Showing papers by "Bruce E. Johnson published in 2010"
TL;DR: Criteria be used to define more precisely acquired resistance to EGFR TKIs and should minimize reporting of false-positive and false-negative activity in these clinical trials and would facilitate the identification of agents that truly overcome acquired Resistance to gefitinib and erlotinib.
Abstract: Ten percent of North American patients with non–small-cell lung cancer have tumors with somatic mutations in the gene for the epidermal growth factor receptor (EGFR). Approximately 70% of patients whose lung cancers harbor somatic mutations in exons encoding the tyrosine kinase domain of EGFR experience significant tumor regressions when treated with the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, the overwhelming majority of these patients inevitably acquire resistance to either drug. Currently, the clinical definition of such secondary or acquired resistance is not clear. We propose the following criteria be used to define more precisely acquired resistance to EGFR TKIs. All patients should have the following criteria: previous treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib); either or both of the following: a tumor that harbors an EGFR mutation known to be associated with drug sensitivity or objective clinical benefit from treatment with an EGFR TKI; syst...
715 citations
TL;DR: A novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors.
Abstract: Purpose: Approximately 5% of lung adenocarcinomas harbor an EML4-ALK gene fusion and define a unique tumor group that may be responsive to targeted therapy. However ALK -rearranged lung adenocarcinomas are difficult to detect by either standard fluorescence in situ hybridization or immunohistochemistry (IHC) assays. In the present study, we used novel antibodies to compare ALK protein expression in genetically defined lung cancers and anaplastic large cell lymphomas. Experimental Design: We analyzed 174 tumors with one standard and two novel monoclonal antibodies recognizing the ALK protein. Immunostained tissue sections were assessed for the level of tumor-specific ALK expression by objective quantitative image analysis and independently by three pathologists. Results: ALK protein is invariably and exclusively expressed in ALK -rearranged lung adenocarcinomas but at much lower levels than in the prototypic ALK -rearranged tumor, anaplastic large cell lymphoma, and as a result, is often not detected by conventional IHC. We further validate a novel IHC that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK -rearranged lung adenocarcinomas in biopsy specimens, with excellent interobserver agreement between pathologists (κ statistic, 0.94). Conclusions: Low levels of ALK protein expression is a characteristic feature of ALK -rearranged lung adenocarcinomas. However, a novel, highly sensitive IHC assay reliably detects lung adenocarcinomas with ALK rearrangements and obviates the need for fluorescence in situ hybridization analysis for the majority of cases, and therefore could be routinely applicable in clinical practice to detect lung cancers that may be responsive to ALK inhibitors. Clin Cancer Res; 16(5); 1561–71
421 citations
TL;DR: The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy, supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC).
Abstract: Summary Background Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). Methods Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB–IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m 2 intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. Findings 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0·79, 97·58% CI 0·70–0·90; p vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group). Interpretation The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. Funding AstraZeneca.
398 citations
TL;DR: The data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advancedNSCLC patients.
Abstract: Purpose: Gefitinib and erlotinib can penetrate into the central nervous system (CNS) and elicit responses in patients with brain metastases (BM) from non–small cell lung cancer (NSCLC). However, there are incomplete data about their impact on the development and control of CNS metastases. Experimental Design: Patients with stage IIIB/IV NSCLC with somatic EGFR mutations initially treated with gefitinib or erlotinib were identified. The cumulative risk of CNS progression was calculated using death as a competing risk. Results: Of the 100 patients, 19 had BM at the time of diagnosis of advanced NSCLC; 17 of them received CNS therapy before initiating gefitinib or erlotinib. Eighty-four patients progressed after a median potential follow-up of 42.2 months. The median time to progression was 13.1 months. Twenty-eight patients developed CNS progression, 8 of whom had previously treated BM. The 1- and 2-year actuarial risk of CNS progression was 7% and 19%, respectively. Patient age and EGFR mutation genotype were significant predictors of the development of CNS progression. The median overall survival for the entire cohort was 33.1 months. Conclusions: Our data suggest a lower risk of CNS progression in patients with advanced NSCLC and somatic EGFR mutations initially treated with gefitinib or erlotinib than published rates of 40% in historical series of advanced NSCLC patients. Further research is needed to distinguish between the underlying rates of developing CNS metastases between NSCLC with and without EGFR mutations and the impact of gefitinib and erlotinib versus chemotherapy on CNS failure patterns in these patients. Clin Cancer Res; 16(23); 5873–82. ©2010 AACR.
200 citations
TL;DR: Almost perfect agreement was observed in response assessment after erlotinib therapy compared with RECIST 1.0, and the recently published revised Response Evaluation Criteria in Solid Tumors guidelines provided almost perfect agreement.
