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Background Nivolumab is a fully humanized IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor, disrupting PD-1-mediated signaling and restoring antitumor immunity. The objective of this study was to develop a nivolumab quantification method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to evaluate its application in clinical therapeutic drug monitoring. Methods Nivolumab was purified from human plasma using rProtein A resin and then digested with trypsin. The ASGITFSNSGMHWVR peptide (multiple reaction monitoring transition: m/z 550.6→661.4) was detected as a surrogate peptide of nivolumab by triple quadrupole mass spectrometry. Plasma samples (126) were collected from 14 patients with non-small cell lung cancer who were undergoing clinical dosing regimen with nivolumab. The pharmacokinetic data were analyzed using Phoenix NLME software (Version 7.0, Certara, St. Louis, MO) based on a previously reported population pharmacokinetics (PPK) model of nivolumab. Results Nivolumab was selectively detected in human plasma and the linear range was 5-200 mcg/mL (R = 0.99). The accuracy and intraday and interday imprecision were within ±15% of the quality control values of 5 (lower limit of quantification), 10 (low), 80 (medium), and 160 (high) mcg/mL. The nivolumab concentrations measured using LC-MS/MS were consistent with those of previously reported PPK models, and the pharmacokinetic parameters could be adequately predicted from a single trough concentration using a Bayesian approach. Conclusions An absolute quantification method for nivolumab using LC-MS/MS was successfully developed and validated. Combined with PPK analysis, this method should be useful for the therapeutic drug monitoring of nivolumab in clinical practice.

BACKGROUND Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR. METHODS Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression. RESULTS Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding. CONCLUSIONS Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations.

Background Irinotecan (CPT-11) is the key drug used in chemotherapy for many malignant tumors. CPT-11 has cholinergic activity and induces perspiration during intravenous administration. In this study, concentrations of CPT-11 and its active metabolite, SN-38, released during perspiration were measured and risk of exposure of these drugs was assessed. Method Beads of sweat were collected using a dropper from four patients undergoing a chemotherapy regimen involving intravenous administration of CPT-11. The concentrations of CPT-11 and SN-38 in sweat were measured using liquid chromatography tandem mass spectrometry. Result Chemotherapy regimens were capecitabine and irinotecan plus bevacizumab (n = 1), CPT-11 monotherapy (n = 1), and oxaliplatin–irinotecan–leucovorin–5-fluorouracil (n = 2). Uridine diphosphate-glucuronosyltransferase 1A1 phenotypes were *6 homo-type (n = 1), *6 hetero-type (n = 1), and wild type (n = 2). CPT-11 dose was 292.3 ± 75.5 mg/body weight (mean ± standard deviation). CPT-11 was detected in sweat secreted by all the four patients, and its mean (±standard deviation) concentration was 252.6 (±111.9) ng/ml. SN-38 was detected in only one of the patients who received oxaliplatin–irinotecan–leucovorin–5-fluorouracil treatment and who had the wild-type uridine diphosphate-glucuronosyltransferase 1A1 phenotype at a concentration of 74.37 ng/ml. Conclusion CPT-11 and SN-38 are detected in sweat released during intravenous CPT-11 administration. Beads of sweat or linen clothes that absorb the sweat might be the source of CPT-11 and SN-38 exposure.

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.

// Akito Hata 1 , Nobuyuki Katakami 1 , Shigeki Nanjo 1 , Chiyuki Okuda 1 , Reiko Kaji 1 , Katsuhiro Masago 1 , Shiro Fujita 1 , Hiroshi Yoshida 2 , Kota Zama 2 , Yukihiro Imai 3 and Yukio Hirata 1 1 Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan 2 Department of Contract Research for Clinical Pathology, GeneticLab Co. Ltd., Sapporo, Japan 3 Department of Clinical Pathology, Kobe City Medical Center, General Hospital, Kobe, Japan Correspondence to: Akito Hata, email: a-hata@fbri.org Keywords: PD-L1; EGFR mutation; non-small cell lung cancer; PD-L1 IHC; PD-L1 antibody Received: April 12, 2017 Accepted: November 11, 2017 Published: December 01, 2017 ABSTRACT Background: Current clinical trials have suggested poorer efficacies of anti-programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapies for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR ) mutations, implying lower PD-L1 expression in EGFR -mutant NSCLC than in EGFR -wild type. Methods: We retrospectively analyzed correlation between PD-L1 expression and EGFR status in clinical samples of pretreated NSCLC. PD-L1 immunohistochemistry was performed using the 28-8 anti-PD-L1 antibody for tumor cell membrane staining. H-score was adopted to evaluate both percentage and intensity. We investigated H-scores ≥1, ≥5, and ≥10 as PD-L1+ cut-offs. H-score ≥10 was defined as strong PD-L1+. Results: We investigated 96 available histologic samples in 77 pretreated patients with NSCLC. Median H-score in EGFR -mutant samples (n=65) was 3 (range, 0-150), whereas EGFR -wild-type (n=31) was 8 (range, 0-134) (p=0.0075). Using H-scores ≥1, ≥5, and ≥10 cut-offs, incidence of PD-L1+ in EGFR -mutant vs. EGFR -wild-type samples were: 85% (55/65) vs. 94% (29/31) (p=0.2159); 42% (27/65) vs. 74% (23/31) (p=0.0027); and 22% (14/65) vs. 48% (15/31) (p=0.0074), respectively. Patient-oriented (n=77) univariate analysis for strong PD-L1+ found age of sample (p=0.0226) and EGFR mutation status (p=0.0490) as significant factors. Multivariate analysis identified EGFR mutation status as the only significant factor (p=0.0121, odds ratio 2.99) for strong PD-L1+. H-scores of PD-L1 expression varied in all 11 cases receiving multiple rebiopsies, and categories of positivity migrated in 10 (91%) of 11 patients. Conclusions: PD-L1 expression was significantly lower in EGFR -mutant NSCLC samples than in EGFR wild-type samples. Its expression could be dynamic and affected by age of sample.

Errors in sequencing are a major obstacle in the interpretation of next-generation sequencing (NGS) results. In the present study, sequencing errors identified from analysis of single nucleotide variants (SNVs) identified during exome sequencing of human germline DNA were studied using the Thermo Fisher Ion Proton System. Two consanguineous cases were selected for sequencing using the AmpliSeq Exome capture kit, and SNVs found in both cases were validated using Sanger sequencing. A total of 98 SNVs detected by NGS were randomly selected for further analysis. Nine of the analyzed SNVs were shown to be false positives when confirmed by Sanger sequencing. All but one SNV were considered to be homopolymer regions, mainly through the insertion or deletion of nucleotides. The remaining error was considered to be related to the primer. The present results revealed that the majority of the SNV sequencing errors originated from homopolymer insertion/deletion errors, which are commonly observed when using the Ion Torrent system.

