Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
1.
Contemp Clin Trials ; 140: 107496, 2024 05.
Article in English | MEDLINE | ID: mdl-38467274

ABSTRACT

BACKGROUND: To develop medicines that are safe and efficacious to all patients, clinical trials must enroll appropriate target populations, but imbalances related to race, ethnicity and sex have been reported. A comprehensive analysis and improvement in understanding representativeness of patient enrollment in industry-sponsored trials are key public health needs. METHODS: We assessed race/ethnicity and sex representation in AstraZeneca (AZ)-sponsored clinical trials in the United States (US) from 2010 to 2022, compared with the 2019 US Census. RESULTS: In total, 246 trials representing 95,372 patients with complete race/ethnicity and sex records were analyzed. The proportions of different race/ethnicity subgroups in AZ-sponsored clinical trials and the US Census were similar (White: 69.5% vs 60.1%, Black or African American: 13.3% vs 12.5%, Asian: 1.8% vs 5.8%, Hispanic: 14.4% vs 18.5%). We also observed parity in the proportions of males and females between AZ clinical trials and US Census (males: 52.4% vs 49.2%, females: 47.6% vs 50.8%). Comparisons of four distinct therapy areas within AZ (Respiratory and Immunology [R&I]; Cardiovascular, Renal, and Metabolism [CVRM]; Solid Tumors; and Hematological Malignancies), including by trial phases, revealed greater variability, with proportions observed above and below US Census levels. CONCLUSION: This analysis provides the first detailed insights into the representativeness of AZ trials. Overall, the proportions of different race/ethnicity and sex subgroups in AZ-sponsored clinical trials were broadly aligned with the US Census. We outline some of AZ's planned health equity initiatives that are intended to continue to improve equitable patient enrollment.


Subject(s)
Clinical Trials as Topic , Female , Humans , Male , Clinical Trials as Topic/statistics & numerical data , Drug Industry , Ethnicity/statistics & numerical data , Patient Selection , Racial Groups/statistics & numerical data , Sex Factors , United States , White , Black or African American , Asian , Hispanic or Latino
3.
Clin Cancer Res ; 29(18): 3566-3572, 2023 09 15.
Article in English | MEDLINE | ID: mdl-37378578

ABSTRACT

In April 2022, the FDA issued draft guidance to help industry develop strategies to improve diversity in clinical trials. Historically, clinical trial sponsors have not systematically incorporated efforts to promote diversity, equity, and inclusion (DEI), particularly during the early design stages of clinical development plans and operational strategies. Unfortunately, a retrospective approach to DEI often results in clinical trial participants not being reflective of the diversity of patients intended to be treated with new therapies. A shift to prospective, intentional DEI strategies for clinical trials, including long-term engagement with diverse patients and communities throughout the development life cycle, is necessary to maximize the benefits and minimize the risks of new drugs and devices for all patients. Sponsors' current practices and opportunities for improving DEI address four major topics: institutional commitment, culture change, and governance; clinical development strategy; setting enrollment goals to ensure trial participant diversity; and development and implementation of the operational strategy. As DEI practices gain wider adoption in clinical trials, shared learning and collaboration among stakeholders on an ongoing and noncompetitive basis will lead to sustainable change. Prioritization of enrollment of diverse populations as an integral part of study start-up planning, clinical trial design, and recruitment capabilities will enhance the clinical development process for oncology therapies. Importantly, these efforts will help provide equitable access to clinical trials and innovative cancer therapies.


Subject(s)
Antineoplastic Agents , Neoplasms , Humans , Prospective Studies , Retrospective Studies , Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Drug Development , Cultural Diversity
5.
J Clin Oncol ; 36(9): 841-849, 2018 03 20.
Article in English | MEDLINE | ID: mdl-28841389

ABSTRACT

Purpose The AURA study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At data cutoff (November 1, 2016), median follow-up was 19.1 months. Overall ORR was 67% (95% CI, 47% to 83%) in the 80-mg group, 87% (95% CI, 69% to 96%) in the 160-mg group, and 77% (95% CI, 64% to 87%) across doses. Median PFS time was 22.1 months (95% CI, 13.7 to 30.2 months) in the 80-mg group, 19.3 months (95% CI, 13.7 to 26.0 months) in the 160-mg group, and 20.5 months (95% CI, 15.0 to 26.1 months) across doses. Of 38 patients with postprogression plasma samples, 50% had no detectable circulating tumor DNA. Nine of 19 patients had putative resistance mechanisms, including amplification of MET (n = 1); amplification of EGFR and KRAS (n = 1); MEK1, KRAS, or PIK3CA mutation (n = 1 each); EGFR C797S mutation (n = 2); JAK2 mutation (n = 1); and HER2 exon 20 insertion (n = 1). Acquired EGFR T790M was not detected. Conclusion Osimertinib demonstrated a robust ORR and prolonged PFS in treatment-naïve patients with EGFRm advanced NSCLC. There was no evidence of acquired EGFR T790M mutation in postprogression plasma samples.


Subject(s)
Piperazines/therapeutic use , Acrylamides , Adult , Aged , Aged, 80 and over , Aniline Compounds , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/blood , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Progression-Free Survival , Protein Kinase Inhibitors/therapeutic use , Survival Rate
6.
J Clin Oncol ; 35(12): 1288-1296, 2017 Apr 20.
Article in English | MEDLINE | ID: mdl-28221867

ABSTRACT

Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Piperazines/therapeutic use , Acrylamides , Adult , Aged , Aged, 80 and over , Aniline Compounds , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Piperazines/adverse effects , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Treatment Outcome
7.
N Engl J Med ; 376(7): 629-640, 2017 02 16.
Article in English | MEDLINE | ID: mdl-27959700

ABSTRACT

BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Pemetrexed/administration & dosage , Piperazines/administration & dosage , Acrylamides , Adult , Aged , Aged, 80 and over , Aniline Compounds , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Disease-Free Survival , Female , Humans , Male , Middle Aged , Mutation , Pemetrexed/adverse effects , Piperazines/adverse effects , Platinum/administration & dosage , Young Adult
8.
Lancet Oncol ; 17(12): 1643-1652, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27751847

ABSTRACT

BACKGROUND: Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. METHODS: In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov, number NCT02094261. FINDINGS: Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6-14·2). 140 (70%; 95% CI 64-77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven [3%]), prolonged electrocardiogram QT (five [2%]), decreased neutrophil count (four [2%]), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three [1%] each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease. INTERPRETATION: Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor. FUNDING: AstraZeneca.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation , Piperazines/therapeutic use , Acrylamides , Adult , Aged , Aged, 80 and over , Aniline Compounds , Antineoplastic Agents/adverse effects , ErbB Receptors/antagonists & inhibitors , Female , Humans , Male , Middle Aged , Piperazines/adverse effects
9.
N Engl J Med ; 372(18): 1689-99, 2015 Apr 30.
Article in English | MEDLINE | ID: mdl-25923549

ABSTRACT

BACKGROUND: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. METHODS: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy. RESULTS: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients. CONCLUSIONS: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).


Subject(s)
Acrylamides/administration & dosage , Aniline Compounds/administration & dosage , Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Acrylamides/adverse effects , Acrylamides/pharmacokinetics , Adult , Aged , Aged, 80 and over , Aniline Compounds/adverse effects , Aniline Compounds/pharmacokinetics , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Disease-Free Survival , Dose-Response Relationship, Drug , ErbB Receptors/antagonists & inhibitors , Female , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics
10.
Xenobiotica ; 44(12): 1083-98, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25007130

ABSTRACT

1. This series of studies in rats, dogs and humans (Clinicaltrials.gov identifier: NCT01284595) investigated the pharmacokinetics, tissue distribution, metabolism and excretion of the EGFR, HER2 and HER3 signalling inhibitor AZD8931. 2. Single oral or intravenous doses of 2-(4-[4-(3-chloro-2-fluoro[U-(14)C]-phenylamino)-7-methoxy-quinazolin-6-yloxy]-piperidin-1-yl)-N-methyl-acetamide difumarate ([(14)C]-AZD8931) were administered. 3. AZD8931 absorption was rapid in all species. Following [(14)C]-AZD8931 administration to rats, radioactivity was widely and rapidly distributed, with the highest levels in organs of metabolism and excretion (gastrointestinal tract, liver). Following oral and intravenous [(14)C]-AZD8931 administration, excretion of radioactivity by all species occurred predominantly via the bile into faeces, with <5% of the dose being eliminated in urine. In all species, AZD8931 was principally cleared by metabolism. The major route of metabolism was hydroxylation and O-demethylation in rat, and aryl ring oxidation in dog. Metabolism of AZD8931 in humans was attributed to three pathways; oxidation and amine or ether cleavage around the piperidine ring with subsequent glucuronide or sulphate conjugation. 4. AZD8931 is largely cleared by metabolism in the rat, dog and human. Excretory profiles indicate that there are no unique human metabolites.


Subject(s)
ErbB Receptors/antagonists & inhibitors , Quinazolines/pharmacology , Quinazolines/pharmacokinetics , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-3/antagonists & inhibitors , Aged , Animals , Carbon Radioisotopes , Dogs , Female , Gene Expression Regulation/drug effects , Humans , Male , Middle Aged , Molecular Structure , Quinazolines/chemistry , Quinazolines/metabolism , Rats , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Species Specificity
11.
Cancer Discov ; 4(9): 1046-61, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24893891

ABSTRACT

UNLABELLED: First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.


Subject(s)
Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Protein Kinase Inhibitors/therapeutic use , Acrylamides/chemistry , Acrylamides/pharmacology , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , ErbB Receptors/chemistry , Female , Genes, erbB-2 , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Models, Molecular , Molecular Conformation , Phosphorylation , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Treatment Outcome , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
12.
J Clin Oncol ; 27(11): 1864-71, 2009 Apr 10.
Article in English | MEDLINE | ID: mdl-19289630

ABSTRACT

PURPOSE: To compare survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with gefitinib 250 or 500 mg/day or standard methotrexate. PATIENTS AND METHODS: Four hundred eighty-six patients with recurrent SCCHN were randomly assigned to oral gefitinib 250 mg/day, gefitinib 500 mg/day, or methotrexate 40 mg/m(2) intravenously weekly. Primary end point was overall survival, secondary end points were objective response rate (ORR), safety, symptom improvement, and quality of life (QOL). Exploratory end points included association of efficacy with epidermal growth factor receptor gene copy number and other biomarkers. RESULTS: Neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate (hazard ratio [HR], 1.22; 95% CI, 0.95 to 1.57; P = .12; and HR, 1.12; 95% CI, 0.87 to 1.43; P = .39, respectively). In the gefitinib 250 mg/day, 500 mg/day, and methotrexate groups, respectively, median overall survival was 5.6, 6.0, and 6.7 months; ORRs (Response Evaluation Criteria in Solid Tumors) were 2.7%, 7.6% and 3.9%, with no statistically significant difference between either gefitinib arm and methotrexate. No unexpected adverse events were observed, except for tumor hemorrhage-type events with gefitinib (8.9%, gefitinib 250 mg/day; 11.4%, gefitinib 500 mg/day; 1.9%, methotrexate). QOL improvement rates (Functional Assessment of Cancer Therapy-Head & Neck total score) were 13.4%, 18.0%, and 6.0% for gefitinib 250 mg/day, 500 mg/day, and methotrexate, respectively. CONCLUSION: In patients with recurrent or metastatic SCCHN, while responses with gefitinib were seen, neither gefitinib 250 nor 500 mg/day improved overall survival compared with methotrexate. With the exception of tumor hemorrhage-type events with gefitinib, the adverse event profiles were generally consistent with those previously observed.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Methotrexate/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Quinazolines/administration & dosage , Administration, Oral , Aged , Carcinoma, Squamous Cell/secondary , Female , Gefitinib , Head and Neck Neoplasms/secondary , Humans , Infusions, Intravenous , Male , Middle Aged , Quality of Life , Survival Analysis , Treatment Outcome
13.
J Clin Oncol ; 26(26): 4253-60, 2008 Sep 10.
Article in English | MEDLINE | ID: mdl-18779612

ABSTRACT

PURPOSE: This phase II, open-label, parallel-group study compared gefitinib with vinorelbine in chemotherapy-naïve elderly patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Chemotherapy-naïve patients (age >or= 70 years) were randomly assigned to gefitinib (250 mg/d orally) or vinorelbine (30 mg/m(2) infusion on days 1 and 8 of a 21-day cycle). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), objective response rate (ORR), quality of life (QOL), pulmonary symptom improvement (PSI), and tolerability. Exploratory end points included epidermal growth factor receptor (EGFR) gene copy number by fluorescent in situ hybridization (FISH). RESULTS: Patients were randomly assigned to gefitinib (n = 97) or to vinorelbine (n = 99). Hazard ratios (HR; gefitinib v vinorelbine) were 1.19 (95% CI, 0.85 to 1.65) for PFS and 0.98 (95% CI, 0.66 to 1.47) for OS. ORR and disease control rates were 3.1% (95% CI, 0.6 to 8.8) and 43.3% (for gefitinib) and 5.1% (95% CI, 1.7 to 11.4) and 53.5% (for vinorelbine), respectively. Overall QOL improvement and PSI rates were 24.3% and 36.6% (for gefitinib) and 10.9% and 31.0% (for vinorelbine), respectively. In the 54 patients who were EGFR FISH-positive, HRs were 3.13 (95% CI, 1.45 to 6.76) for PFS and 2.88 (95% CI, 1.21 to 6.83) for OS. There were fewer treatment-related grade 3 to 5 adverse events with gefitinib (12.8%) than with vinorelbine (41.7%). CONCLUSION: There was no statistical difference between gefitinib and vinorelbine in efficacy in chemotherapy-naïve, unselected elderly patients with advanced NSCLC, but there was better tolerability with gefitinib. Individuals who were EGFR FISH-positive benefited more from vinorelbine than from gefitinib; this unexpected finding requires further study.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Quinazolines/therapeutic use , Vinblastine/analogs & derivatives , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/mortality , Disease Progression , Female , Gefitinib , Humans , Lung Neoplasms/mortality , Male , Survival Analysis , Vinblastine/therapeutic use , Vinorelbine
14.
AJR Am J Roentgenol ; 182(5): 1159-65, 2004 May.
Article in English | MEDLINE | ID: mdl-15100111

ABSTRACT

OBJECTIVE: We explored CT and demographic predictors for unfavorable outcome of nonoperative treatment in patients with a first event of left colonic diverticulitis. MATERIALS AND METHODS: We retrospectively analyzed the medical files and CT scans of 312 consecutive patients who were diagnosed as having diverticulitis on an admission CT report or who had a final diagnosis of left colonic diverticulitis. Patients who did not undergo nonoperative treatment or were lost to follow-up (n = 144) were excluded from the study. Admission CT scans of 168 consecutive patients with a diagnosis of left colonic diverticulitis who underwent nonoperative treatment and had an 18-month follow-up were reassessed by three radiologists unaware of the clinical findings. Nonoperative treatment was defined as an attempt to treat the patient with only antibiotics without scheduling them for elective (delayed) surgery. Unfavorable outcome was defined as a failure of nonoperative treatment 18 months after admission that required either surgery or rehospitalization for antibiotic treatment. The risk of unfavorable outcome was modeled using logistic regression as a function of sex, age, and CT criteria including the maximum number of diverticula per 10 cm of colon; the presence of intraabdominal abscess or extraintestinal gas bubbles (< 5 mm diameter) or gas pockets (>or=5 mm); the length and location of the abnormal colonic segment; the maximum thickness of the colonic wall; the presence of associated free intraperitoneal fluid; and the extent of fatty infiltration. RESULTS: Among these 168 patients, 115 (68%) had an uneventful outcome, but nonoperative treatment failed in 53 (32%). The presence of an abscess (n = 19) or extraintestinal gas pocket (n = 14) were the only CT findings significantly associated with failure of nonoperative treatment. Adjusted odds ratios (95% confidence interval) for failure were 6.18 (1.76-21.68) when an abscess was diagnosed and 4.26 (1.04-17.57) when pockets of free air were observed. Sex and age were not significantly associated with unfavorable outcome of nonoperative treatment. CONCLUSION: Abscess and pockets of extraintestinal gas 5 mm in diameter or larger correlated with unfavorable outcome of nonoperative treatment. None of the other criteria evaluated were predictive of failure of nonoperative treatment, including bubbles of extraintestinal gas smaller than 5 mm in diameter.


Subject(s)
Colonography, Computed Tomographic , Diverticulitis/diagnostic imaging , Diverticulum, Colon/diagnostic imaging , Acute Disease , Adult , Age Factors , Aged , Aged, 80 and over , Diverticulitis/therapy , Diverticulum, Colon/therapy , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prognosis , Recurrence , Retrospective Studies , Sex Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...