Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial.

BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer. METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23-4·50, for gefitinib vs 3·67 months, 95% CI 2·97-4·37, for placebo; hazard ratio [HR] 0·90, 95% CI 0·74-1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -8·61, 95% CI -14·49 to -2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI -2·33 to 7·72, n=231, p=0·293), dysphagia (-3·18, 95% CI -8·36 to 2·00, n=231, p=0·228), and eating (-4·11, 95% CI -9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23-1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07-1·37 in the placebo group; HR 0·80, 95% CI 0·66-0·96, p=0·020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. FUNDING: Cancer Research UK.

Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas.

PURPOSE: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents. EXPERIMENTAL DESIGN: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX). RESULTS: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition. CONCLUSIONS: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors.See related commentary by Openshaw et al., p. 2964.

Testicular cancer: improving outcomes with national quality performance indicators.

Testicular cancer is the most common malignancy in young adult men. The prognosis is excellent in limited disease and cure is possible even in advanced disease. Quality performance indicators (QPI) are used in many developed countries as a measure of healthcare performance. We report and discuss the development of a national set of QPIs in Scotland for testicular cancer as a method of gathering demographic data and driving improvement in nationwide testicular cancer outcomes.

Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer.

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Biomarkers and novel agents in esophago-gastric cancer: are we making progress?

Esophago-gastric cancer (EGC) provides a formidable healthcare challenge. Conventional chemotherapy provides modest survival benefit in patients with advanced disease especially in the second-line setting. The recent paradigm shift in the oncology community towards targeting growth factor pathways and the immune system using novel targeted agents has now demonstrated clinical utility in EGC, but recent trial results have highlighted the complexity of disease pathogenesis and significant challenges remain. Here, we describe the current role of targeted therapies in EGC, and their corresponding biomarkers. We aim to provide a comprehensive review of the current climate of novel agents and their biomarkers in advanced EGC.

Epidermal Growth Factor (EGFR) copy number aberrations in esophageal and gastro-esophageal junctional carcinoma.

BACKGROUND: Clinical trials of agents targeting epidermal growth factor receptor (EGFR) in esophageal carcinoma (EC) have indicated a minority subgroup responsive to anti-EGFR therapies. Other investigations suggest increases in EGFR copy number are associated with poor prognosis in EC, but have used a variety of different techniques and tested numbers remain small. A validated assay for EGFR copy number in EC is needed, to allow investigation of EGFR copy number gain as a predictive biomarker for the anti-EGFR responsive subgroup of patients. We developed a scoring system in EC based upon established systems for EGFR fluorescence in-situ hybridisation (FISH) in lung cancer, and applied this in a series of 160 UK patients with advanced EC. RESULTS: Dual colour FISH on formalin fixed paraffin embedded (FFPE) biopsies were scored independently by two operators as: disomy (score = 1), low trisomy (score = 2), high trisomy (score = 3), low polysomy (score = 4), high polysomy (score = 5) and amplification (score = 6). EGFR FISH positive cases (scores 5 and 6) were found in 32/160 (20 %) tumours, with high polysomy in 22 (13.8 %) and amplification in 10 (6.3 %). Two independent operator scores for FISH positivity were 100 % concordant. EGFR FISH positive status was not associated with clinic-pathological features. EGFR amplification was associated with worse survival (HR = 2.64, 95 % CI 1.04 to 6.71, p = 0.03). CONCLUSION: Our FISH scoring system for EGFR in advanced EC identifies a significant subgroup (20.0 %) of FISH positive patients. EGFR amplification, which is found in 6.3 %, is associated with poor survival. It is not known if there is a role for EGFR targeted treatment in this subgroup of patients, however we are now utilising this EGFR FISH assay and scoring system in biopsies from clinical trials utilising anti-EGFR targeted therapies.

Isolated Meningeal Recurrence of Transitional Cell Carcinoma of the Bladder.

Meningeal carcinomatosis occurs in 1-18% of patients with solid tumours, most commonly carcinomas of the breast and lung or melanomas. There are relatively few reports of meningeal carcinomatosis in transitional cell carcinoma of the bladder. Isolated meningeal recurrence is particularly uncommon, and we present an unusual case of this in a 58-year-old man. The case was further complicated by the somewhat atypical presentation with a confirmed ischaemic stroke. The patient died one month after presentation.