Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy.

PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival. RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed. CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

Management of epidermal growth factor receptor tyrosine kinase inhibitor-related cutaneous and gastrointestinal toxicities.

Patients with advanced stage non-small cell lung cancer with sensitizing epidermal growth factor receptor (EGFR) mutations using EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib and afatinib as first-line treatment had better progression-free survival, overall response rate and quality of life than those on chemotherapy. Although EGFR TKIs are commonly associated with skin-related (rash, xerosis and paronychia) and gastrointestinal-related (diarrhea and stomatitis) adverse events (AEs), these effects are usually mild. But severe cases can occur, significantly affecting patient's well-being, treatment compliance and quality of life. Therefore, patient education, early diagnosis, and prophylactic treatment are important strategies to optimally manage EGFR TKI-related adverse effects. In this review, we summarize the commonly encountered EGFR TKI-related AEs and provide a current overview of AE management in local practice with a focus on Asian patients.

Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR-mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non-druggable genetic information that may guide clinical management.

Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies.

PURPOSE: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype. PATIENTS AND METHODS: We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1. RESULTS: Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5' regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients. CONCLUSION: Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.

Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy.

PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m(2) intravenously (i.v.) day 1 with vitamin B(12), folic acid, and dexamethasone or docetaxel 75 mg/m(2) i.v. day 1 with dexamethasone every 21 days. The primary end point was overall survival. RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P =.105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P <.001), febrile neutropenia (12.7% v 1.9%; P <.001), neutropenia with infections (3.3% v 0.0%; P =.004), hospitalizations for neutropenic fever (13.4% v 1.5%; P <.001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P =.092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P <.001) and all grade alopecia (37.7% v 6.4%; P <.001) compared with patients receiving pemetrexed. CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.