Abstract: OBJECTIVE. The purpose of this article is to compare the recently published revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1) to the original guidelines (RECIST 1.0) for advanced non–small cell lung cancer (NSCLC) after erlotinib therapy and to evaluate the impact of the new CT tumor measurement guideline on response assessment.MATERIALS AND METHODS. Forty-three chemotherapy-naive patients with advanced NSCLC treated with erlotinib in a single-arm phase 2 multicenter open-label clinical trial were retrospectively studied. CT tumor measurement records using RECIST 1.0 that were generated as part of the prospective clinical trial were reviewed. A second set of CT tumor measurements was generated from the records to meet RECIST 1.1 guidelines. The number of target lesions, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0.RESULTS. The number of target lesions according to RECIST 1.1 decreased in 22 patients (51%) and did not change in ...
191 citations
TL;DR: Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone; CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.
Abstract: Purpose There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. Methods Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non–small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. Results VEGF increased and sVEGFR-2 decreased by day 43...
127 citations
TL;DR: The ATLAS study was designed to evaluate B + placebo following B + platin-containing doublet chemo in patients with stage III cancer and showed promising results.
Abstract: 7526 Background: The ATLAS study (n=768) was designed to evaluate B (15 mg/kg q3w)+ E (150 mg qd) vs. B + placebo (PL) following B + platin-containing doublet chemo in patients (pts) with stage III...
112 citations
TL;DR: It is concluded that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphoteric in B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.
Abstract: Background. Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients. Methods. We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and highperformance liquid chromatography-MS-MS were used to measure amphotericin B. Results.Concentrations of amphotericin B in ELF (median, 25–75 IQR) were at 4 hr (n5) 7.20g/mL (1.3–17.6), 24 hr(n6)8.26g/mL(3.9–82.7),48hr(n5)2.15g/mL(1.4–5.5),72hr(n4)1.25g/mL(0.75–5.5),96hr(n6) 0.86g/mL(0.55–1.4),120hr(n4)1.04g/mL(0.44–1.6),144hr(n1),4.25g/mL,168hr(n3)1.14g/mL,and 192hr(n1)1g/mL.Theplasmaconcentrationofthedrugremainedbelow0.08g/mLatalltimepoints.Duringthe study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec. Conclusions. We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.
47 citations
TL;DR: In this single center trial, ACsA appears to ameliorate important pulmonary function parameters in lung transplant recipients compared to aerosol placebo and historical control patients.
Abstract: Background: Chronic rejection, manifesting as bronchiolitis obliterans, is the leading cause of death in lung transplant recipients. In our previously reported double-blinded, placebo-cont...
44 citations
TL;DR: The case of a 63-year-old woman with PAM who is the oldest successful lung transplant recipient with end-stage PAM reported is presented and the outcomes of other cases of PAM after lung transplantation are reviewed.
25 citations
TL;DR: A protective association between childbearing and lung cancer is observed, adding to existing evidence that reproductive factors may moderate lung cancer risk in women.
Abstract: Patterns of lung cancer incidence suggest that gender-associated factors may influence lung cancer risk. Given the association of parity with risk of some women's cancers, the authors hypothesized that childbearing history may also be associated with lung cancer. Women enrolled in the Lung Cancer Susceptibility Study at Massachusetts General Hospital (Boston, Massachusetts) between 1992 and 2004 (1,004 cases, 848 controls) were available for analysis of the association between parity and lung cancer risk. Multivariate logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. After results were controlled for age and smoking history, women with at least 1 child had 0.71 times the odds of lung cancer as women without children (odds ratio = 0.71, 95% confidence interval: 0.52, 0.97). A significant linear trend was found: Lung cancer risk decreased with increasing numbers of children (P < 0.001). This inverse association was stronger in never smokers (P = 0.12) and was limited to women over age 50 years at diagnosis (P = 0.17). Age at first birth was not associated with risk. The authors observed a protective association between childbearing and lung cancer, adding to existing evidence that reproductive factors may moderate lung cancer risk in women.
TL;DR: This phase I/II study is evaluating the combination of RAD001 and E (R+E) in pts with advanced NSCLC who progressed after ≤2 prior chemotherapy regimens, and phase I results established the recommended dose for the R+E combination.
Abstract: 7524 Background: Everolimus (RAD001) is an oral mTOR inhibitor that has been evaluated as monotherapy in a phase II study of NSCLC patients (pts) previously treated with platinum-based chemotherapy...
TL;DR: VAN (100 mg/day) + D significantly prolonged PFS in ZODIAC, which included prospective exploratory analyses of...
Abstract: 7516 Background: VAN is a once-daily oral inhibitor of VEGFR, EGFR, and RET signaling. VAN (100 mg/day) + D significantly prolonged PFS in ZODIAC, which included prospective exploratory analyses of...
TL;DR: Given the reservations about survival advantage and economic viability of cardiac transplantation in United Network for Organ Sharing status II patients, properly structured clinical trials to compare LVADs with transplantation or continued medical therapy are indicated and probably overdue.
TL;DR: Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised, double-blind, placebo-controlled trial shows promising results.
Abstract: Source Citation Chlebowski RT, Schwartz AG, Wakelee H, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised...