Anaplastic lymphoma kinase gene rearrangements in patients with advanced-stage non-small-cell lung cancer: CT characteristics and response to chemotherapy.

Few articles have been published on the imaging findings of anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). To investigate the radiological findings of ALK-positive NSCLC in the advanced stage, CT scans were examined. In addition, the response to chemotherapy was evaluated. Of the 36 patients with ALK-rearranged NSCLC, a mass and a nodule were identified in 17 (47.2%) and 16 (44.4%), respectively, indicating that more than 40% had a small-sized tumor. Overall, 31 (86.1%) patients had lymphadenopathy, seven (19.4%) had extranodal lymph node invasion, and three (8.3%) had lymphangitis. A pleural effusion was seen in 15 patients (41.7%). All but one patient had no ground-glass opacity (GGO) lesions, indicating that most ALK-positive tumors showed a solid growth pattern without GGO on CT. Twenty were evaluable for response to chemotherapy; 10 (50.0%) had a partial response (PR), nine (45.0%) had stable disease (SD), and one (5.0%) had progressive disease (PD) with first-line chemotherapy. With second-line chemotherapy, five (26.3%) had PR, 11 (57.9%) had SD, and three (15.8%) had PD. The five patients with PR were all treated by using crizotinib. Time to progression was 8.2 months with first-line chemotherapy, and 6.0 months with second-line chemotherapy. Advanced-stage ALK-positive tumors have a relatively aggressive phenotype, which cannot be inferred from the size of the tumor alone. ALK-positive patients have a good response to first-line cytotoxic drugs and to crizotinib as second-line therapy, but a relatively poor response to cytotoxic drugs as second-line therapy.

Crizotinib-induced esophageal ulceration: a novel adverse event of crizotinib.

This report describes esophageal ulcer as a novel adverse event associated with crizotinib therapy. Although crizotinib is generally well tolerated, physicians should be aware of the possibility of this adverse event.

Clinical outcomes of advanced non-small cell lung cancer patients screened for epidermal growth factor receptor gene mutations.

PURPOSE: To evaluate the relationship between the epidermal growth factor receptor (EGFR) mutation status and the effectiveness of gefitinib monotherapy or chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed a cohort of 100 patients with stage IIIB/IV NSCLC screened for two major EGFR mutations (exon 19 deletions and L858R mutation). RESULTS: Forty-six out of 48 EGFR mutation-positive patients (96%) received gefitinib, whereas only 3 out of 52 EGFR mutation-negative patients (6%) received gefitinib. Favorable objective response rates to gefitinib as first- and second-line treatment (87 and 80%, respectively) were observed in EGFR mutation-positive patients. Overall response rate to chemotherapy as first-line treatment did not differ significantly between patients with EGFR mutations and those without mutation (32 vs. 28%, respectively; P = 0.7198). As to first-line treatment, EGFR mutation-positive patients treated with gefitinib experienced significantly longer progression-free survival (PFS) than did patients who received chemotherapy (median survival, 7.8 months vs. 5.1 months, respectively; P = 0.0323). Similarly, as to second-line treatment, EGFR mutation-positive patients treated with gefitinib had significantly longer PFS than did patients who received chemotherapy (median survival, 6.5 months vs. 4.0 months, respectively; P = 0.0048). Patients with EGFR mutations survived longer than those without EGFR mutations after first-line treatment (median, 24.3 vs. 12.6 months, respectively; P = 0.0029). CONCLUSION: EGFR mutation-positive patients benefit from either first- or second-line gefitinib monotherapy. Further large-scale prospective studies to confirm this finding are needed.

Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations.

PURPOSE: Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non-small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation-positive non-small cell lung cancer. EXPERIMENTAL DESIGN: We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non-small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials. RESULTS: Seven eligible trials were identified for a total of 148 non-small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naïve status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61 received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782). CONCLUSIONS: Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non-small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.

Gefitinib for the treatment of non-small-cell lung cancer.

Gefitinib is an orally bioavailable, EGF receptor tyrosine kinase inhibitor and was the first targeted drug to be approved for non-small-cell lung cancer (NSCLC). Identification of objective tumor regressions with gefitinib in NSCLC patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of gefitinib in NSCLC. A recent large international Phase III study (IRESSA NSCLC Trial Evaluating Response and Survival Against Taxotere [INTEREST]) comparing gefitinib and docetaxel in unselected pretreated patients showed equivalent survival with better tolerability and quality of life. In addition, a Phase III study (WJTOG0203) evaluating gefitinib as sequential therapy after platinum-doublet chemotherapy showed the improved progression-free survival time. Furthermore, a large-scale randomized study (IRESSA Pan-Asia study [IPASS]) comparing gefitinib monotherapy with carboplatin/paclitaxel for previously untreated patients with adenocarcinoma who were never- or light-smokers showed an improved progression-free survival time in the gefitinib arm. A smaller Phase III study of pretreated Japanese patients (V-15-32) also demonstrated no difference in overall survival compared with docetaxel, with a statistically greater overall response rate. Somatic mutations in the EGFR gene, the target of gefitinib, were associated with dramatic and durable regressions in patients with NSCLC. Currently, investigators are trying to determine the optimal approach to select patients for treatment with gefitinib. This article aims to briefly summarize the profile of gefitinib, EGFR mutations, landmark trials with gefitinib and, also, ongoing trials that may herald an era of individualized therapy in at least some NSCLC patients.

Randomized phase II trial of three intrapleural therapy regimens for the management of malignant pleural effusion in previously untreated non-small cell lung cancer: JCOG 9515.

To evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin (BLM), OK-432 (a pulverized product of heat-killed Streptococcus pyogenes) or cisplatin plus etoposide (PE) for the management of malignant pleural effusion (MPE) in previously untreated non-small cell lung cancer. Eligible patients were randomized to the BLM arm: BLM 1mg/kg (maximum 60mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10KE/body), or the PE arm: cisplatin (80mg/m(2)) and etoposide (80mg/m(2)). Pleural response was evaluated every 4 weeks according to the study-specific criteria. All responders received systemic chemotherapy consisting of PE every 3-4 weeks for two or more courses. Pleural progression-free survival (PPFS) was defined as the time from randomization to the first observation of pleural progression or death due to any cause. The primary endpoint was the 4-week PPFS rate. Of 105 patients enrolled, 102 were assessed for response. The 4-week PPFS rate for the BLM arm was 68.6%, 75.8% for the OK-432 arm, and 70.6% for PE arm. Median survival time (MST) for the BLM arm was 32.1 weeks, 48.1 weeks for the OK-432 arm, and 45.7 weeks for the PE arm. However, the outcomes did not differ significantly between groups. Toxicity was tolerable in all arms except for one treatment-related death due to interstitial pneumonia induced by BLM. We will select intrapleural treatment using OK-432 in the management of MPE in NSCLC for further investigation because it had the highest 4-week PPFS rate.

Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer.

INTRODUCTION: We evaluated the efficacy of gefitinib monotherapy prospectively in patients with advanced or pretreated non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. METHODS: Patients with NSCLC were examined for EGFR exon 19 deletion mutations by fragment analysis and for EGFR L858R point mutations by the Cycleave polymerase chain reaction technique. EGFR mutation-positive patients with locally advanced, metastatic, or recurrent/refractory NSCLC that was not curable with surgery or thoracic radiotherapy were candidates for gefitinib treatment administered at 250 mg/day until disease progression. RESULTS: Mutations of the EGFR gene were detected in 27 (41%) of 66 patients. Ten had exon 19 deletion, and 17 had L858R. Twenty-one patients harboring EGFR mutations were treated with gefitinib and were considered assessable for responses and adverse events. Nineteen patients with EGFR mutations achieved objective responses (three complete responses and 16 partial responses), resulting in an overall response rate of 90.5% (95% confidence interval, 69.6%-98.8%). The median progression-free survival was 7.7 months (95% confidence interval, 6.0 mo to not reached). The median overall survival has not been reached. Common adverse events were skin toxicity, diarrhea, and elevated aminotransferases, but no pulmonary toxicity was observed. CONCLUSIONS: Detection of common EGFR mutations seems to be useful for selecting patients with NSCLC who would likely benefit from gefitinib monotherapy.

Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib.

PURPOSE: Non-small cell lung cancers carrying activating mutations in the gene for the epidermal growth factor receptor (EGFR) are highly sensitive to EGFR-specific tyrosine kinase inhibitors. However, most patients who initially respond subsequently experience disease progression while still on treatment. Part of this "acquired resistance" is attributable to a secondary mutation resulting in threonine to methionine at codon 790 (T790M) of EGFR. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of the EGFR gene to look for secondary mutations in tumors with acquired resistance to gefitinib in 14 patients with adenocarcinomas. Subcloning or cycleave PCR was used in addition to normal sequencing to increase the sensitivity of the assay. We also looked for T790M in pretreatment samples from 52 patients who were treated with gefitinib. We also looked for secondary KRAS gene mutations because tumors with KRAS mutations are generally resistant to tyrosine kinase inhibitors. RESULTS: Seven of 14 tumors had a secondary T790M mutation. There were no other novel secondary mutations. We detected no T790M mutations in pretreatment specimens from available five tumors among these seven tumors. Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration. None of the tumors had an acquired mutation in the KRAS gene. CONCLUSIONS: A secondary T790M mutation of EGFR accounted for half the tumors with acquired resistance to gefitinib in Japanese patients. Other drug-resistant secondary mutations are uncommon in the EGFR gene.

Association between smoking habits and dopamine receptor D2 taqI A A2 allele in Japanese males: a confirmatory study.

Our previous study showed that A2 allele of dopamine D2 (DRD2) TaqI A polymorphism related to smoking habits, which was opposed to the results of studies for Caucasians. In order to confirm our finding, a similar study was conducted for the first-visit outpatients of Aichi Cancer Center Hospital, who participated in HERPACC-II (Hospital-based Epidemiologic Research Program at Aichi Cancer Center-II). Among consecutive 1,577 first-visit patients between November 2000 and February 2001, 800 patients provided a 7 ml of peripheral blood. Smoking habit data were available for 798 participants. Excluding five participants aged < 20 years or > 80 years, the remaining 793 participants (346 males and 447 females) were analyzed. The DRD2 genotype was determined by a new method, polymerase chain reaction with confronting two-pair primers (PCR-CTPP). In males, current smokers were 35.3% of individuals with A1A1 genotype, 43.1% of individuals with A1A2 genotype, and 57.0% of individuals with A2A2 genotype, while in females, they were 19.6%, 14.6%, and 10.9%, respectively. Age-adjusted odds ratio (OR) of current smoking relative to A1A1 was 1.61 (95% confidence interval, 0.71-3.46) for A1A2 and 2.32 (1.02-5.29) for A2A2 in males, and 0.72 (0.32-1.61) and 0.51 (0.22-1.18) in females, respectively. The present study indicated that Japanese males with A2A2 genotype have a higher risk of being current smokers. No association for Japanese females suggested that female smoking behavior is differently affected in biological and/or psychological manner.