Aim The aim of this study was to evaluate whether irradiation induces the expression of tumor programed cell death ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC). Patients and methods Seventeen patients with NSCLC who received chemoradiotherapy and underwent tumor resection and six patients whose pre-treatment biopsy specimens were available, were analyzed by immunohistochemistry for PD-L1 expression between September 2011 and June 2016 at the Institute of Biomedical Research and Innovation Hospital. Results Among six patients for which pre-irradiation biopsy samples were available, the H-score for PD-L1 was reduced after irradiation following staining with two different antibody clones (SP28-8 and SP142). A PD-L1 H-score >5 with SP28-8 antibody (hazard ratio=6.46; 95% confidence interval=1.209-34.53; p=0.029) was a significant negative factor for duration of progression-free survival after curative operation or chemoradiation. Conclusion We showed that tumor PD-L1 expression decreased in patients with NSCLC who received chemoradiotherapy and radiation resistance might be due to pre-treatment PD-L1 expression.

Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non–small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. Patients and Methods Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). Results Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinib were 6.5 and 7.5 months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P = .257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P = .768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation–positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P = .424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). Conclusion The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.

Background Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor ( EGFR ) mutation on CRT efficacy. Methods From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status. Results Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR -mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6–19.0] versus 16.5 [95% CI: 11.8–19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR -mutant and wild-type patients, respectively ( p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR -mutant patients (35%). However, locoregional recurrence was less common in EGFR -mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR -mutant and wild-type patients (51.1 [95% CI: 28.2–70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras -mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024). Conclusion Concurrent CRT resulted in shorter progression-free survival in EGFR -mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR -mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed.

Afatinib, the second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been postulated to be associated with improved inhibition of EGFR-dependent tumor growth compared with first-generation EGFR-TKIs for advanced non-small cell lung cancer (NSCLC). We present a case of lung adenocarcinoma (cT3N0M0) treated with neoadjuvant afatinib and sleeve lobectomy. Because of the location of the tumor, reduced FEV1 value, and the presence of EGFR mutation, the patient was planned to be prescribed afatinib (30 mg daily) for 3 weeks as neoadjuvant therapy and underwent sleeve lobectomy to avoid pneumonectomy as much as possible. Although the patient presented with grade 3 diarrhea and dose reduction of afatinib to 20 mg daily was needed, several image findings showed a partial response of the tumor on Day 20. Oral administration of afatinib was discontinued on Day 22. A right upper sleeve lobectomy combined with partial resection of lower lobe was performed after oral administration of afatinib on Day 24. The patient’s postoperative course was uneventful and she has been free of recurrence for 26 months. This strategy could reduce the risk of pneumonectomy with acceptable side effects. The treatment, clinical course and pathological findings of the patient are discussed.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of gefitinib in dried blood spots (DBSs). Gefitinib was extracted with methanol from DBS of 3 mm in diameter and detected using a triple quadrupole mass spectrometer. The method was validated by evaluating its precision, accuracy, selectivity, carryover, matrix effect, recovery, and stability. For clinical validation, paired finger-prick DBS and plasma concentrations were compared for 10 patients with non-small cell lung cancer (NSCLC) taking gefitinib. The calibration linear range was 37.5–2400 ng/mL (coefficient of determination [R2] = 0.99), encompassing the therapeutic concentrations of gefitinib. The accuracy and precision were within 15% of the quality control (QC) concentrations of 80, 200, and 2000 ng/mL. The lower limit of quantification was determined to be 40 ng/mL. Gefitinib was stable in DBSs for up to 5 months at room temperature and −20 °C, and at 40 °C for 24 h. A good correlation was observed between the gefitinib levels measured by the DBS method and plasma concentrations (R2 = 0.99). This method provides a simple, fast, and accurate approach to the quantitative analysis of gefitinib in finger-prick DBSs. The method would be useful for minimally invasive evaluation of the clinical gefitinib blood concentration.

Introduction Epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Because T790M is mediated by TKI exposure, its penetration and "on–off" may affect T790M status. Methods We retrospectively reviewed T790M status and clinical course of patients who had undergone multiple rebiopsies after acquired resistance to EGFR-TKI. Results Of 145 patients with EGFR-mutant NSCLC receiving rebiopsy after acquired resistance, 30 underwent multiple site rebiopsies, and 24 received repeated rebiopsies at the same lesion. In 22 patients who underwent rebiopsies from both central nervous system (CNS; 20 cerebrospinal fluids [CSF] and 2 brain tumoral tissues) and thoracic lesions (7 lung tissues, 14 pleural effusions, and 1 lymph node), 12 were thoracic-T790M-positive. Of these 12 patients, 10 were CNS-T790M-negative, despite exhibiting thoracic-T790M-positive. All 10 thoracic-T790M-negatives were CNS-T790M-negative. Three patients revealed a spatial heterogeneous T790M status among their thoracic lesions. In 24 patients receiving repeated rebiopsies at the same lesion (12 lung tissues, 6 CSFs, and 6 pleural effusions), T790M status of lung lesions varied in five patients after TKI-free interval. In all five patients whose T790M status changed from positive to negative, EGFR-TKI rechallenge was effective. In three of these five patients, after further TKI exposure, T790M status changed from negative to positive again. There was also a patient whose CSF T790M status changed from negative to positive after high-dose erlotinib therapy. Conclusions T790M status in an individual patient can be spatiotemporally heterogeneous because of selective pressure from EGFR-TKI.

Introduction Atezolizumab, an anti–programmed death-ligand 1 (PD-L1) agent, is effective and well tolerated in patients with pretreated advanced non–small-cell lung cancer (NSCLC). We assessed its efficacy and safety in Japanese patients through subgroup analyses of the phase 3 OAK study ( NCT02008227 ). Patients and Methods Key eligibility criteria of this randomized, controlled, open-label, international study include locally advanced/metastatic NSCLC, ≥ 1 prior platinum-based chemotherapy, age ≥ 18 years, measurable disease (Response Evaluation Criteria in Solid Tumors v1.1), and Eastern Cooperative Oncology Group performance status 0 or 1. Atezolizumab 1200 mg or docetaxel 75 mg/m2 was provided intravenously every 3 weeks. Co-primary end points were overall survival (OS) in the intention-to-treat (ITT) population and those with ≥ 1% PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC; TC1/2/3 or IC1/2/3). Results Sixty-four ITT patients were Japanese; 19 had TC1/2/3 or IC1/2/3 status. In Japanese ITT patients, median OS in the atezolizumab arm (n = 36) was longer than the docetaxel arm (n = 28; 21.3 months [95% confidence interval (CI), 11.0-not estimable (NE)] versus 17.0 months [95% CI, 12.5-NE], respectively; hazard ratio 0.80 [95% CI, 0.41-1.57]). In the TC1/2/3 or IC1/2/3 population, median OS was 21.3 months (95% CI, 15.0-NE) and NE in the atezolizumab (n = 11) and docetaxel (n = 8) groups, respectively (hazard ratio, 0.81 [95% CI, 0.22-3.05]). Atezolizumab was generally well tolerated, with no treatment-related deaths. Conclusion Atezolizumab was effective and well tolerated in pretreated Japanese patients with NSCLC. Results are consistent with the primary analysis of OAK.

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.

Background: Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose. Methods: T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled. Results: We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%. Conclusions: Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.

Background Differential biology and prognosis between T790M+ and T790M- populations imply immunological differences also. Methods We retrospectively analyzed programmed death-ligand 1 (PD-L1) expression and T790M status in rebiopsied samples of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). PD-L1 immunohistochemistry was performed using the SP142 antibody for tumour cell (TC) and tumour-infiltrating immune cell (IC) and the 28-8 antibody for TC. PD-L1+ was defined as TC or IC ≥1%. Results We investigated 67 available rebiopsied histologic samples in 47 patients. Using the SP142, prevalence of PD-L1 any+, moderate+, and strong+ in T790M+ vs. T790M- samples were 31% vs. 61%, 8% vs. 15%, and 0% vs. 2%, respectively, representing PD-L1+ prevalence of T790M+ samples was significantly lower than that of T790M- (p = 0.0149). Prevalence of any TC+/IC+ in T790M+ vs. T790M- samples were TC: 31% vs. 51% (p = 0.0997) and IC: 8% vs. 27% (p = 0.0536), respectively. Using the 28-8, median percentage of PD-L1+ in T790M+ samples was 1.9 (range, 0–27.2), whereas T790M- was 4.1 (range, 0–89.8) (p = 0.0801). Prevalence of PD-L1+ ≥1%, ≥5%, and ≥10% in T790M+ vs. T790M- samples were 77% vs. 83% (p = 0.5476), 31% vs. 49% (p = 0.1419), and 12% vs. 27% (p = 0.1213), respectively. In 9 of 11 patients receiving multiple rebiopsies, T790M and/or PD-L1 expression revealed temporal dynamism. Survival curves according to PD-L1 expression/T790M status suggested better prognosis in PD-L1-/T790M+ population. Conclusions T790M+ status was correlated to lower PD-L1 expression. PD-L1 expression might have a prognostic value and interaction with T790M mutation in EGFR-mutant NSCLC.

Aim The aim of the present study was to compare successful rate, failure reasons, and complications among procedures of histological rebiopsy. Patients and methods We retrospectively reviewed medical records of histologically rebiopsied cases with non-small cell lung cancer. Results One hundred and eleven histological rebiopsies were performed in: 86 (77%) lung; 11 (10%) lymph node; 5 (5%) pleura; 4 (4%) liver; 2 (2%) muscle; 2 (2%) adrenal gland; and 1 (1%) rib. Successful rate by computed tomography-guided biopsy (CTGB), transbronchial biopsy (TBB), and ultrasound-guided biopsy were 86% (48/56), 90% (28/31), and 100% (24/24), respectively. Reasons for rebiopsy failure by CTGB were no/insufficient malignant cells (n=5) and pneumothorax (n=3), and those by TBB were no/insufficient malignant cells (n=2) and bleeding (n=1). Severe complications (≥grade 3): one grade 3 pneumothorax and one grade 4 air embolization were observed in two (2%, 2/111) cases receiving CTGB. Conclusion Rebiopsy of histological samples can be highly successful and feasible by optimal procedural selection.

BackgroundEGFR gene mutation is independently associated with a favorable response in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs), regardless of sex or smoking history. Squamous cell carcinoma patients harboring EGFR mutations show a significantly worse response to EGFR-TKIs compared with adenocarcinoma patients. We hypothesized that the serum cytokeratin 19 fragment (CYFRA 21-1) is associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients.MethodsWe retrospectively screened 160 NSCLC patients harboring EGFR mutations, who had received either gefitinib, or erlotinib between 1992 and 2011. Patients were screened for clinical characteristics, the efficacy of EGFR-TKI, and tumor markers (carcinoembryonic antigen [CEA]/CYFRA 21-1) at the initial diagnosis.ResultsOf 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA 21-1 level (>2 ng/ml) showed significantly shorter progression-free survival (PFS) than the 83 patients with normal CYFRA 21-1 level (median PFS, 7.5 versus 13.3 months; p < 0.001). No significant difference in PFS was observed between the high-CEA group (>5 ng/ml) and the normal-CEA group (median PFS, 8.6 versus 11.2 months; p = 0.242). A multivariate analysis revealed that high CYFRA 21-1 level is independently associated with PFS (hazard ratio, 1.27; p = 0.002). No significant difference in overall survival was observed between the high- and the normal-CYFRA 21-1 groups (median overall survival, 24.8 versus 39.1 months; p = 0.104).ConclusionsPatients with a high CYFRA 21-1 level have significantly shorter PFS. CYFRA 21-1 is not a prognostic but a predictive marker of EGFR-TKI treatment in EGFR-mutated NSCLC patients.

Background Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy. Methods One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009. Results The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5–15%), 44% (95% CI, 35–53%), and 2.0 months (95% CI, 1.4–2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4–16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12–43%); DCR, 72% (95% CI, 53–86%); and median PFS, 3.4 months (95% CI, 2.4–4.9 months). Conclusions Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.

Background: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). Objectives: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). Methods: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003–2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. Results: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO2/FiO2 at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). Conclusion: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.

Background Recent reports have suggested the efficacy of amrubicin (AMR) for relapsed small-cell lung cancer (SCLC). However, doses of AMR in these reports were 40 mg/m2 or 45 mg/m2, and severe and frequent myelosuppression were observed. Such side effects are occasionally intolerable, as serious myelosuppression may induce fatal infections. To overcome this clinical problem, we investigated whether 35 mg/m2 of AMR administration with routine prophylactic use of granulocyte-colony stimulating factor (G-CSF) can reduce myelosuppression, while maintaining efficacy. Methods Between July 2003 and November 2008, 30 relapsed SCLC patients receiving 35 mg/m2/day of AMR were evaluated. Amrubicin was administered on days 1–3 every 3 or 4 weeks. Routine prophylactic use of G-CSF was performed beginning on day 8 and continuing for at least 5 consecutive days or until neutrophils recovered to the normal level. Results The median number of treatment cycles was four (range 1–9). No complete responses and 13 partial responses were observed, with response rates of: overall 43% (95% confidence interval [CI]: 26–63%); sensitive cases 33% (95% CI: 10–65%); and refractory cases 50% (95% CI: 26–74%) (p = 0.4651). The disease control rate (partial response and stable disease) was 80% (95% CI: 61–92%). The progression-free survival times were: overall 4.2 months (95% CI: 3.2–5.2 months); sensitive cases 4.7 months (95% CI: 2.6–5.4 months); and refractory cases 3.5 months (95% CI: 2.6–5.2 months) (p = 0.7124). The median OS times were: overall 9.6 months (95% CI: 7.2–12.5 months); sensitive cases 8.4 months (95% CI: 4.6–13.4 months); and refractory cases 11.0 months (95% CI: 6.5–12.6 months) (p = 0.9315). The 1-year survival rate was 33%. Regarding grade 3/4 hematological toxicities: leukopenia (47%); neutropenia (50%); anemia (30%); and thrombocytopenia (33%) were observed. Febrile neutropenia occurred in three patients (10%). Transfusions of red blood cells and platelets were performed for eight (27%) and one (3%) patients, respectively. Treatment-related deaths and grade 3/4 non-hematological toxicities were not observed at all. Conclusions Considering both safety and efficacy, AMR at a dose of 35 mg/m2 with routine prophylactic use of G-CSF may be more desirable for the treatment of relapsed SCLC in clinical practice.

// Akito Hata 1 , Daijiro Harada 3 , Chiyuki Okuda 1 , Reiko Kaji 1 , Yoshio Masuda 2 , Yoshika Takechi 4 , Toshiyuki Kozuki 3 , Naoyuki Nogami 3 and Nobuyuki Katakami 1 1 Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan 2 Department of Pharmacy, Kobe City Medical Center General Hospital, Kobe, Japan 3 Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan 4 Department of Pharmacy, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan Correspondence to: Akito Hata, email: akitohata@hotmail.com Keywords: docetaxel; ramucirumab; febrile neutropenia; pegylated-granulocyte-colony stimulating factor Received: March 22, 2018 Accepted: May 21, 2018 Published: June 12, 2018 ABSTRACT Purpose: The aim of our study was to evaluate the efficacy and safety of docetaxel plus ramucirumab with primary prophylactic pegylated (PEG)-granulocyte-colony stimulating factor (G-CSF) for pretreated non-small cell lung cancer (NSCLC). Results: Sixty-one pretreated NSCLC patients underwent docetaxel plus ramucirumab. Primary prophylactic PEG-G-CSF was performed in 52 (85%) patients (prophylactic group). No febrile neutropenia (FN) (0%) was confirmed in 52 prophylactic group patients, whereas FN was observed in 3 (33%) of 9 non-prophylactic group patients. Among prophylactic group, median lines of prior therapy was 2 (range, 1–9). Median cycles of docetaxel plus ramucirumab was 3 (range, 1–25) (9 and 3 cases moved to ramucirumab and docetaxel monotherapies, respectively). Response rate and disease control rate were 30.8% and 73.1%, respectively. Median progression-free survival was 4.5 (95% confidence interval [CI], 3.0–6.6) months. Median overall survival was 11.4 (95% CI, 8.0–13.9) months. Six (11.5%) patients had grade 3/4 neutropenia. Observed grade 3 (incidence ≥10%) adverse event (AE) was oral mucositis (13.5%). There were no grade 4/5 non-hematological AEs. Conclusions: Our study demonstrated the efficacy and safety of docetaxel plus ramucirumab with PEG-G-CSF in clinical practice. Primary prophylactic PEG-G-CSF could markedly reduce incidence of FN. Methods: We retrospectively reviewed medical records of pretreated NSCLC cases who had received docetaxel plus ramucirumab in our departments.

Introduction: Mutation of the epidermal growth factor receptor (EGFR) gene can predict the efficacy of EGFR-tyrosine kinase inhibitors. Different mutations have been shown to co-occur in a single tumor. However, the frequency of these so-called "complex mutations" and the efficacy of gefitinib in treating patients with these mutations are unclear. Methods: We investigated the frequency of complex mutations in 783 patients with non-small cell lung cancer seen at our institutes between April 2006 and May 2009. Mutational analysis was performed using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method. Gefitinib efficacy was evaluated in patients found to have complex mutations. Results: EGFR mutations were detected in 318 (41%) patients, with 21 (6.6%) of these individuals having complex mutations. Sixteen of these 21 patients received gefitinib. The response rate (RR) was 67% (95% confidence interval [CI], 35–90%) and median progression-free survival was 12.2 months (95% CI, 1.3 months to undeterminable). Analysis of RR according to mutation type revealed that patients with deletional mutation in exon 19 (Del-19) and a point mutation in exon 21 (L858R) had a better RR (86%, 6 of 7) than those with other complex mutation patterns such as a point mutation in exon 18 (G719S) + L858R (40%, 2 of 5) (p = 0.2222). The median progression-free survival was also longer in these patients (16.5 months; 95% CI, 1.1 months to undeterminable versus 3.8 months; 95% CI, 0.7–10.0 months) (p = 0.0459). Conclusions: Complex EGFR mutations are not rare. Gefitinib has different efficacy according to the type of complex EGFR mutations. Patients with Del-19 and L858R mutations may benefit more from gefitinib than other types of complex mutations.

Summary Background Trial of noninvasive ventilation (NIV) in the emergency department (ED) for heterogeneous acute respiratory failure (ARF) has been optional and its clinical benefit unclear. Methods We conducted a retrospective cohort study comparing between two periods, October 2001–September 2003 and October 2004–September 2006, i.e., before and after adopting an NIV-trial strategy in which NIV was applied in the ED to any noncontraindicated ARF patients needing ventilatory support and was then continued in the intermediate-care-unit. During these two periods, we retrieved cases of ARF treated either invasively or with NIV, and compared the patients' in-hospital mortalities and the length of ICU and intermediate-care-unit stay. Results Compared were 73 (invasive 56, NIV 17) and 125 cases (invasive 31, NIV 94) retrieved from 271 and 415 emergent admissions with proper pulmonary etiologies for mechanical ventilation, respectively. Of their respiratory failures, type (hypercapnic/non-hypercapnic, 0.97 vs. 0.98) and severity (pH 7.23 vs. 7.21 for hypercapnic; PaO 2 /FiO 2 133 vs. 137 for non-hypercapnic) were similar, and the rate of predisposing etiologies was not significantly different. However, excluding those with recurrent aspiration pneumonia for whom NIV was mostly used as "ceiling" treatment, significant reductions in both overall in-hospital mortality (38%–19%, risk ratio 0.51, 95% CI 0.31–0.84), and median length of ICU and intermediate-care-unit stay (12 vs. 5 days, P Conclusions NIV-trial in the ED for all possible patients with ARF of pulmonary etiologies, excluding those with recurrent aspiration pneumonia, may reduce overall in-hospital mortality and ICU stays.

背景．肺癌における髄膜癌腫症の予後は，無治療では4∼6週，治療した場合でも2∼3ヶ月の生存と報告され，きわめて不良である．症例．58歳女性（cT4N0M1; 肺内転移），72歳男性（cT4N1M0），68歳女性（cT1N0M1; 骨転移）のstage IIIBまたIV期の肺腺癌の3症例である．各種抗癌剤治療中に，神経症状を伴った髄膜癌腫症を発症した．上皮成長因子受容体チロシンキナーゼ阻害薬（EGFR-TKIs）投与が奏効し，神経症状や頭部MRI画像所見と髄液細胞診での改善が確認できた．最長1年を超える生存が得られた．2症例は髄液検体でEGFR遺伝子変異の検索を施行し，ともに陽性であった．変異の有無によりEGFR-TKIsの治療効果を予測できる可能性がある．結語．髄膜癌腫症を合併した非小細胞肺癌3症例について報告した．EGFR遺伝子変異を有する例では髄膜癌腫症に対してEGFR-TKIsが有用であると考えられた．

Efficacies of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) rechallenge have been demonstrated in EGFR-mutant non-small cell lung cancer (NSCLC). However, their efficacies were only moderate. Some preclinical studies suggested synergistic effects of bevacizumab to EGFR-TKI in TKI-resistant models.We retrospectively evaluated clinical efficacy and safety of EGFR-TKI rechallenge with bevacizumab. Rebiopsy was performed on all studied cases to examine T790M-resistant mutation status.Between January 2010 and June 2014, a total of 24 EGFR-mutant NSCLC patients who had been previously treated with EGFR-TKIs (gefitinib, erlotinib, and/or afatinib) received EGFR-TKI rechallenge with bevacizumab. Twenty-two (92 %) patients underwent erlotinib and two (8 %) gefitinib as rechallenge EGFR-TKIs in combination with bevacizumab. Three patients achieved partial response, and 18 had stable disease, resulting in the response rate (RR) of 13 % and disease control rate (DCR) of 88 %, respectively. The median progression-free survival (PFS) was 4.1 [95 % confidence interval (CI) 2.3-4.9] months, and the median overall survival (OS) was 13.5 (95 % CI 9.7-27.4) months. The RR, DCR, median PFS, and median OS for T790M-positive versus T790M-negative were 0 versus 18 % (p = 0.530), 86 versus 88 % (p = 1.00), 3.3 versus 4.1 months (p = 0.048), and 15.1 versus 13.5 months (p = 0.996), respectively. Severe adverse events (≥grade 3): grade 3 of 1 (4 %) rash; grade 3 of 1 (4 %) paronychia; grade 3 of 1 (4 %) hypertension; and grade 3 of 1 (4 %) anemia, were observed.EGFR-TKI rechallenge with bevacizumab demonstrated higher DCR and modestly longer PFS than historical data on EGFR-TKI rechallenge alone. Its activity was notably higher in T790M-negative population.

Non-small cell lung cancer (NSCLC) with minor mutations in the epidermal growth factor receptor (EGFR) gene, except for the common 15 base-pair deletions in exon 19 and the L858R mutation in exon 21, is rare, and only few data exist on this patient population. The aim of the present study was to describe the clinical characteristics and to clarify the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in patients with NSCLC harboring minor mutations of the EGFR gene.This was a multicenter, retrospective study that analyzed specimens from patients with NSCLC who had minor EGFR gene mutations and were treated with EGFR-TKIs between June 2002 and March 2012.Out of 56 patients with minor mutations of the EGFR gene, 44 were treated with either gefitinib or erlotinib. Mutation sites were G719X in exon 18 (n=35), L861Q in exon 21 (n=11), and G874S in exon 21 (n=1). Three patients had both the G719S and the L861Q mutation. The response rate to TKI treatment was 29.5%, and the disease control rate was 63.6%. The median progression-free survival (PFS) was 6.7 months [95% confidence interval (CI)=2.06-8.66 months]. The median PFS was 7.2 months (95% CI=4.23-12.3 months) in 32 patients who received first- or second-line treatment with EGFR-TKIs, whereas the median PFS was 1.57 months (95% CI=0.73-3.8 months) in 12 patients treated with EGFR-TKIs as a third-line or later treatment. In multivariate Cox analysis, erlotinib therapy was associated with a longer PFS than gefitinib (p=0.025).Patients with NSCLC harboring minor mutations of the EGFR gene exhibited a modest response to EGFR-TKI treatment. Treatment with first-generation EGFR-TKIs, in particular erlotinib, may be considered a first- or second-line option for patients with NSCLC with minor EGFR mutations.

Patients with malignant lung cancer often develop a solitary pulmonary nodule after treatment of the initial cancer. In those cases, it is difficult to distinguish primary lung cancer (PLC) from lung metastasis. Therefore, both local therapy for a single lung lesions and systemic therapy for micrometastases are needed. This retrospective study aimed to evaluate the safety and tolerability of concurrent stereotactic body radiation therapy (SBRT) and chemotherapy in patients with metachronous PLC.We reviewed the records of 10 patients with metachronous PLC treated with SBRT and concurrent chemotherapy with curative intent from 2007 to 2013. The delivered radiation dose was 48 Gy in four fractions.All patients received SBRT with concurrent chemotherapy on schedule. Complete response rate was 90%. Safety profile of this treatment was compatible with that of traditional chemoradiotherapy.Our study showed good feasibility and safety for SBRT with concurrent chemoradiotherapy.

