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PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

V‐raf murine sarcoma viral oncogene homologue B1 (BRAF) is a proto‐oncogene that regulates cell proliferation and survival. BRAF V600E‐mutated lung cancer has aggressive characteristics and is resistant to chemotherapies. Combination of BRAF‐specific inhibitor dabrafenib and mitogen‐activated protein kinase kinase (MEK) inhibitor trametinib is the standard treatment for BRAF V600E‐mutated lung cancer. We report a case of BRAF V600E‐mutated lung adenocarcinoma, which presented with respiratory distress due to deterioration of advanced cancer. The tumour responded rapidly and significantly to BRAF/MEK inhibitors, and the patient's symptoms improved within 2 weeks. BRAF/MEK inhibitors are effective treatment in BRAF‐mutated lung cancer even under critical conditions., Combination of BRAF (V‐raf murine sarcoma viral oncogene homologue B1)‐specific inhibitor dabrafenib and MEK inhibitor trametinib is the standard treatment for BRAF V600E‐mutated lung cancer. We report a case of BRAF V600E‐mutated lung adenocarcinoma, which presented with respiratory distress due to deterioration of advanced cancer. The tumour responded rapidly and significantly to BRAF/MEK inhibitors, and the patient's symptoms improved within 2 weeks.

Crizotinib has been approved for patients with advanced lung adenocarcinoma harboring rearrangements of the c-ROS-1 (ROS1) and anaplastic lymphoma kinase (ALK) genes. We report a patient with ROS1-rearranged lung adenocarcinoma who developed a crizotinib-induced mixed/cholestatic type of liver injury. The patient discontinued crizotinib after 34 days due to liver toxicity. Twenty-four days later, when transaminases and C reactive protein (CRP) were normalized, crizotinib was resumed using an oral desensitization method. The patient was successfully treated for manageable recurrence of liver injury and has been able to continue the treatment.

Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non-small-cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKIs). ASP8273 is an irreversible EGFR-TKI, given orally, that inhibits EGFR activating mutations and has shown clinical activity in patients with EGFR mutation-positive NSCLC. Epidermal growth factor receptor-TKI-naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT02500927). Patients received ASP8273 300 mg once daily until discontinuation criteria were met. The primary end-point was to determine the safety of ASP8273 300 mg; the secondary end-point was antitumor activity defined by RECIST version 1.1. Thirty-one patients (12 men and 19 women; median age, 64 years [range, 31-82 years]) with EGFR mutation-positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an exon 19 deletion (n = 13, 42%) or an L858R (n = 14, 45%) EGFR activating mutation, and two (7%) had an L861Q mutation. Five patients (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment-emergent adverse event was diarrhea (n = 24, 77%). All patients had at least one post-baseline scan; one patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate, 94% [n = 29/31]) per investigator assessment. Once-daily ASP8273 at 300 mg was generally well tolerated and showed antitumor activity in TKI-naïve Japanese patients with EGFR mutation-positive NSCLC.

Metastases to the breast from extramammary neoplasms are extremely rare, with an incidence ranging from 0.2% to 2.7% among reported clinical cases.1, 2 In addition to leukemia and lymphoma, primary tumors that commonly metastasize to the breast include melanoma, rhabdomyosarcoma, and lung cancer.3 The scarcity of breast metastasis may be explained by the poor blood supply of the large amount of fibrous tissue in the breast4 or hormone status.5 Moreover, breast metastasis from lung cancer is highly unusual. In addition, it can be difficult to distinguish a metastasis from primary breast cancer when lung cancer histology indicates adenocarcinoma, and such metastases can be misinterpreted as triple‐negative breast cancer. We report a case of metastases to the breast from lung adenocarcinoma. Immunohistochemical and genetic methods enabled differentiation of metastatic disease from primary breast carcinoma.

Objectives Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is a lack of data from routine clinical practice. This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting. Materials and methods Clinical characteristics, information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan. In addition to overall survival (OS), subgroup analyses were conducted based on first- and second-line treatments and combinations, and for patients who had survived >5 years from initiation of first-line treatment. Results The full analysis set comprised 1656 patients (mean 67 years, 80.6% with performance status 0 or 1). Median follow-up was 29.5 months and median OS was 29.7 months; 3- and 5-year survival rates were 41.2% and 21.5%, respectively. Significant predictors of OS were younger age, no smoking history, histological diagnosis of adenocarcinoma, less advanced clinical stage, good performance status and major EGFR-activating mutation. Despite some imbalances in baseline characteristics, patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs. Conclusions This large, long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice. Updated analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents, including immunotherapies.

Objective The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. Patients and methods Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naive) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m 2 ). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). Results Scans from 186 IPASS patients (gefitinib n = 88, carboplatin/paclitaxel n = 98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p = 0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p = 0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. Conclusion BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy.

Background The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. Methods Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years × 100. Results The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with ≥2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. Conclusion Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.

Background We performed an individual patient data meta-analysis to examine the impact of first-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor (TKI) therapy on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods Data from trials comparing EGFR-TKI against chemotherapy in exon 19 deletion (del19) or exon 21 L858R (L858R) EGFR mutations patients were used. We performed Cox regression to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). Impact of postprogression therapies was examined in exploratory analyses. All statistical tests were two-sided. Results Six eligible trials (gefitinib = 3, erlotinib = 3) included 1231 patients; 632 received EGFR-TKI and 599 received chemotherapy. At a median 35.0 months follow-up, there were 780 deaths and 1004 progressions. There was no difference in OS between EGFR-TKI and chemotherapy (HR = 1.01, 95% CI = 0.88 to 1.17, P = .84). There was also no difference in OS for Del19 (n = 682, HR = 0.96, 95% CI = 0.79 to 1.16, P = .68) and L858R (n = 540, HR = 1.06, 95% CI = 0.86 to 1.32, P = .59) subgroups ( P interaction = .47), or according to smoking status, sex, performance status, age, ethnicity, or histology. However, EGFR-TKI statistically significantly prolonged progression-free survival (PFS) overall (HR = 0.37, 95% CI = 0.32 to 0.42, P

Introduction Although interstitial lung disease (ILD) is a known serious adverse effect of epidermal growth factor receptor tyrosine kinase inhibitors, the risk factors for its development are poorly defined. To determine the risk factors for the development of drug-induced ILD and poor-prognosis (fatal) drug-induced ILD after erlotinib treatment, we assessed the baseline pulmonary status in patients with non–small cell lung cancer enrolled in a postmarketing clinical study of erlotinib. Patients and Methods In the present prospective cohort study, the baseline pulmonary status of all patients was evaluated using conventional or high-resolution computed tomography. The patients were monitored for the development of drug-induced ILD for 120 days after the start of treatment. All diagnoses of drug-induced ILD were confirmed by an independent ILD safety review committee. The risk factors were determined using logistic regression analysis. Results A total of 645 patients were enrolled, of whom 627 were evaluable. The committee confirmed the diagnoses of drug-induced ILD in 19 patients, 6 of whom had fatal outcomes. Multivariate logistic regression analysis revealed that pre-existing ILD and limited residual normal lung were significant risk factors for the development of drug-induced ILD. An additional multivariate logistic regression analysis revealed that limited residual normal lung was a significant risk factor for the development of poor-prognosis (fatal) drug-induced ILD. Conclusion Pre-existing ILD and the amount of residual normal lung (≤ 50%) were identified as risk factors for the development of drug-induced ILD. The amount of residual normal lung (≤ 50%) was identified as a risk factor for the development of poor-prognosis (fatal) drug-induced ILD.

ObjectiveMore tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC.Materials and methodsFrom December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (

The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60 mg/m(2) ) with (group DZ) or without (group D) zoledronic acid every 21 days. There were 50 patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94 patients (DZ, 48; D, 46), the median progression-free survival was 2.7 months (95% confidence interval [CI], 1.5-3.5 months) for the DZ group and 2.6 months (95% CI, 1.5-3.4 months) for the D group (stratified log-rank test, P = 0.89). The median overall survival was 10.4 months (95% CI, 7.0-15.8 months) for the DZ group and 9.7 months (95% CI, 6.1-12.5 months) for the D group (stratified log-rank test, P = 0.62). There were no clinically relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).

ObjectivesEpidermal growth factor receptor (EGFR) mutation testing is standard practice after lung adenocarcinoma diagnosis, and provision of high-quality tumor tissue is ideal. However, there are knowledge gaps regarding the utility of cytology or low tumor content histology samples to establish EGFR mutation status, particularly with regard to the proportion of testing performed using these sample types, and the lack of an established link with efficacy of treatment.MethodsThe randomized phase III Iressa Pan-ASia Study (IPASS; ClinicalTrials.gov identifier NCT00322452) of first-line gefitinib versus chemotherapy analyzed samples meeting preplanned specifications (n=437 evaluable for EGFR mutation; n=261 mutation-positive). This supplementary analysis assessed tumor content and mutation status of histology (n=99) and cytology samples (n=116) which were previously unanalyzed due to sample quality, type, and tumor content (

Nimotuzumab is a humanized IgG₁ monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors.Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens.Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression.Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.

Background In IPASS ( NCT00322452 ), progression-free survival (PFS, primary endpoint) was significantly longer with first-line gefitinib versus carboplatin/paclitaxel in never/light ex-smokers with advanced pulmonary adenocarcinoma in Asia, both in the overall intent-to-treat (ITT) population and in the EGFR mutation-positive subgroup. To further characterize the clinical relevance of these data, we investigated objective response rate (ORR) and health-related quality of life (HRQoL) in patients treated with gefitinib. Methods Objective response was assessed (RECIST) 6-weekly (previously reported). Post hoc assessments included median time to response, median duration of response and change in tumor size. The analysis of response population included those patients treated with gefitinib who responded ( n = 262 from ITT; n = 94 from EGFR mutation-positive subgroup). The percentage of patients with deterioration in HRQoL (Functional Assessment of Cancer Therapy-Lung [FACT-L], Trial Outcome Index [TOI]) and symptoms (Lung Cancer Subscale [LCS]) at 4 months post-randomization was analyzed according to progression status (EFQ population grouped by progressors/non-progressors in both treatment arms). The ORR (ITT) and incidence of skin rash/acne (evaluable-for-safety) were summarized. Results In patients whose tumors responded to gefitinib, median time to response was 6.1 weeks in the ITT population ( n = 262) and 6.0 weeks in the EGFR mutation-positive subgroup ( n = 94); median duration of response was 9.7 and 8.7 months in these groups, respectively. There was significant tumor shrinkage with gefitinib. A greater percentage of patients in the EFQ population whose tumors progressed experienced deterioration in HRQoL and symptoms at 4 months versus patients whose tumors did not progress (FACT-L 33.7% vs 16.3%; TOI 33.7% vs 13.2%; LCS 31.7% vs 15.5%). In the gefitinib arm of the EFS population, incidence of rash was 75.8% and 68.1% in EGFR mutation-positive and -negative subgroups, respectively (with ORR for the gefitinib arm of the ITT 71.2% vs 1.1%, respectively). Conclusions Patients whose tumors responded to first-line gefitinib experienced significant tumor shrinkage and a rapid, durable response. Deterioration in HRQoL and lung cancer symptoms at 4 months post-randomization was found to be associated with tumor progression, highlighting the role of patient-reported outcomes in the evaluation of advanced NSCLC disease. Rash was not supported as a predictive marker of response to gefitinib.

