Enriched Patient Population Research Articles

Multifaceted and personalized therapy of advanced prostate cancer

A number of molecular and genomic biomarkers that possess the ability to guide treatment or 'actionable targets' are being reported in metastatic prostate cancer. In addition, pathways of resistance to existing therapies and novel agents to overcome them are currently under active investigation. The next wave of investigations is focused on personalized therapy of prostate cancer. The focus of this review article is to provide an update on clinical development in advanced prostate cancer and to highlight the ongoing investigations of biomarker discovery, and ways of overcoming therapeutic resistance. The next generation of clinical trials developing novel targets and compounds promises to be in populations enriched with specific marker expression. The breakthrough report, of the ability of the androgen receptor variant 7 mutation, detected in circulating tumor cells, to predict the lack of response to abiraterone or enzalutamide, and the remarkable responses of poly adenosine diphosphate ribose polymerase inhibitors in prostate cancer with DNA repair mutations have elevated hopes of a bright future in the biomarker-driven therapeutic arena. Novel targets such as bromodomain extra terminal-1 and phosphatidylinositol 3-kinase hold promise for the possibility of overcoming resistance. Novel hormone agents are also under active study. As the clinical application of the multifaceted therapies narrows down to enriched patient populations selected by genomic testing, the therapeutic efficiency will escalate considerably. Novel targets, resistance mechanisms and relevant agents are being avidly tested, and the dream of personalized medicine is emerging into reality.

The promising role of poly(ADP-ribose) polymerase inhibitors in prostate cancer.

The TOPARP study showed the beneficial utility of olaparib in a heavily pretreated population of metastatic castration-resistant prostate cancer who were biomarker-positive for aberrations in DNA repair gene. A higher response rate to olaparib of 88% (14 out of 16 patients), time to radiographic progression as well as overall survival, was seen in patients who were biomarker-positive compared to those who were not. This study showed a promising way of targeting prostate cancer with an enriched population of patients who harbor these deleterious genes. This paves the way for offering new therapeutic opportunities for men who have otherwise few remaining options.

Options in metastatic urothelial cancer after first-line therapy

The treatment of patients with metastatic urothelial carcinoma is evolving with recent advances holding promise for improved outcomes. Historically, patients with metastatic urothelial carcinoma had a poor prognosis with no standard treatment options in the second-line setting. Currently, with an increased understanding of the heterogeneity of clinical bladder cancer subtypes and molecular diversity of the disease, there is optimism that outcomes will start to improve. The present review will evaluate historical second-line treatment options and focus on emerging therapies in this setting. Single-agent cytotoxic chemotherapy agents continue to be evaluated in patients with metastatic urothelial carcinoma with variable results. Targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have also been extensively evaluated in this disease. Early phase data have as yet failed to demonstrate improvements in survival; however evaluations of targeted agents in enriched patient populations and in combination with chemotherapeutic agents are ongoing. Novel immunotherapeutic approaches have shown encouraging results and are currently being evaluated extensively. The optimal treatment for patients with metastatic urothelial carcinoma in the second-line setting is unknown. Recent advances in the field gives rise to optimism as the focus shifts to individualization of therapy based on clinical and molecular characteristics of the patient and the disease.

Design of a Confirmatory Phase 3, Multicenter, Randomized, Double Blind, Placebo-Controlled Study (ACT DMD) of Ataluren in Patients with Nonsense Mutation Duchenne Muscular Dystrophy

Aim: Approximately 13% of Duchenne muscular dystrophy (DMD) is caused by nonsense mutation (nm) in the dystrophin gene. Nonsense mutations in DNA correspond to premature stop codons in mRNA. Ataluren an oral drug designed to promote ribosomal read through of premature stop codons, enabling production of full length, and functional protein. Currently ongoing is a Phase 3, randomized, double-blind, placebo-controlled study (ACT DMD) designed to confirm the efficacy and safety of ataluren 40 mg/kg/d in boys with nmDMD, initially demonstrated in a Phase 2b study. The design of ACT DMD reflects lessons learned from previous study and evolving understanding of the natural history of DMD. The study design targets an enriched study population of patients in the ambulatory decline phase of DMD to efficiently demonstrate disease stabilization over 48 weeks.

Clinicopathologic features of patients with non-small cell lung cancer harboring the EML4-ALK fusion gene: a meta-analysis.

