Brian Holloway

Bio: Brian Holloway is an academic researcher from AstraZeneca. The author has contributed to research in topics: Epidermal growth factor receptor & Gefitinib. The author has an hindex of 4, co-authored 5 publications receiving 840 citations.

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer

Abstract: Purpose The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non–small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. Methods Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). Results High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expressio...

Epidermal growth factor receptor immunohistochemistry: comparison of antibodies and cutoff points to predict benefit from gefitinib in a phase 3 placebo-controlled study in advanced nonsmall-cell lung cancer.

Abstract: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs, gefitinib and erlotinib) are active in a subset of nonsmall-cell lung cancer (NSCLC) patients. The response rates and disease control rates reported in clinical trials of EGFR TKIs in advanced pretreated NSCLC patients in Western populations are 10% to 20% and 40%, respectively,1–3 indicating that a proportion of NSCLC patients do not derive any benefit from EGFR TKIs. A major research effort over the last decade focused on the identification of predictive biomarkers for response and survival benefit to EGFR TKIs, and many of these studies analyzed EGFR protein expression by immunohistochemistry as the most applicable method to assess the presence of molecular target in the tumor. Results of the ISEL (Iressa Survival Evaluation in Lung cancer) phase 3 clinical trial in advanced NSCLC patients who were refractory to or intolerant of their latest chemotherapy regimen showed some improvement in survival with gefitinib (plus best supportive care), which failed to reach statistical significance compared with placebo (plus best supportive care), in the overall population and in patients with adenocarcinoma.4 Preplanned subgroup analysis of the ISEL demonstrated a statistically significant increase in survival with gefitinib in patients of Asian ethnicity and in patients who had never smoked. A biomarker analysis of this study demonstrated a nonsignificant 23% reduction in the risk of death for gefitinib-treated patients who expressed EGFR protein as assessed by the EGFR Dako PharmDx kit with a cutoff point of 10% of cells exhibiting the staining of at least slight intensity.5 No benefit was observed in the subset of patients who were classified as EGFR protein-negative. The National Cancer Institute of Canada BR.21 clinical trial that demonstrated a significant improvement in survival of erlotinib versus placebo-treated advanced NSCLC patients who failed at least 1 chemotherapy regimen6 showed a 32% reduction in the risk of death for patients with EGFR protein-positive tumor samples.7 No survival advantage was seen among patients with EGFR protein-negative tumor samples. This study also used a cutoff point of 10% stained cells and the Dako PharmDx kit. In a retrospective evaluation of gefitinib-treated NSCLC patients, Cappuzzo et al.8 used Zymed anti-EGFR monoclonal antibody and a staining index that takes into account the percent of positive cells and staining intensity, scored from 0 to 4. Using a cutpoint of 200 on the scale from 0 to 400, superior survival was demonstrated in EGFR protein-positive versus negative patients (P = .01). However, other studies performed on tumor samples from phase 3 clinical trials investigating the combination of gefitinib or erlotinib with chemotherapy failed to show any predictive value of EGFR protein expression for either clinical response or survival.9,10 Also, there was no association with EGFR protein expression and survival for NSCLC patients who received gefitinib monotherapy in the phase 2 clinical studies IDEAL1 and 2 (Iressa Dose Evaluation in Advanced Lung cancer).11 Clinical trials of cetuximab, a monoclonal antibody targeted against the EGFR in both lung and colorectal cancer required EGFR protein expression in tumor samples for study entry in most trials. EGFR protein expression was evaluated by the EGFR PharmDx kit with cutoff points of at least 1+ (at least 1% or at least 10% of cells with weak staining according to individual study). More than 90% of screened patients were scored as EGFR protein-positive in phase 2 clinical studies with cetuximab in lung cancer12–14 and >75% in phase 2 or 3 colorectal cancer trials.15,16 Because these trials were performed largely in EGFR protein-positive patients, the efficacy of cetuximab in EGFR-negative patients remains unknown, although 1 report suggests that EGFR protein-negative colorectal cancer patients may respond to cetuximab.17 In a pivotal phase 3 clinical trial comparing cetuximab versus cetuximab and irinotecan in metastatic colorectal cancer that was refractory to treatment with irinotecan, the degree of EGFR staining did not associate with response rates in either study groups.15 The presence of mutations in the EGFR gene has also been investigated in tumor samples and is linked with increased responsiveness to EGFR TKIs in numerous NSCLC studies.5,18–20 An additional approach of measuring the EGFR gene copy number in tumor samples has also demonstrated a survival advantage for patients with a high copy number in prospective placebo-controlled clinical trials.5,7,21 These 2 gene-based biomarkers appear to outperform EGFR protein evaluation in predicting the benefit from EGFR TKIs, but, particularly for EGFR mutations, prospective placebo-controlled clinical studies are lacking. In contrast to the above evaluations of EGFR gene mutations and copy number, EGFR immunohistochemistry is a widely applicable and inexpensive test to conduct. HER-2 protein expression evaluation by immunohistochemistry, in conjunction with HER-2 FISH assay, is used for the selection of breast cancer patients most likely to benefit from trastuzumab therapy,22 and HER-2 gene copy number has been closely associated with HER-2 protein expression.23 This biomarker study of the placebo-controlled ISEL trial has provided us the opportunity to compare 2 antibodies (Dako and Zymed), which have previously been associated with clinical outcome for NSCLC patients treated with gefitinib, and evaluate whether different cutoff levels of protein expression could improve the prediction of response and survival benefit from gefitinib.