Objective Information regarding multiple primary malignancies is important, as it has the potential to clarify etiological factors and may indicate the need to refine patient follow-up to include screening for associated malignancies. Upper aerodigestive tract cancer often develops in patients with smoking-related lung cancer; however, little is known about the frequencies or types of other primary malignancies in patients with non-small cell lung cancer (NSCLC) without a history of smoking. Methods We retrospectively evaluated the records of patients examined and/or treated for NSCLC at the Institute of Biomedical Research and Innovation between January 2007 and June 2012. Patients In total, 938 patients, including 599 men (never-smoker/ever-smoker: 35/564) and 339 women (never-smoker/ever-smoker: 236/103), were analyzed. Results Among the 209 patients (22.3%) with multiple primary malignancies, 151 had a history of smoking and 58 were never-smokers. The most common cancers were gastric (43 cases), colorectal (33 cases), and prostate (29 cases) cancer. Smoking-related cancer was more common in current smokers and ex-smokers for both men and women. Among women with NSCLC, never-smokers were more likely to have thyroid cancer than those with a history of smoking (5.1% vs. 0%, p=0.021). Conclusion In this study, several differences in malignancies were observed between never-smokers and patients with a history of smoking. Thyroid cancer and NSCLC co-existed in some women without a history of smoking, implicating predisposing factors other than tobacco smoke in the onset of these cancers.

The aim of the present study was to investigate the prognostic impact of central nervous system metastases (CNS) after acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in EGFR-mutant non-small cell lung cancer (NSCLC).We defined CNS-collapse as death due to uncontrolled and progressive CNS metastases. Post-progression survival (PPS) after initial TKI failure and T790M status were retrospectively compared in 92 patients with or without CNS collapse.The median PPS in 32 patients with CNS-collapse (16.7 months) was significantly shorter than that of 60 without (26.8 months) (p=0.0002). T790M was detected in four (12%) out of the 32 CNS-collapse patients and in 26 (43%) out of 60 without (p=0.0026). Median PPS in 39 patients with leptomeningeal metastases (LM) (11.4 months) was significantly shorter versus 53 without (26.8 months) (p=0.0006). The median PPS was 25.1 months in 40 patients with brain metastases and 11.2 months in 52 without (p=0.0387). T790M was detected in 4/5 resected brain tumors (80%) and in 1/26 cerebrospinal fluid (CSF) samples (4%) (p=0.0008).CNS-collapse represented poorer prognosis, which was associated with T790M-negative status and LM. Controlling CNS metastases, especially LM, is important to achieve longer survival.

Background Treatment for patients with advanced non-small cell lung cancer (NSCLC) is often determined by the presence of biomarkers that predict the response to agents targeting specific molecular pathways. Demands for multiplex analysis of the genes involved in the pathogenesis of NSCLC are increasing. Methods We validated the Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel and compared the results with those obtained using the gold standard methods, conventional PCR and Sanger sequencing. The cycleave PCR method was used to verify the results. Results and Conclusion The Ion Torrent PGM resulted in a similar level of accuracy in identifying multiple genetic mutations in parallel, compared with conventional PCR and Sanger sequencing; however, the Ion Torrent PGM was superior to the other sequencing methods in terms of increased ease of use, even when taking into account the small amount of DNA that was obtained from formalin-fixed paraffin embedded (FFPE) biopsy specimens.

CT-guided lung biopsy is a well-established diagnostic method for pulmonary lesions. The aim of our study was to evaluate the diagnostic outcomes and safety profile of conventional CT-guided lung biopsies.We retrospectively analyzed the results of CT-guided lung biopsies for 750 patients to determine the diagnostic accuracy, complication rates, and independent risk factors for diagnostic failure and severe pneumothorax.Diagnostic accuracy was 92.9%. Independent risk factors for diagnostic failure were malignant lesions (odds ratio [OR], 4.20; 95% CI, 1.66-14.1; p = 0.001), lesions in the lower lobe (OR, 2.01; 95% CI, 1.17-3.47; p = 0.011), lesions 2.0 cm or smaller (OR, 2.87; 95% CI, 1.59-5.48; p0.001), and the presence of pneumothorax during the procedure (OR, 2.18; 95% CI, 1.27-3.78; p = 0.004). Pneumothorax requiring drainage occurred in 7% of patients. Independent risk factors for pneumothorax requiring drainage were age of 73 years or older (OR, 2.19; 95% CI, 1.21-4.05; p = 0.009), the presence of emphysema (OR, 4.29; 95% CI, 2.05-8.82; p0.001), benign lesions (OR, 2.33; 95% CI, 1.20-4.40; p = 0.012), supine positioning of the patient (OR, 2.61; 95% CI, 1.44-4.84; p = 0.001), and length from the pleura to the lesion of 1.5 cm or greater (OR, 3.08; 95% CI, 1.63-6.17; p0.001).CT-guided lung biopsy has a high diagnostic accuracy. Complication rates were acceptable and comparable to those of previous studies.

The aim of the present study was to analyze factors that affect progression-free survival (PFS) of patients with previously treated advanced non-small cell lung cancer (NSCLC) after S-1 therapy, in particular epidermal growth factor receptor (EGFR) mutation status.Between October 2009 and June 2013, 56 patients with advanced NSCLC were analyzed for EGFR somatic mutations and treated with S-1 with or without bevacizumab. Risk factors associated with PFS were evaluated using a Cox proportional hazards regression model with a step-down procedure. Proportional hazards assumptions were checked and satisfied and only variables with statistical significance in univariate analysis were included in multivariate analysis.The median PFS of patients with EGFR mutations who received S-1 therapy was significantly longer than that of patients with wild-type EGFR. The median PFS of patients with good performance status (PS) was significantly longer than that of patients with poor PS. In multivariate analysis, wild-type EGFR and poor PS were significant and independent negative factors that affect PFS after S-1 therapy.EGFR mutation and good PS were positive predictive factors for PFS after S-1 therapy, suggesting that S-1 therapy is efficacious for patients with EGFR-activating mutations even in a multi-line setting.

