Kozo Yoshimori

Gefitinib or Chemotherapy for Non-Small- Cell Lung Cancer with Mutated EGFR

BACKGROUND Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy. METHODS We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects. RESULTS In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease. CONCLUSIONS First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)

Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).

BACKGROUND NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS). MATERIALS AND METHODS For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated. RESULTS The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P=0.483). The OS of patients who received platinum throughout their treatment (n=186) was not statistically different from that of patients who never received platinum (n=40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n=76) was around 3 years. CONCLUSIONS No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.

S-1 Plus Cisplatin Combination Chemotherapy in Patients with Advanced Non–Small Cell Lung Cancer A Multi-Institutional Phase II Trial

Purpose: To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent, S-1 that consisted of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, for non–small-cell lung cancer (NSCLC) patients. Experimental Design: In this phase II trial, patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m2 twice a day for 21 consecutive days while cisplatin (60 mg/m2) was administered intravenously on day 8. This schedule was repeated every 5 weeks. Results: Of 56 patients enrolled in the study, 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range, 1–12 cycles). Among these 55 patients, one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval, 34–61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%). No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%), vomiting (7%), or diarrhea (7%). Conclusions: S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC.

A steady increase in nontuberculous mycobacteriosis mortality and estimated prevalence in Japan.

RATIONALE Pulmonary disease caused by nontuberculous mycobacteria is generally reported to have a good prognosis. However, the actual mortality rate over time has not been reported in a large-scale survey. OBJECTIVES To determine the annual trend in mortality from nontuberculous mycobacteriosis, based on nearly four decades of patient data, and to estimate the prevalence of these cases in 2005. METHODS The annual mortality rate and regional distribution of nontuberculous mycobacteriosis-related deaths in Japan were obtained from Vital Statistics of Japan, which is published annually. The crude and age-adjusted mortality rates and associated regional differences were calculated from the Japanese census data. A 5-year follow-up study including 309 patients with pulmonary nontuberculous mycobacteriosis who visited and registered at our institute from 2004 to 2006 was conducted to determine the 5-year prognosis and the annual mortality rate. MEASUREMENTS AND MAIN RESULTS The crude mortality rates for both sexes have increased since 1970, and the mortality rate from pulmonary disease was greater in women after 2005. The age-adjusted rates of disease also showed a gradual increase until 2010 in women. Geographically, higher standardized mortality ratios were observed in middle and western Japan, particularly in the southern coastal regions along the Pacific Ocean. In a clinical follow-up study, the mortality rate was approximately 1-2% annually. The prevalence of pulmonary nontuberculous mycobacteriosis was estimated to be 6- to 10-fold higher than the annual incidence. CONCLUSIONS There was a constant and steady increase of nontuberculous mycobacteriosis-related mortality in Japan, and this mortality rate showed significant geographical variation. The prevalence of environmental mycobacterial disease in Japan is higher than reported in most other countries.

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial

Background We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. Patients and methods Patients receiving chemotherapy including cisplatin (≥70 mg/m2) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 μg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1–3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0–120 h). Results The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0–24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24–120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). Conclusions Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Docetaxel in combination with either cisplatin or gemcitabine in unresectable non-small cell lung carcinoma: a randomized phase II study by the Japan Lung Cancer Cooperative Clinical Study Group.

Purpose: To evaluate whether cisplatin-free chemotherapy (docetaxel and gemcitabine [DG]) provides a comparable alternative to cisplatin-based chemotherapy (docetaxel and cisplatin [DC]) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Patients and Methods: Patients (n = 133) with stage IIIB to IV NSCLC were randomly assigned to receive DG (docetaxel 60 mg/m2, day 8 + gemcitabine 800 mg/m2, days 1 and 8, every 3 weeks; n = 65) or DC (docetaxel 60 mg/m2, day 1 + cisplatin 80 mg/m2, day 1, every 3 weeks; n = 68). The primary end point of the study was overall response rate. No prophylactic use of human recombinant granulocyte colony stimulating factor was allowed. Results: The planned patient number was 150. However, an unexpectedly high incidence of grade 3 interstitial lung disease (11.1%) was identified in the DG arm, so the study was closed early. The overall response rates of the DG and DC arms were 27% and 23.5%, respectively, which demonstrated that the DG treatment was not inferior to the DC arm. Gastrointestinal toxicities were less frequent in the DG arm than in DC arm. Interstitial lung disease was exclusively observed in seven of 63 patients in the DG arm (11.1%). Median survival and 1-year survival rate were comparable between the two arms (median survival, DG 13.7 months versus DC 11.4 months; 1-year survival, DG 56.6% versus DC 47.7%). Conclusion: The DG regimen has a response rate and survival rate comparable to those of the DC regimen and can therefore be considered from an efficacy point of view to be comparable. However, the DG regimen may have induced pulmonary toxicity in 11% of the patients exposed and therefore should be used cautiously among patients with advanced NSCLC.

Phase I/II study of docetaxel and S-1, an oral fluorinated pyrimidine, for untreated advanced non-small cell lung cancer

The purpose of this phase I/II study is to evaluate a new combination chemotherapy consisting of docetaxel and S-1 as front-line therapy for patients with untreated advanced non-small cell lung cancer (NSCLC). The treatment included docetaxel on day 1 and oral S-1 at a fixed dose of 40mg/m(2) administered twice daily on days 1-14 and repeated every 3 weeks. In phase I, docetaxel at escalating doses of 40 (level 0), 50 (level 1) and 60mg/m(2) (level 2) was administered starting from level 1. Because only one patient among the 6-patient cohort at level 1 and no patient among the 3-patient cohort at level 2 experienced defined dose-limiting toxicity (DLT), level 2 was determined as the recommended dose. In phase II, 60 patients were treated at the recommended dose for median 3 cycles, and the overall response rate was 30% (95% confidence interval [CI], 18.9-43.2%), and the median overall and progression-free survival times were 15.2 (95% CI: 10.5-17.7) and 4.9 (95% CI: 3.5-5.6) months, respectively. The most frequent toxicities experienced were neutropenia, febrile neutropenia and appetite loss; all toxicities were however well manageable. The present regimen showed a potent activity with mild toxicity in untreated NSCLC.

Anamorelin (ONO-7643) for the treatment of patients with non–small cell lung cancer and cachexia: Results from a randomized, double-blind, placebo-controlled, multicenter study of Japanese patients (ONO-7643-04)

Cachexia, described as weight loss (mainly in lean body mass [LBM]) and anorexia, is common in patients with advanced cancer. This study examined the efficacy and safety of anamorelin (ONO‐7643), a novel selective ghrelin receptor agonist, in Japanese cancer patients with cachexia.