BackgroundThe frequencies of EML4-ALK fusion gene in non-small cell lung cancer (NSCLC) with different clinicopathologic features described by previous studies are inconsistent. The key demographic and pathologic features associated with EML4-ALK fusion gene have not been definitively established. This meta-analysis was conducted to compare the frequency of the EML4-ALK fusion gene in patients with different clinicopathologic features and to identify an enriched population of patients with NSCLC harboring EML4-ALK fusion gene.MethodsThe Pubmed and Embase databases for all studies on EML4-ALK fusion gene in NSCLC patients were searched up to July 2014. A criteria list and exclusion criteria were established to screen the studies. The frequency of the EML4-ALK fusion gene and the clinicopathologic features, including smoking status, pathologic type, gender, and EGFR status were abstracted.ResultsSeventeen articles consisting of 4511 NSCLC cases were included in this meta-analysis. A significant lower EML4-ALK fusion gene positive rate was associated with smokers (pooled OR = 0.40, 95% CI = 0.30–0.54, P<0.00001). A significantly higher EML4-ALK fusion gene positivity rate was associated with adenocarcinomas (pooled OR = 2.53, 95% CI = 1.66–3.86, P<0.0001) and female (pooled OR = 0.61, 95% CI = 0.41–0.90, P = 0.01). We found that a significantly lower EML4-ALK fusion gene positivity rate was associated with EGFR mutation (pooled OR = 0.07, 95% CI = 0.03–0.19, P<0.00001). No publication bias was observed in any meta-analysis (all P value of Egger's test >0.05); however, because of the small sample size, no results were in the meta-analysis regarding EGFR gene status.ConclusionThis meta-analysis revealed that the EML4-ALK fusion gene is highly correlated with a never/light smoking history, female and the pathologic type of adenocarcinoma, and is largely mutually exclusive of EGFR.

Diagnosis of the Alk-Eml4 Translocation with Fish, Immunohistochemistry, and Real Time-Polymerase Chain Reaction in Patients with Non-Small-Cell Lung Cancer: the Latin American Experience

ABSTRACT Aim: To evaluate the value of ALK immunohistochemistry (IHC) with the 5A4 antibody and real-time polymerase chain reaction (RT-qPCR) in the diagnosis of ALK-rearranged NSCLC in the Mexican population. Methods: 170 advanced NSCLC were evaluated by FISH. Demographic and clinicopathologic characteristics were analyzed. Additional IHC and RT-qPCR (variants 1-5) was done in 63 and 48 patients, respectively. Performance characteristics of IHC and RT-qPCR were calculated. Results: 18 (10.5%) patients were positive for ALK-rearrangements (ALK+) by FISH. ALK+ patients were significantly younger at the time of diagnosis compared with ALK-negative patients (46 vs. 58 years, P = 0.02), and had a lighter smoking history. We found no significant differences in terms of sex, wood smoke exposure, histologic type, carcinoembryonic antigen, or clinical stage at presentation. When we compared IHC with FISH, using an IHC cutoff of 1+ staining, there were 15 true positive (TP) cases, 3 false positives (FP), 3 false negatives (FN), and 42 true negatives (TN), yielding a sensitivity and specificity of 83% and 93%, respectively. Compared with FISH, RT-qPCR identified 5 TP cases with variant 1, no FP, 4 FN for variants 1-5, and 39 TN, yielding a sensitivity and specificity of 55% and 100%, respectively. Conclusions: This is the first report of ALK-rearranged NSCLC in Latin America. The high prevalence of ALK+ patients found in our study reflects a clinically enriched patient population. Our results show that ALK+ patients in Mexico are younger than ALK-negative patients and have a lighter smoking history. Our findings suggest that IHC with 5A4 clone is relatively sensitive for the detection of ALK+ NSCLC and may help select patients to undergo FISH testing. Disclosure: All authors have declared no conflicts of interest.

Advanced non-small cell lung cancer management in patients progressing after first-line treatment: results of the cross-sectional phase of the Italian LIFE observational study

LIFE (non-small cell Lung cancer management In patients progressing after First-linE of treatment in the metastatic setting) is a multicentre Italian observational study, including a cross-sectional and a longitudinal phase, with the aim of describing the therapeutic approach in clinical practice for advanced non-small cell lung cancer (NSCLC) patients, progressing after first-line treatment. In this paper, the cross-sectional phase is outlined, with the primary endpoint of describing the proportion of patients receiving second-line treatment among those progressed during or after first-line treatment according to clinical practice. From July 2011 to January 2012, 603 patients were enrolled and 541 (90 %) were evaluable. A total of 464 (86 %) patients received a second-line therapy outside clinical trials. Chemotherapy and targeted therapies were administered to 65 and 34 % of patients, respectively (1 % both). No tissue collection was required within the observational trial, and biomarkers analysis was performed at diagnosis or later in 314 patients (58 %). In details, activating epidermal growth factor receptor mutations were detected in 21 % of 311 evaluable patients, Kirsten rat sarcoma 2 viral oncogene homolog mutation in 22 % of the 77 evaluable patients and anaplastic lymphoma kinase translocations analysis was performed in 74 patients and resulted positive in 23 % of cases. These high proportions were probably due to enriched patient population tested. These results showed a pattern of care for NSCLC second-line therapy which reflects international guidelines recommendations and current expected clinical practice. Interestingly, biomarkers analyses were performed in a higher percentage than expected.

A Double-Blind Randomized Discontinuation Phase-II Study of Sorafenib (BAY 43–9006) in Previously Treated Non–Small-Cell Lung Cancer Patients: Eastern Cooperative Oncology Group Study E2501

Sorafenib is a raf kinase and angiogenesis inhibitor with activity in multiple cancers. This phase-II study in heavily pretreated non-small-cell lung cancer (NSCLC) patients (≥ 2 prior therapies) used a randomized discontinuation design. Patients received 400 mg of sorafenib orally twice daily for two cycles (2 months) (step 1). Responding patients on step 1 continued on sorafenib; progressing patients went off study, and patients with stable disease were randomized to placebo or sorafenib (step 2), with crossover from placebo allowed upon progression. The primary endpoint of this study was the proportion of patients having stable or responding disease 2 months after randomization. There were 299 patients evaluated for step 1; of these, 81 eligible patients were randomized on step 2 and received sorafenib (n = 50) or placebo (n = 31). The 2-month disease control rates after randomization were 54% and 23% for patients initially receiving sorafenib and placebo, respectively, p = 0.005. The hazard ratio for progression on step 2 was 0.51 (95% [confidence interval] CI 0.30, 0.87, p = 0.014) favoring sorafenib. A trend in favor of overall survival with sorafenib was also observed (13.7 versus 9.0 months from time of randomization), hazard ratio 0.67 (95% CI 0.40-1.11), p = 0.117. A dispensing error occurred, which resulted in the unblinding of some patients, but not before completion of the 8-week initial step 2 therapy. Toxicities were manageable and as expected. The results of this randomized discontinuation trial suggest that sorafenib has single-agent activity in a heavily pretreated, enriched patient population with advanced NSCLC. These results support further investigation with sorafenib as a single agent in larger, randomized studies in NSCLC.

Molecular targeted therapies in advanced gastric cancer: does tumor histology matter?

It is increasingly recognized that gastric cancer is a heterogeneous disease which may be divided into subgroups based on histological, anatomical, epidemiological and molecular classifications. Distinct molecular drivers and tumor biology, and thus different treatment targets and predictive biomarkers, may be implicated in each subtype. However, there is little evidence in the literature regarding the correlation among these different classifications, and particularly the molecular aberrations present in each subtype. In this review, we approach advanced gastric cancer (AGC) by presenting aberrant molecular pathways and their potential therapeutic targets in gastric cancer according to histological and anatomical classification, dividing gastric cancer into proximal nondiffuse, distal nondiffuse and diffuse disease. Several pathways are involved predominantly, although not exclusively, in different subtypes. This may help to explain the disappointing results of many published AGC trials in which study populations were heterogeneous regardless of clinicopathological characteristics of the primary tumor. Histological and anatomical classification may provide insights into tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic. However, some molecular pathways implicated in gastric cancer have not been studied in correlation with histological or anatomical subtypes. Further studies are necessary to confirm the suggestion that such classification may predict tumor biology and facilitate selection of an enriched patient population for targeted agents in future studies and in the clinic.

Application of Monoclonal Antibodies as Cancer Therapy in Solid Tumors

Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.

P2-12-06: Nomogram To Predict Subsequent Bone Metastasis in Patients with Non Metastatic Breast Carcinomas.

Abstract Background Bone metastasis (BM) is one of the most common sites of distant metastasis for breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of patients at high risk for BM. Patients and Methods Medical records of patients with non metastatic breast cancer were prospectively collected for the period between January 1997 and February 2007 at the M.D. Anderson Cancer Center (Texas, USA). A multivariate logistic regression analysis of selected prognostic features was done. Based on Cox proportional hazards regression model, a nomogram to predict BM was constructed and validated in an independent cohort of 579 patients with non metastatic breast cancer at time of diagnosis treated at the Tenon Hospital (Paris, France) between January 2003 and December 2005. Results: Of 4175 patients with non metastatic breast cancer, 314 developed subsequent BM. Age, T stage, lymph node status, lymphovascular space invasion, breast cancer molecular subtype, adjuvant hormonotherapy were significantly and independently associated with subsequent BM. The nomogram had a concordance index of 0.69 (95% CI, 0.68 to 0.70) in the training set. The validation set showed a good discrimination with a concordance index of 0.65 (95% CI, 0.57 to 0.72). At 3, 5 and 7 years, the nomogram was well calibrated. Conclusion: We have developed a robust tool that is able to predict subsequent BM in patients with non metastatic breast cancer. Selection of an enriched patient population at high risk for BM will allow to practice individualized therapeutic strategies, an adapted medical supervision and will facilitate the design of trials aiming at its prevention with the use of biphosphonate treatment. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-06.

Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy

PurposeGefitinib and erlotinib are potent EGFR TKIs, with antitumor activity. In this randomized, single-center, non-comparative phase II trial, the efficacy and safety of gefitinib and erlotinib was evaluated as the second-line therapy for advanced non-small cell lung cancer (NSCLC). Patients and methodsPatients with locally advanced, metastatic stage IIIB/IV NSCLC who failed first-line chemotherapy and had either EGFR mutation or at least two out of three clinical factors associated with higher incidence of EGFR mutations (female, adenocarcinoma histology, and never-smoker) were eligible. ResultsA total of 96 (48 per arm) patients were randomly assigned to gefitinib- or erlotinib-arm, respectively. Baseline characteristics were well-balanced between the two arms. The response rates (RR) were 47.9% in the gefitinib arm and 39.6% in the erlotinib arm. Median PFS was 4.9months (95% CI, 1.3–8.5) in the gefitinib arm and 3.1months (95% CI, 0.0–6.4) in the erlotinib arm. The most common grade 3/4 toxicity was skin rash. Exploratory analyses showed that there was no significant difference in RR and PFS in the gefitinib arm compared to the erlotinib arm (RR (%) 47.9 vs. 39.6, p=0.269; median survival (months) 4.9 vs. 3.1, p=0.336). There was no significant difference in QOL between the two arms. ConclusionBoth gefitinib and erlotinib showed effective activity and tolerable toxicity profiles as second-line treatment for the selected population of NSCLC. We may consider conducting a phase III trial to directly compare the efficacy and toxicity between gefitinib and erlotinib in an enriched patient population.

Farnesyl transferase expression determines clinical response to the docetaxel‐lonafarnib combination in patients with advanced malignancies

Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies. Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m², 100 mg; 2) 36 mg/m², 100 mg; 3) 30 mg/m², 150 mg; or 4) 36 mg/m², 150 mg of DTX intravenously weekly, LNF orally twice daily, respectively. Of the 38 patients enrolled, 36 were treated, and 29 were evaluable for toxicity and response assessment. The combination of LNF and DTX was tolerated in all cohorts with the exception of a 28% incidence of grade 3/4 diarrhea, which was manageable with aggressive antidiarrheal regimens. Seven patients derived clinically meaningful benefit from this combination treatment; these patients had significantly lower basal FTase-beta mRNA expression levels than the mean study population level (P < .05). Correlation of clinical benefit with tubulin acetylation content as well as basal acetyl-tubulin content were evaluated. However, no significant correlation was found. Despite the small number of patients, these findings support our preclinical mechanistic studies and warrant further clinical investigations using FTase-beta mRNA expression as a potential predictive biomarker to select for an enriched patient population to study the effects of taxane and FTase inhibitor combination therapies.

Should Biomarkers Be Used to Design Personalized Medicine for the Treatment of Glioblastoma?

Significant progress has been made in understanding the molecular pathogenesis of gliomas and in predicting general outcome depending on a limited set of clinical parameters and molecular markers. However, methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter is the only molecular marker linked to sensitivity of a specific treatment, that is, alkylating agent chemotherapy, and this predictive value may be limited to glioblastoma. Moreover, in the absence of potent alternative drugs, temozolomide chemotherapy should not be withheld from patients with newly diagnosed glioblastoma without MGMT promoter methylation in general practice. In the context of clinical trials, however, irrespective of whether classical cytotoxic drugs, tyrosine kinase inhibitors or antiangiogenic agents are used, tissue should be centrally collected. Appropriate research programs should seek to define enriched patient populations for future trials and ultimately facilitate individualized cancer treatments.

Annual Review of Advances in Lung Cancer Clinical Research: A Report for the Year 2009

The use of positron emission tomography compared with conventional staging increases the detection of extrathoracic metastases and reduces the number futile thoracotomies in patients being evaluated for surgical resection. Long-term follow-up of one of the two adjuvant chemotherapy trials revealed a continued overall survival (OS) benefit to adjuvant chemotherapy. In locally advanced non-small cell lung cancer, a phase III trial of chemoradiotherapy alone and with surgical resection revealed no statistically significant difference in OS between the treatment arms. In advanced stage non-small cell lung cancer, a phase III trial compared gefitinib with carboplatin and paclitaxel in a clinically enriched patient population for epidermal growth factor receptor (EGFR) tyrosine kinase (TK) mutations; among patients with an EGFR TK mutation, patients in gefitinib arm compared with carboplatin and paclitaxel arm experienced a statistically significant superior response rate and progression-free survival, and among patients without EGFR TK mutation patients in the gefitinib arm compared with carboplatin and paclitaxel experienced a statistically significant inferior response rate and progression-free survival. A phase III trial of platinum-based therapy with and without cetuximab in the first-line setting revealed improved OS in the cetuximab arm. A phase III trial of maintenance pemetrexed compared with placebo in patients who had not progressed after initial platinum-based therapy revealed an improvement in OS of patients in the pemetrexed arm with nonsquamous histology. In limited-stage small cell lung cancer, a phase III trial compared standard and high-dose prophylactic cranial irradiation and revealed no significant difference in the rate of brain metastases between the two treatment arms.

Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer

PURPOSE Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials. PATIENTS AND METHODS Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada). Results Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities. CONCLUSION We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.

Rapid Oral Transmucosal Absorption of Sumatriptan, and Pharmacodynamics in Acute Migraine

(1) To determine whether sumatriptan can be absorbed across the oral mucosa, and, if so; then (2) to describe its pharmacokinetics; and (3) to investigate whether there are pharmacodynamic correlates of such pharmacokinetics in patients experiencing migraine attacks. Two clinical trials. The first, in normal volunteers, compared the pharmacokinetic performance of a lingual spray (LS) formulation of sumatriptan (2 dose sizes, one of which in both the fed and fasted state) with an orthodox 50-mg sumatriptan tablet. The second clinical trial, in a patient population enriched by documenting suboptimal response to an initial 50-mg sumatriptan tablet, was a multiple-attack, crossover, fixed dose-order, open-label comparison of sumatriptan administered by LS (up to 3 different dose sizes) and a 100-mg sumatriptan tablet. The LS formulations resulted in double-peaked time-plasma concentration curves that are consistent with absorption of sumatriptan across the oral mucosa. The first T(max) was usually about 10-15 minutes. In the enriched patient population, this corresponded with evidence of earlier efficacy for the LS in comparison with a 50-mg tablet; the lower dose size for the former was consistent with oral mucosal drug absorption, and evasion of first-pass metabolism. The initial pharmacokinetics of LS approximate to those of a subcutaneous injection, albeit some fraction of these doses is also swallowed. These pharmacokinetics correspond with earlier effectiveness of LS in comparison with a 50-mg sumatriptan tablet, and at lower dose, in an enriched, relevant patient population. These initial studies support further development of this innovative formulation of sumatriptan and this new route of administration.

Oxymorphone extended release for the treatment of chronic low back pain: A retrospective pooled analysis of enriched-enrollment clinical trial data stratified according to age, sex, and prior opioid use