Potentially life-threatening, serious hemoptysis is an adverse event associated with bevacizumab in non-squamous non-small-cell lung cancer (NSCLC) trials. Suggested risk factors include central tumor location and cavitation; however, the profile of hemoptysis occurrence in clinical practice is still unclear. A nested case-control study was conducted to assess the onset profile and risk factors for hemoptysis in bevacizumab-treated patients in a real-world setting in Japan. After bevacizumab was approved for NSCLC, physicians registered all NSCLC patients scheduled for bevacizumab therapy, from November 2009 to August 2011. Patients developing grade 2 hemoptysis requiring an injectable hemostatic agent or grade ≥3 hemoptysis were selected as case subjects, matched with four control subjects each. Case report forms were collected after an observation period of 24 weeks. Radiologists assessed blinded thoracic images. Risk factors for hemoptysis were assessed by univariate and stepwise multivariate analysis. Of 6774 patients registered, 23 (0.3%) experienced grade ≥2 drug-related hemoptysis. A total of 104 patients (21 cases, 83 controls) were analyzed by central reviewers for risk factors of hemoptysis occurrence. In the univariate analysis seven factors were associated with hemoptysis. In the step-wise multivariate analysis, prior thoracic radiotherapy (P = 0.1844), presence of tumor exposure in the central airway (P = 0.0256) and concomitant radiotherapy (P = 0.1169) were identified as risk factors for hemoptysis. While the incidence of hemoptysis was low in the real-world setting in Japan, the three risk factors identified, prior thoracic radiotherapy, presence of tumor exposure in the central airway and concomitant radiotherapy, should be considered when selecting patients for bevacizumab treatment. Although technically classed as a clinical trial, a nested case-control study was a non-interventional surveillance study analyzing all NSCLC patients receiving bevacizumab in Japan, therefore it was not registered as a phase II/III clinical trial would be.

BACKGROUND: This study sought to ascertain whether induction-concurrent radiotherapy added to chemotherapy could improve the survival of patients undergoing surgery for stage IIIA N2 nonsmall cell lung cancer (NSCLC). METHODS: Patients with pathologically proven N2 disease were randomized to receive either induction chemotherapy (docetaxel 60 mg/m2 and carboplatin AUC [area under the receiver operating characteristic curve] = 5 for 2 cycles) plus concurrent radiation therapy (40 Gy) followed by surgery (CRS arm) or induction chemotherapy followed by surgery (CS arm). They subsequently underwent pulmonary resection when possible. RESULTS: Sixty patients were randomly assigned between December 2000 and August 2005. The study was prematurely terminated in January 2006 because of slow accrual. The most common toxicity was grade 3 or 4 leukopenia in 92.9% of patients in the CRS arm and 46.4% in the CS arm. Induction therapy was generally well tolerated, and there were no treatment-related deaths in either arm. Downstaging in the CS arm and CRS arm was 21% and 40%, respectively. The progression-free survival (PFS) and overall survival (OS) in the CS arm were 9.7 months and 29.9 months (PFS, hazard ratio [HR] = 0.68, P = .187), and those in the CRS arm were 12.4 months and 39.6 months (OS, HR = 0.77, P = .397), respectively. The PFS with and without downstaging was 55.0 and 9.4 months, respectively (HR = 3.39, P = .001). The OS with and without downstaging was 63.3 and 29.5 months, respectively (HR = 2.62, P = .021). CONCLUSIONS: The addition of radiotherapy to induction chemotherapy conferred better local control without significant adverse events. Tumor downstaging is important for prolonging the OS in patients with stage IIIA (N2) NSCLC. Cancer 2012. © 2012 American Cancer Society.

Purpose This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods Chemonaive patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone ( p =0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p =0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p =0.9526). No new safety signals were detected. Conclusion Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Objective: The actual condition of drug utilization and the adverse drug reactions profile of irinotecan hydrochloride hydrate (irinotecan), an antitumor drug, were examined on the basis of all the case survey results from April 1995 to January 2000. Methods: Drug utilization and the adverse drug reactions profile of irinotecan were figured out by checking of the patient conditions at the start of therapy and monitoring during ontherapy period in this survey. Results: Among the 13 935 patients investigated, 32% had non-small cell lung cancer, 16% had colorectal cancer, 15% had ovarian cancer and 14% had small cell lung cancer, all principal cancers in which irinotecan was domestically approved for use. Most frequent regimens of each cancer were concomitant use with cisplatin for non-small cell lung cancer and small cell lung cancer (38 and 46%, respectively), concomitant use with cisplatin or mitomycin for ovarian cancer (each 30%) and irinotecan alone for colorectal cancer (51%). The major (grade 3 or more) adverse drug reactions were myelosuppressions such as leukopenia (23.8 and 38.3% for lone and concomitant use, respectively) thrombocytopenia (6.5 and 14.3%) and gastrointestinal tract disorders such as diarrhea (10.2 and 10.0%). Conclusions: It was reconfirmed that the incidences of serious leukopenia, thrombocytopenia and diarrhea were high among the patients with contraindication or careful administration of its use prescribed in the drug package insert. Therefore, for proper use of irinotecan, it is important to discriminate the patient on the basis of risk status.

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Introduction: A feasibility study was performed to examine the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive thoracic radiation therapy (TRT) in patients with unresectable non-small cell lung cancer (NSCLC) of stage III. Methods: Patients received a 14-day induction therapy with gefitinib at 250 mg daily. TRT was initiated on day 15 in 2-Gy fractions administered five times weekly to a total dose of 60 Gy. The primary end point of the study was the rate of treatment completion. Mutation status of the epidermal growth factor receptor gene (EGFR) was evaluated for patients with available tumor specimens. Results: Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of >5 years. Conclusions: Our results do not support further trials of gefitinib and TRT for unselected NSCLC patients. This therapeutic strategy may hold promise, however, for locally advanced NSCLC in patients with sensitizing EGFR mutations.

Most non–small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKI) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827-HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827-HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, extracellular signal-regulated kinase, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK-701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation. Mol Cancer Ther; 9(10); 2785–92. ©2010 AACR.

Purpose This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non–small-cell lung cancer (NSCLC). Patients and Methods Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m2 on day 1)/vindesine (3 mg/m2 on days 1, 8)/cisplatin (80 mg/m2 on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m2)/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m2 on day1)/carboplatin (AUC 5 on day 1). Results The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. Conclusion Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC.

Purpose We conducted a phase I trial of the topoisomerase I inhibitor topotecan for the purpose of determining the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of topotecan when administered weekly to patients with advanced non–small-cell lung cancer. Patients and Methods Twelve patients with stage IIIB or IV disease were treated with topotecan by 30-minute intravenous infusion on days 1, 8, and 15 every 4 weeks. The dose was escalated in 2-mg/m 2 increments from the starting dose of 4 mg/m 2 until the MTD was reached. After the MTD had been reached in previously treated patients, chemotherapy-naive patients were enrolled for treatment at that dose, and the dose was escalated to estimate the MTD in the treatment-naive group. Results The MTD of topotecan was determined to be 6 mg/m 2 in the previously treated group and 8 mg/m 2 in the chemotherapy-naive group. All 3 previously treated patients experienced DLT at the 6-mg/m 2 dose level. Although only 1 of the 3 previously treated patients experienced DLT (grade 4 neutropenia for ≥ 3 days) at the 8-mg/m 2 dose level, skipping the topotecan dose on day 15 because of neutropenia was reported in 2 patients. Anorexia and general fatigue were the common nonhematologic toxicities. Conclusion The recommended dose of topotecan for phase II studies in previously untreated patients is 6 mg/m 2 on days 1, 8, and 15, every 28 days, and 4 mg/m 2 appears to be a suitable dose for use in previously treated patients with this schedule.

Background: Thymidylate synthase (TS), a key enzyme in the de novo synthesis of thymidine, is an important chemotherapeutic target for malignant tumours including lung cancer. Although inhibition of TS has an antiproliferative effect in cancer cells, the precise mechanism of this effect has remained unclear. Methods: We examined the effects of TS inhibition with an RNA interference-based approach. The effect of TS depletion on the growth of lung cancer cells was examined using colorimetric assay and flow cytometry. Results: Measurement of the enzymatic activity of TS in 30 human lung cancer cell lines revealed that such activity differs among tumour histotypes. Almost complete elimination of TS activity by RNA interference resulted in inhibition of cell proliferation in all tested cell lines, suggestive of a pivotal role for TS in cell proliferation independent of the original level of enzyme activity. The antiproliferative effect of TS depletion was accompanied by arrest of cells in S phase of the cell cycle and the induction of caspase-dependent apoptosis as well as by changes in the expression levels of cyclin E and c-Myc. Moreover, TS depletion induced downregulation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP), and it seemed to activate the mitochondrial pathway of apoptosis. Conclusion: Our data provide insight into the biological relevance of TS as well as a basis for clinical development of TS-targeted therapy for lung cancer.

Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effects of the combination of YM155, a novel small-molecule inhibitor of survivin expression, and platinum compounds (cisplatin and carboplatin) on human non-small cell lung cancer (NSCLC) cell lines. Methods: The anti-cancer efficacy of YM155 in combination with platinum compounds was evaluated on the basis of cell death and progression of tumour xenografts. Platinum compound-induced DNA damage was evaluated by immunofluorescence analysis of histone γ-H2AX. Results: Immunofluorescence analysis of histone γ-H2AX showed that YM155 delayed the repair of double-strand breaks induced in nuclear DNA by platinum compounds. The combination of YM155 and platinum compounds also induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Finally, combination therapy with YM155 and platinum compounds delayed the growth of NSCLC tumour xenografts in nude mice to an extent greater than that apparent with either treatment modality alone. Conclusion: These results suggest that YM155 sensitises tumour cells to platinum compounds both in vitro and in vivo, and that this effect is likely attributable to the inhibition of DNA repair and consequent enhancement of apoptosis.

9007Background: In JO25567 (Clinical trials registry number. JapicCTI-111390), EB significantly prolonged progression-free survival (PFS) in patients with NSCLC with activating EGFR mutation compar...

Purpose We conducted a phase I trial of BNP7787 (disodium 2,2′-dithio-bis-ethane sulfonate, Tavocept™), a novel chemoprotective and antitumor enhancing agent administered in combination with paclitaxel and cisplatin. The primary aim was to determine a safe and potentially efficacious BNP7787 dose for preventing and mitigating paclitaxel- and cisplatin-induced toxicities and to evaluate for preliminary evidence of efficacy of treatment. Patients and methods Twenty-two patients with stage IIIB/IV non-small cell lung cancer (NSCLC) received BNP7787 alone 1 week before co-administration of BNP7787 with paclitaxel followed by cisplatin. Twenty-one patients were treated with BNP7787 in escalating doses of 4.1–41.0 g/m2 concurrently with paclitaxel 175 mg/m2 and cisplatin 75 mg/m2 every 3 weeks. Results The appropriate dose was determined to be 18.4 g/m2 of BNP7787 although no dose-limiting toxicity was observed up to 41.0 g/m2. Mild intravenous site discomfort, thirst, and nausea were the most common toxicities. One patient developed grade 2 skin rash, which was severe enough to preclude further study treatment. The AUC0-inf of the metabolite mesna was approximately 6.3% of the AUC0-inf of BNP7787. Co-administration of paclitaxel and cisplatin did not appear to influence the pharmacokinetics of BNP7787 and mesna. The overall response rate was encouraging; 43% including 11 patients with prior chemotherapy. Conclusions The recommended dose for phase II/III studies is 18.4 mg/m2 of BNP7787 in combination with paclitaxel and cisplatin. Further studies are warranted to assess whether BNP7787 prevents and mitigates common and serious paclitaxel- and cisplatin-related side effects and enhances the efficacy of paclitaxel and cisplatin in advanced NSCLC patients.

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G1 arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G1 arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188–97. ©2010 AACR.

PurposeGefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).Patients and MethodsChemotherapy-naïve patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life.ResultsBetween March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P < .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03).ConclusionThis trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.

Objective: The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. Methods: The records of elderly (� 70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. Results: Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide‐cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19‐33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3‐18.2) and 24.1 months (95% confidence interval, 11.3‐27.2), respectively. Conclusions: Etoposide‐cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients.

Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non–small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G1 arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G1 arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G1 arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G1 arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G1 arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [Cancer Res 2009;69(16):6515–21]

The objective of this phase I/II study was to determine the recommended dose (RD) of S-1 and carboplatin (CBDCA), and to evaluate the efficacy and safety of this combination in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 given orally on days 1-14, and CBDCA infused intravenously on day 1, repeated every 3 weeks. RD was AUC5 of CBDCA and 80 mg/m(2) of S-1. Nineteen patients were treated at the RD. The overall response was 30.8% (95% confidence interval: 17.1-58.3%). The response rate in the RD was 36.8% (95% CI: 16.3-61.6%). The median overall survival time was 11.1 months (95% CI: 8.1-15.3 months) and the median progression-free survival time was 5.0 months (95% CI: 3.6-6.0 months). Major grades 3-4 toxicities were thrombocytopaenia (47%), anaemia (26%) and infection (16%). This is the first report to show promising activity of this combination in phase II, including survival data and manageable toxicity, especially in outpatients receiving treatment for advanced NSCLC.

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.

S-1 (also known as TS-1; Taiho Pharmaceutical Co. Ltd.; Tokyo, Japan) is a new oral fluoropyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1. Single-agent S-1 has demonstrated marked activity against non-small-cell lung cancer (NSCLC) as well as a broad array of other solid tumors, including gastric, colorectal, breast, cervical, and pancreatic cancers. This comprehensive review summarizes the results of previous clinical studies and describes ongoing clinical trials of S-1 in advanced NSCLC. S-1 combined with platinum compounds, irinotecan, and gemcitabine has produced promising results in terms of feasibility, safety, and effectiveness. Available data have stimulated further research, including phase III trials for the first-line treatment of advanced NSCLC.

Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles. Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m2/d. The MTD was determined to be 8.0 mg/m2/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m2/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m2/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.

D-19575 (glufosfamide: β-D-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to β-D-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of D-19575 in Japanese patients with advanced solid tumorsPatients were treated with escalating doses of D-19575 administered by a two-step (fast-slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1-11) at D-19575 doses of 3,200, 4,500, or 6,000 mg/m(2).Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of D-19575 was 6,000 mg/m(2), at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for5 months, and eight patients achieved disease stabilization.Our results show that D-19575 can be safely administered by infusion over 6 h at 4,500 mg/m(2) every 3 weeks. The safety profile and potential antitumor activity of D-19575 show that phase II studies of this drug are warranted.

Objective: The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Methods: Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts ,0.5 � 10 9 cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 mg/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Results: Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration‐time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. Conclusions: A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.

TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD) of TZT-1027, and to assess its pharmacokinetic profile in Japanese patients with advanced solid tumors following administration of the drug weekly for 3 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and met the following criteria: performance status ≤2 and acceptable organ function. The MTD was defined as the highest dose at which more than two-thirds of the patients experienced grade 4 hematological toxicity or grade 3/4 non-hematological toxicity during weekly TZT-1027 administration for 3 weeks. Forty patients were enrolled in the present study. Twelve doses between 0.3 and 2.1 mg/m2 were evaluated. Grade 4 neutropenia was the principal dose-limiting toxicity (DLT). At a dose of 2.1 mg/m2, two patients developed DLT: one patient developed grade 4 neutropenia, grade 3 myalgia, and grade 4 constipation, and the other one developed grade 4 neutropenia and grade 3 constipation. At a dose level of 1.8 mg/m2, toxicity was acceptable and no DLT was observed. The area under the curve and maximum concentration of TZT-1027 tended to increase linearly with the dose. The DLT observed were neutropenia, myalgia, and constipation, and the MTD was 2.1 mg/m2. The recommended dose for a phase II study was determined to be 1.8 mg/m2 for the drug administered weekly for 3 weeks.

Purpose: Most non–small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET proto-oncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines.Experimental Design: The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice.Results: Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-fluorouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, but not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification.Conclusions: Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC.

Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC. Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m2) on day 1 and with oral S-1 (80 mg/m2) on days 1 to 14 every 3 weeks. Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment. Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.

Purpose: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). Experimental Design: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m2 pemetrexed (P500) or 1,000 mg/m2 pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate. Results: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. Conclusion: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.

The purpose of this study was to evaluate the efficacy of gefitinib and the feasibility of screening for epidermal growth factor receptor (EGFR) mutations among select patients with advanced non-small cell lung cancer (NSCLC). Stage IIIB/IV NSCLC, chemotherapy-naive patients or patients with recurrences after up to two prior chemotherapy regimens were eligible. Direct sequencing using DNA from tumour specimens was performed by a central laboratory to detect EGFR mutations. Patients harbouring EGFR mutations received gefitinib. The primary study objective was response; the secondary objectives were toxicity, overall survival (OS), progression-free survival (PFS), 1-year survival (1Y-S) and the disease control rate (DCR). Between March 2005 and January 2006, 118 patients were recruited from 15 institutions and were screened for EGFR mutations, which were detected in 32 patients – 28 of whom were enrolled in the present study. The overall response rate was 75%, the DCR was 96% and the median PFS was 11.5 months. The median OS has not yet been reached, and the 1Y-S was 79%. Thus, gefitinib chemotherapy in patients with advanced NSCLC harbouring EGFR mutations was highly effective. This trial documents the feasibility of performing a multicentre phase II study using a central typing laboratory, demonstrating the benefit to patients of selecting gefitinib treatment based on their EGFR mutation status.

The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.

Summary Background The skeleton is one of the most common sites of metastasis in patients with advanced cancer. Bone metastases often cause SREs (skeletal-related events). Despite advances in the treatment of primary lung cancer, SREs still affect many patients. Therefore, we planned a retrospective study to investigate the clinical impact of SREs, and to compare differences in the therapeutic outcome between patients with and without skeletal metastases or SRE. Patients and methods We retrospectively investigated the charts of all 259 patients with non-small cell lung cancer (NSCLC) who consulted the Department of Medical Oncology at Kinki University School of Medicine between February 2002 and January 2005. We assessed their TNM stage, presence of skeletal metastases (on bone scintigraphy, MRI, and plain X-ray films), and outcome parameters such as SREs, analgesic use, and survival. Results A total of 70 patients (30.4%) were found to have skeletal metastases during their clinical course and 35 patients (50%) out of all 70 patients had SREs. Among 135 stage IV patients, a total of 56 (41%) had skeletal metastases, and 25 of these 56 patients (45%) had SREs. The most common SREs were the need for radiotherapy (34.3%) and hypercalcemia (20%). Patients with SREs tended to have worse survival, while no significant difference of survival was observed between patients with and without skeletal metastases. Conclusion It seems to be important to prevent SREs during the treatment of NSCLC, so further studies evaluating bisphosphonates in combination with chemotherapy are warranted.

TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to gamma-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy.

Deregulation of survivin expression is implicated in tumorigenesis. To examine the regulation of survivin expression in response to DNA damage, we exposed A549 human lung cancer cells to ultraviolet C (UVC) radiation, which induces DNA single-strand breakage. UVC irradiation induced G 2 –M arrest that was accompanied by accumulation of p53 and subsequent down-regulation of survivin. Depletion of p53 by RNA interference prevented the UVC-induced down-regulation of survivin. Furthermore, depletion of survivin resulted in G 2 –M arrest, suggesting that down-regulation of survivin by p53 contributes to the p53-dependent G 2 –M checkpoint triggered by DNA damage.