Identification of biomarkers in human head and neck tumor cell lines that predict for in vitro sensitivity to gefitinib.

Abstract: Potential biomarkers were identified for in vitro sensitivity to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in head and neck cancer. Gefitinib sensitivity was determined in cell lines, followed by transcript profiling coupled with a novel pathway analysis approach. Eleven cell lines were highly sensitive to gefitinib (inhibitor concentration required to give 50% growth inhibition [GI(50)] 7 microM); an exploratory principal component analysis revealed a separation between the genomic profiles of sensitive and resistant cell lines. Subsequently, a hypothesis-driven analysis of Affymetrix data (Affymetrix, Inc., Santa Clara, CA, USA) revealed higher mRNA levels for E-cadherin (CDH1); transforming growth factor, alpha (TGF-alpha); amphiregulin (AREG); FLJ22662; EGFR; p21-activated kinase 6 (PAK6); glutathione S-transferase Pi (GSTP1); and ATP-binding cassette, subfamily C, member 5 (ABCC5) in sensitive versus resistant cell lines. A hypothesis-free analysis identified 46 gene transcripts that were strongly differentiated, seven of which had a known association with EGFR and head and neck cancer (human EGF receptor 3 [HER3], TGF-alpha, CDH1, EGFR, keratin 16 [KRT16], fibroblast growth factor 2 [FGF2], and cortactin [CTTN]). Polymerase chain reaction (PCR) and enzyme-linked immunoabsorbant assay analysis confirmed Affymetrix data, and EGFR gene mutation, amplification, and genomic gain correlated strongly with gefitinib sensitivity. We identified biomarkers that predict for in vitro responsiveness to gefitinib, seven of which have known association with EGFR and head and neck cancer. These in vitro predictive biomarkers may have potential utility in the clinic and warrant further investigation.

Epidermal growth factor receptor (EGFR) immunohistochemistry: Comparison of antibodies (Abs) and cut points to predict benefit from gefitinib in a phase III placebo-controlled study in advanced non-small cell lung cancer (NSCLC)

Abstract: 7576 Background: Tumor tissues obtained from the ISEL phase III trial assessing the efficacy of gefitinib vs placebo in chemotherapy-pretreated NSCLC were used to evaluate two Abs (DAKO and Zymed) ...

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

Abstract: METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

Epidermal growth factor receptor mutations in lung cancer

Abstract: The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.

EGFR Antagonists in Cancer Treatment

Abstract: Functional activation of growth factors and receptors of the epidermal growth factor receptor (EGFR) family occurs in most epithelial-cell cancers, rendering EGFR a target for cancer treatment. This article discusses the mechanisms of action of EGFR inhibitors, their anticancer activity, and clinical issues concerning their use in the treatment of patients with cancer.

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

Abstract: Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatmen...