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1.
Clin Cancer Res ; 19(3): 743-51, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23224737

ABSTRACT

PURPOSE: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. EXPERIMENTAL DESIGN: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. RESULTS: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). CONCLUSION: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Mutation , Neoplasm Staging , Niacinamide/administration & dosage , Niacinamide/adverse effects , Niacinamide/therapeutic use , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/adverse effects , Platinum/therapeutic use , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Sorafenib , Treatment Outcome , ras Proteins/genetics
2.
J Thorac Oncol ; 5(9): 1477-80, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20736807

ABSTRACT

INTRODUCTION: Currently, the inhibitor of the epidermal growth factor receptor tyrosine kinase erlotinib is widely used for the treatment of non-small cell lung cancer. Patients with a mutation or deletion in the epidermal growth factor receptor gene will benefit most and are likely to receive the drug for long periods and willing to accept side effects if responding. METHODS: Twenty-two cases with prolonged administration of erlotinib (at least 6 months) and side effects are reported. Three cases with specific side effects are described in detail. RESULTS: In addition to the well-known side effects such as folliculitis and diarrhea, patients reported paronychia, fatigue, and hair changes. DISCUSSION: After prolonged administration of erlotinib in most patients, the initial side effects persist while other inconvenient ones may develop. This may lead to dose reductions or even cessation of treatment.


Subject(s)
Adenocarcinoma/drug therapy , Brain Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Quinazolines/adverse effects , Adenocarcinoma/complications , Adenocarcinoma/secondary , Adult , Brain Neoplasms/complications , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/pathology , Diarrhea/chemically induced , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Erlotinib Hydrochloride , Fatigue/chemically induced , Female , Folliculitis/chemically induced , Humans , Lung Neoplasms/complications , Lung Neoplasms/pathology , Male , Middle Aged , Mutation/genetics , Paronychia/chemically induced , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Time Factors , Treatment Outcome
3.
Clin Cancer Res ; 13(8): 2414-21, 2007 Apr 15.
Article in English | MEDLINE | ID: mdl-17438100

ABSTRACT

PURPOSE: To investigate the safety and pharmacokinetics of aerosolized Sustained Release Lipid Inhalation Targeting (SLIT) Cisplatin in patients with lung carcinoma. EXPERIMENTAL DESIGN: Phase I, dose-escalating study of SLIT Cisplatin given in two sessions daily. Safety data, including laboratory variables, adverse events, pulmonary function tests, and radiographic imaging, were collected and analyzed for all patients to determine toxicity. Pharmacokinetic monitoring was done during the first course. RESULTS: Seventeen patients and one tracheostomy patient on compassionate use received treatment. Aerosolized cisplatin was well tolerated. No dose-limiting toxicity was observed at the maximum delivered dose. Safety data showed no hematologic toxicity, nephrotoxicity, ototoxicity, or neurotoxicity. Most common adverse events were nausea (64.7%), vomiting (47.1%), dyspnea (64.7%), fatigue (64.7%), and hoarseness (47.1%). Pharmacokinetic data showed very low plasma platinum levels only with the longest repeated inhalations. Common Toxicity Criteria grade 2 decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide after one course occurred both in two patients and grade one decrease in forced expiratory volume in one second and diffusing lung capacity for carbon monoxide in six and five patients, respectively. Direct airway deposition via the tracheostomy resulted in clinical deterioration after two cycles best described as bronchitis, completely reversible within days. Overall response: stable disease in 12 patients and progressive disease in 4 patients (one patient received one cycle). CONCLUSIONS: Aerosolized liposomal cisplatin was found to be feasible and safe.


Subject(s)
Aerosols , Cisplatin/toxicity , Lung Neoplasms/drug therapy , Administration, Inhalation , Adult , Aged , Antineoplastic Agents/toxicity , Cisplatin/administration & dosage , Delayed-Action Preparations , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , Middle Aged , Safety
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