sixty‐three (28%) surgical specimens showed EGFR mutations, whereas 143 (63%) were negative, 8 (3.5%) failed, and 14 (6.2%) were inconclusive (negative result in a heterogeneous sample). Seven (58%) cytologic specimens showed EGFR mutations, whereas 4 (33%) were negative, and 1 (8.3%) was inconclusive. Cytologic specimens were more likely to have a mutation than surgical specimens (P = .02). There was no significant difference in the frequency of inconclusive results.

CONCLUSIONS:

Cytologic specimens are suitable for EGFR sequencing and show comparable sensitivity for mutation detection as compared with surgical specimens. The suitability of a sample should be determined on a case‐by‐case basis, and cytologic samples should not be dismissed as inadequate without a thorough review. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

表皮生长因子受体与酪氨酸激酶抑制剂在肿瘤防治中的应用进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)信号传递系统可调控细胞周期，调节细胞生长与分化，促进损伤修复。EGFR在包括非小细胞肺癌(non-small-cell lung cancer,NSCLC)在内的多种上皮源性肿瘤中过表达预示存活率低、预后差、转移可能性大，可作为肿瘤基因治疗的靶位。酪氨酸激酶抑制剂(tyrosine kinase inhibitors，TKIs)可选择性抑制EGFR酪氨酸激酶活性，抑制肿瘤生长，增加放化疗敏感性。     

Response to dual blockade of epidermal growth factor receptor (EGFR) and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutational status of the tumor

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefit in patients with nonsmall cell lung cancer (NSCLC), particularly those with tumors that have EGFR-TK domain mutations. Moreover, the EGFR and cyclooxygenase (COX)-2 pathways are known to enhance the procarcinogenic effects of each other in different tumor types. Therefore, it was hypothesized that tumor EGFR mutation status may influence the effectiveness of simultaneous EGFR and COX-2 inhibition in patients with NSCLC. METHODS: Three NSCLC cell lines with varying EGFR mutation status and sensitivities to EGFR-TKIs were selected: H3255 (L858R), H1650 (del E746-A750), and H1781 (wild-type EGFR). Cells were treated with erlotinib, gefitinib, or celecoxib alone, and the combination of both EGFR-TKI inhibitors with celecoxib. Cell survival and apoptosis was assessed and correlated with the expression of COX-2, EGFR, pEGFR, Akt, pAkt, expression, and derived prostaglandin E2 (PGE(2)). RESULTS: Celecoxib by itself was found to have no effects on cell growth or apoptosis in any of the cell lines. Erlotinib and gefitinib inhibited cell growth and induced apoptosis in both mutant cell lines and did so in H1781 cells at 10-fold higher concentrations. Celecoxib when added to erlotinib or gefitinib significantly enhanced the antiproliferative and proapoptotic effects in both mutant cell lines but had no additional effects in H1781 cells. Greater down-regulation of COX-2, EGFR, pEGFR, Akt, pAkt, and PGE(2) was found when H3255 cells were treated with the combination compared with any of the single agents alone. CONCLUSIONS: The results of the current study demonstrate that the effectiveness of the addition of celecoxib to an EGFR-TKI is significantly greater in NSCLC cells with EGFR mutations, which is likely due to more complete inhibition of both pathways.     

Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials

The epidermal growth factor receptor (EGFR) is a growth factor receptorthat induces cell differentiation and proliferation upon activation throughthe binding of one of its ligands. The receptor is located at the cellsurface, where the binding of a ligand activates a tyrosine kinase in theintracellular region of the receptor. This tyrosine kinase phosphorylates anumber of intracellular substrates that activates pathways leading to cellgrowth, DNA synthesis and the expression of oncogenes such as fos and jun.EGFR is thought to be involved the development of cancer, as the EGFRgene is often amplified, and/or mutated in cancer cells.In this review we will focus on: (I) the structure and function of EGFR,(II) implications of receptor/ligand coexpression and EGFR mutations oroverexpression, (III) its effect on cancer cells, (IV) the development of themalignant phenotype and (V) the clinical aspects of therapeutic targeting ofEGFR.     

Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell lung cancer: a multicenter phase 2 study

BACKGROUND.

Cetuximab, an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, has demonstrated evidence of activity in nonsmall cell lung cancer (NSCLC). When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab has exhibited synergistic interaction in preclinical studies. Therefore, a phase 2 study was conducted to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC.

METHODS.

Chemotherapy‐naïve patients aged ≥18 years with stage IIIB (with effusion) or stage IV NSCLC received cetuximab (at a dose of 400 mg/m² on Day 1 and 250 mg/m² on Days 8 and 15) plus docetaxel (at a dose of 75 mg/m² on Day 1) and carboplatin (area under the concentration vs time curve [AUC] = 6 on Day 1) every 21 days for up to 6 cycles (graded according to the American Joint Committee on Cancer Staging System). Thereafter, patients without evidence of disease progression were continued on single‐agent cetuximab for a maximum of 1 year or until disease progression. The primary endpoint was response rate.

RESULTS.

Eighty patients were enrolled. The median number of cycles administered was 4 (range, 1‐6 cycles). The objective response rate was 15.2%, with a median progression‐free survival of 4.6 months and a median overall survival of 10.3 months. The salient grades 3 of 4 adverse events were neutropenia (30%), hypotension (3%), hypokalemia (4%), and hypomagnesemia (3%). Twenty‐five patients received single‐agent cetuximab (median duration, 12 weeks) and this was well tolerated.

CONCLUSIONS.

The results of this large, multicenter, phase 3 study indicate that the novel combination of cetuximab with docetaxel and carboplatin demonstrate modest anticancer activity for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. Cancer 2008. © 2008 American Cancer Society.     

Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer

Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated antitumour activity and favourable tolerability in Phase II studies. We investigated whether EGFR expression levels could predict for response to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC), who received gefitinib (250 mg day(-1)) as part of a worldwide compassionate-use programme. Tissue samples were analysed by immunohistochemistry to assess membrane EGFR immunoreactivity. Of 147 patients enrolled in our institution, 50 patients were evaluable for assessment of both clinical response and EGFR expression. The objective tumour response rate was 10% and disease control was achieved in 50% of patients. Although high EGFR expression was more common in squamous-cell carcinomas than adenocarcinomas, all objective responses were observed in patients with adenocarcinoma. Response and disease control with gefitinib were not associated with high EGFR expression. Overall, median survival was 4 months, and the 1-year survival rate was 18%. Strong EGFR staining correlated with shorter survival time for all patients. Gefitinib demonstrated promising clinical activity in this group of patients with NSCLC. These results have also shown that EGFR expression is not a significant predictive factor for response to gefitinib.