Recent reports have shown gefitinib, epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) induced marked improvement in ECOG performance status (PS) as first-line therapy in EGFR mutation-positive patients with extremely poor PS. EGFR mutations frequently occur in east-Asian, female, non-smoking, adenocarcinoma patients, however they are occasionally detected in patients with non-adenocarcinomas or with a heavy smoking history. We describe a case in which EGFR mutation was detected in a male, current smoker, squamous cell carcinoma (SCC) patient with PS 4, who showed a marked response to the first-line gefitinib therapy. EGFR mutational analysis is recommended even for SCC patients especially in east-Asian populations.

9034 Background: Irreversible EGFR-TKI monotherapies showed only moderate efficacy after AR to reversible EGFR-TKIs. Preclinical studies suggested that addition of Bev to EGFR-TKIs could overcome AR, and Bev demonstrated synergistic effects with Afa in TKI-resistant xenograft models. Methods: ECOG PS 0-2 patients (pts) with EGFR-mutant NSCLC after AR to EGFR-TKIs were enrolled at any lines. Rebiopsy was essential to confirm T790M status after AR. Afa was prescribed at 30 mg, and Bev administered at 15 mg/kg tri-weekly until progression. Results: Between October 2014 and September 2016, 33 eligible pts were enrolled. Median age was 66 (range, 48-86). Twenty-one (64%) pts were female, and 22 (67%) were never smoker. Mutation subtypes were 20 (61%) Del-19, 12 (36%) L858R, and 1 (3%) L861Q. T790M was detected in 14 (42%) pts. Median number of prior regimens was 4 (range, 1-10). First prior TKIs were 20 (61%) gefitinib, 10 (30%) erlotinib or 3 (9%) Afa. Six pts obtained partial response and 23 stable disease, resulting in response rate (RR) of 18.2% (95% confidence interval [CI], 7.0-35.5%) and disease control rated of 87.9% (95% CI, 71.8-96.6%). Median progression-free survival (PFS) and overall survival were 5.9 (95% CI, 3.5-8.8) months and not reached, respectively. Median RR and PFS of T790M+ vs. T790M- were 14.3% vs. 21.2% (p = 0.6189) and 6.2 vs. 5.2 months (p = 0.8619), respectively. Median RR and PFS of Del-19 vs. L858R were 20.0% vs. 8.3% (p = 0.3789) and 5.9 vs. 5.1 months (p = 0.8996), respectively. Afa dosage was reduced to 20 mg in 15 (45%) pts and increased to 40 mg in 2 (6%) pts. Median number of Bev administrations was 6 (range, 1-14). Bev was interrupted in 5 (15%) pts. Adverse events ≥grade 3: rash (3%); paronychia (24%); mucositis (6%); diarrhea (3%); liver dysfunction (3%); hypertension (39%); and proteinuria (15%) were observed. There were no treatment-related deaths, interstitial lung disease, nor Bev-associated severe bleedings. Conclusions: Afa + Bev demonstrated the efficacy and safety after AR to EGFR-TKIs. It could be a therapeutic salvage option for T790M- populations. Clinical trial information: UMIN000014710.

Placebo-controlled randomized trials have demonstrated that prophylactic levofloxacin (LVFX) significantly reduced the incidence of febrile neutropenia (FN) in patients receiving chemotherapy for advanced solid tumors. Garenoxacin (GRNX) has been reported to be more effective than LVFX against gram-positive bacteria especially Streptococcus pneumoniae. Against this background we conducted a study to compare the efficacy and safety of GRNX with that of LVFX for the prophylaxis of FN. We retrospectively analyzed 127 patients at high risk for FN who were administered GRNX or LVFX for the prophylaxis of FN that occurred during chemotherapy for advanced solid tumors. Our primary outcome of interest was the incidence of febrile episodes. Secondary outcomes included evidence of bacterial infection and infection focus when febrile episodes were observed; adverse drug reactions and mortality were also evaluated. Febrile episodes were observed in 2 patients administered GRNX and 7 patients administered LVFX (p=0.044). Definitive pathogenic bacteria and infection focus could not be identified in any patient with febrile episodes and all cases of fever resolved simultaneously with the recovery from neutropenia. We observed 4 cases of rashes and 3 cases of liver dysfunction in the GRNX group and 2 cases of rashes and 2 cases of liver dysfunctions were observed in the LVFX group(not statistically significant in both the groups). No severe adverse effects or deaths were associated with either of these drugs. These results suggest that GRNX is useful for the prophylaxis of FN.

Objectives We have conducted a phase 2 study to evaluate the efficacy and safety of carboplatin, paclitaxel, and bevacizumab in patients with non-squamous non-small-cell lung cancer (NSCLC) who are epidermal growth factor receptor ( EGFR ) mutation positive and for whom EGFR-tyrosine kinase inhibitor (TKI) 1st-line has failed. Materials and methods Patients with stage IIIB or IV non-squamous NSCLC harbored activating EGFR mutations that has failed 1st-line EGFR-TKI and an Eastern Cooperative Oncology Group performance status of 0 or 1 were included in this study. Patients received carboplatin at an area under the concentration–time curve 5 or 6, paclitaxel 200mg/m 2 , and bevacizumab 15mg/kg on D1. The combination therapy was repeated every 21 days for up to three to six cycles. Bevacizumab was continued until disease progression or unacceptable toxicity for patients without disease progression (PD). The primary endpoint was objective response rate (ORR). Results Thirty-one patients were enrolled between March 2010 and January 2013, with 30 patients being eligible. ORR was 37% (90% CI; 24–52%) and disease control rate, 83% (95% CI; 66–92%). The median progression free survival (PFS) was 6.6 months (95% CI; 4.8–12.0 months) and median overall survival, 18.2 months (95% CI; 12.0–23.4 months). The most common grade ≥3 hematologic toxicity was neutropenia (93%), and non-hematologic toxicity, febrile neutropenia (20%). There were no clinically relevant grade ≥3 bleeding events and no treatment-related deaths. Conclusion The combination therapy of carboplatin, paclitaxel and bevacizumab did not achieve the initial treatment goal.

Background Exon 19 deletion mutations (Del-19s) and the exon 21 L858R point mutation are the most common epidermal growth factor receptor (EGFR) mutations. In Del-19, several subtypes actually exist, consisting of the deletional location with or without amino acid insertion/substitution. Little evidence has been described whether the Del-19 subtype affects EGFR-tyrosine kinase inhibitor (TKI) efficacy. Methods Between December 2005 and July 2012, we investigated 105 patients harboring a Del-19 who had received EGFR-TKIs. Efficacies of EGFR-TKIs such as response rate (RR), progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated among various patient characteristics. Results Among these 105 patients with Del-19s, 78 (74%) patients had a deletion from E746 (Del-E746), and 27 (26%) exhibited a deletion from L747 (Del-L747). Median PFS of Del-E746 (11.7 months, 95% confidence interval [CI]: 9.3–15.6) was significantly longer than Del-L747 (10.0 months, 95% CI: 6.4–12.7) ( p = 0.022). Insertions/substitutions were found in 19 patients (18%), and 91 patients (82%) were without insertions/substitutions. Median PFS without insertions/substitutions (11.7 months, 95% CI 9.3–15.2) was significantly longer than with insertions/substitutions (10.0 months, 95% CI: 4.0–10.6) ( p = 0.024). No relationships were found for RR among all patient characteristics. In multivariate analysis, performance status (PS) (0/1 vs 2/3) and initial deletion site (Del-E746 vs Del-L747) were significant factors for longer PFS, whereas PS, gender (male vs female) and histology (adeno vs squamous) for longer OS. Conclusions Our data indicated better efficacy of EGFR-TKI in Del-E746 than Del-L747. Deletional locations may affect EGFR-TKI efficacy.

Elderly patients with stage III non-small-cell lung cancer (NSCLC) are frequently underrepresented in clinical trials that evaluate chemoradiotherapy, due to their poor functional status, coexisting illnesses and limited life expectancy. The Japan Clinical Oncology Group 0301 trial (JCOG0301) was the first study to demonstrate that thoracic radiation therapy (TRT) with daily low-dose carboplatin may improve the outcome of elderly patients with stage III NSCLC. However, the efficacy and safety profiles of chemoradiotherapy, including platinum doublets, have not been clearly determined in this patient population. We retrospectively assessed the efficacy and toxicity of weekly paclitaxel in combination with carboplatin and concurrent TRT in patients aged ≥75 years with previously untreated locally advanced NSCLC. Between February, 2004 and July, 2013, we collected the data of 20 patients treated with weekly paclitaxel and carboplatin for 6 weeks and concurrent TRT. The objective response rate was 90%, the disease control rate was 95%, the median progression-free survival was 8.63 months [95% confidence interval (CI): 5.7-16.7] and the median overall survival (OS) was 16.1 months (95% CI: 10.7-41.6). There were no grade 4 hematological or non-hematological toxicities and no reported treatment-related deaths. Therefore, platinum doublet therapy in combination with TRT did not provide a clinically significant survival benefit in our population of elderly patients with locally advanced NSCLC. However, the present study demonstrated the good feasibility and safety of this regimen. Further prospective clinical trials are required to evaluate the efficacy and safety of platinum doublet with TRT in elderly patients.

The aim of this retrospective study was to evaluate bevacizumab combined with weekly paclitaxel with and without carboplatin in pre-treated patients with non-squamous non-small cell lung cancer (NSCLC).Between November 2009 and October 2011, 43 pre-treated patients with non-squamous NSCLC received bevacizumab (15 mg/kg, day 1) plus weekly paclitaxel (60-80 mg/m(2), days 1, 8, 15) with carboplatin (area under the curve=4-5, day 1) (n=36), or bevacizumab plus weekly paclitaxel (n=7) alone every four weeks.The response rate and disease control rates were 48.8% (21/43) and 86.0% (37/43), respectively. Median progression-free survival was 5.7 months, and overall survival was 14.5 months. Grade 3/4 neutropenia was observed in 37.2% of patients and peripheral neurotoxicity in 0%. No bevacizumab-related death was observed.Even for heavily pre-treated patients, bevacizumab plus weekly paclitaxel with or without carboplatin was effective and tolerable in non-squamous NSCLC.

BACKGROUND The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation. METHODS The study investigated 78 EGFR-mutant patients who had undergone rebiopsy after TKI failure. The peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp method was used in EGFR mutational analyses. Various patient characteristics and postprogression survivals (PPSs) after initial TKI failure were retrospectively compared in patients with and without T790M. RESULTS The T790M mutation was identified in 4 (17%) of 24 central nervous system lesions, and in 22 (41%) of 54 other lesions (P = .0417). No other characteristics had a statistical association with T790M prevalence. Median PPS was 31.4 months in 26 patients with T790M, and 11.4 months in 52 patients without T790M (P = .0017). In the multivariate analysis, statistically significant factors for longer PPS included T790M-positive, good performance status, and no carcinomatous meningitis. CONCLUSIONS The emergence of T790M in central nervous system lesions was rare, compared with other lesions. Patients with T790M after TKI failure appear to have better prognoses than those without T790M. TKI rechallenge or continuous administration beyond progression may be effective after initial TKI failure. Cancer 2013;119:4325–4332. © 2013 American Cancer Society.

Pemetrexed has shown substantial activity in non-squamous non-small cell lung cancer (NSCLC) and is one of the current standard agents in second-line settings due to its efficacy and favorable tolerability profile. We conducted phase II study to evaluate the safety and efficacy of pemetrexed in Japanese patients with previously heavily treated, advanced non-squamous NSCLC. Patients with stage IIIB or IV non-squamous NSCLC, performance status (PS) 0–2, previous two to five regimens of chemotherapy were enrolled and received pemetrexed (500 mg/m2) on day 1 every 21 days until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. From August 2009 to May 2010, 46 patients were enrolled: median age 65 years; 52 % women; PS 0/1/2 26/67/7 %; previous treatment regimen 2/3/4/5 48/28/20/4 %; epidermal growth factor receptor activating mutation positive/wild/unknown 30/48/22 %. The median follow-up period was 13.5 months. The median number of treatment cycles was 4 (range 1–18 cycles). The median PFS was 5.2 months (95 % CI 3.0–5.8 months). The median OS was 14.4 months (95 % CI 9.4–21.3 months). The ORR was 8.7 % and DCR was 63.0 %. The grade 3/4 hematological adverse events include 8 patients with leukopenia, 11 with neutropenia, 5 with anemia, and 2 with thrombocytopenia. There were no reports of febrile neutropenia and no treatment-related death was observed. Treatment with pemetrexed in previously heavily treated Japanese non-squamous NSCLC patients is feasible and shows encouraging activity.