Objective: This study assessed the potential effects of age, sex, and prior opioid use on the response to oxymorphone extended release (ER) in patients with moderate to severe chronic low back pain. Methods: Combined data from 2 placebo-controlled clinical trials with an enriched-enrollment, randomized-withdrawal design were analyzed. In patients aged ≥18 years with chronic low back pain, the dose of oxymorphone ER was titrated to a stable, tolerable, effective dose. Patients who completed titration were randomly assigned to a 12-week double-blind study period with oxymorphone ER or placebo. Oxymorphone immediate release 5 mg was permitted q4-6h, as needed for rescue medication or withdrawal symptoms, for 4 days after randomization and restricted to 10 mg/d thereafter. Pain intensity (100-mm visual analog scale [VAS]; 0 = no pain to 100 = worst pain imaginable) and time to study discontinuation due to lack of efficacy were compared with stratification by age (<65 vs ≥65 years), sex, and prior opioid use. Adverse events were categorized by severity and relation to study medication. Results: Of 575 patients, 348 completed titration and 347 entered the double-blind study phase. There were no significant between-group differences in demographic variables, except that the mean age in the oxymorphone ER group was significantly higher ( P = 0.04), and the proportion of men was significantly lower ( P = 0.01). There was no significant age difference between the oxymorphone ER and placebo groups stratified by age (<65 vs ≥65 years). Fewer patients aged ≥65 years versus <65 years completed titration (45.0% [36/80] vs 63.0% [312/495]; P = 0.002). The least-squares mean (SEM) differences in VAS pain scores between the oxymorphone ER (n = 174) and placebo (n = 169) groups were significant at each postbaseline assessment ( P < 0.001) and at study completion (12.3 [2.8] mm; P < 0.001) and was not significantly affected by age, sex, or prior opioid use. Age and sex had no significant influence on adverse events or discontinuations due to lack of efficacy. More discontinuations due to lack of efficacy occurred among patients in the placebo group (hazard ratio, 5.01; P < 0.001) and among opioid-experienced patients. The latter effect was limited to opioid-experienced patients who received placebo. The rates of discontinuation due to lack of efficacy were similar between oxymorphone ER-treated opioid-naive and opioid-experienced patients (11.4% vs 11.6%). The proportion of patients who experienced opioid-related adverse events was significantly greater in the oxymorphone ER group compared with the placebo group (25.7% vs 16.3%; P = 0.03). The most frequent treatment-emergent adverse events in the oxymorphone ER group were nausea (8.0%), constipation (6.3%), vomiting (4.6%), and diarrhea (4.0%); in the placebo group were nausea (5.8%), diarrhea (4.7%), and increased sweating (2.3%). Conclusion: In the enriched population of patients who successfully titrated to oxymorphone ER, oxymorphone ER was effective and generally well tolerated, independent of patients' age, sex, or previous opioid use.

Gefitinib in Advanced Non-Small Cell Lung Cancer: Does It Deserve a Second Chance?

There has been intense investigation into the epidermal growth factor receptor (EGFR) as a therapeutic target in the treatment of non-small cell lung cancer (NSCLC). Currently there are two EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, approved for the treatment of advanced NSCLC. In a phase III trial (BR.21), treatment with erlotinib resulted in a statistically significant improvement in overall survival in patients who had experienced progression after one or two previous chemotherapy treatments in comparison with best supportive care (BSC). In contrast, in the Iressa Survival Evaluation in Lung Cancer (ISEL) trial, treatment with gefitinib did not result in a statistically significant improvement in overall survival time in comparison with BSC in patients who had received one or two previous chemotherapy treatments and were refractory to or intolerant of the previous chemotherapy. After the results of the ISEL trial, the U.S. Food and Drug Administration restricted the use of gefitinib, and gefitinib was effectively removed from routine clinical practice within the U.S. However, gefitinib was approved in other countries and clinical trials investigating gefitinib continued. Recently the Iressa Non-small cell lung cancer Trial Evaluating REsponse and Survival against Taxotere (INTEREST) trial met the primary endpoint of demonstrating noninferiority in terms of overall survival for gefitinib (250 mg daily) in comparison with docetaxel (75 mg/m(2) every 3 weeks). Patients treated with gefitinib experienced a lower rate of treatment-related toxicity and higher rate of improvement in quality of life. Results of recent gefitinib trials have been provocative, and suggest a role for gefitinib in the treatment of advanced NSCLC.

Qualification of Biomarkers for Drug Development in Organ Transplantation

The drug development process is dependent upon having established end points for measuring drug efficacy and adverse effects. New drug development in organ transplantation suffers from having end points which are either outdated or which do not serve the purpose of addressing the current critical drug therapy problems. Numerous biomarkers have been examined in organ transplantation, but almost all would be classified as exploratory for drug development purposes. Some of the possible pathways out of this dilemma include investigator- or consortium-initiated research that would qualify the biomarkers as either probable or known valid biomarkers, help in identification of new end points in transplantation and their associated biomarkers, co-development of a new biomarker and drug for transplantation and the use of new clinical trial design methods which facilitate enriched or stratified transplant patient populations. With new biomarkers and new study design methodologies for drug development, improvement in the drug development process for transplantation is a real possibility that the transplant clinical and research community can help to bring about.