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Background: Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown., Methods: We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0., Results: Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7-698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55)., Conclusion: The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Investigate the frequency and prognostic factors of severe drug-induced interstitial lung disease (DILD) caused by antineoplastic drugs regardless of cancer types or type of drugs., Methods: From 2014 to 2018, we reviewed patients with a history of antineoplastic agents administration in the real-world database of our hospital's electronic medical record and extracted patients who experienced "severe" DILD, requiring hospitalization with treatment or developed during hospitalization and required treatment. We collected patients' backgrounds, clinical and radiological features, laboratory data, treatment, and survival outcomes., Results: 19,132 cancer patients received antineoplastic drug therapy during the study period, and 120 (0.62%) experienced severe DILD. The incidence of severe DILD in patients with thoracic cancer was highest among the patients included in this analysis (2.52% vs. 0.34% other cancers). Diffuse alveolar damage (DAD) pattern on CT was associated with higher mortality in patients with severe DILD compared with non-DAD pattern (hazard ratio [HR], 11.24; 95% CI, 4.82-26.2). Multivariate analysis revealed that the DAD pattern at diagnosis as severe DILD (HR, 3.59; 95% CI, 1.17-11.03), concurrent/previous interstitial lung disease (HR, 3.20; 95% CI, 1.27-8.10), and ECOG performance status of 2-4 (HR, 3.81; 95% CI, 1.10-13.17) were independent risk factors for mortality in patients with severe DILD., Conclusions: The frequency of severe DILD was highest in patients with thoracic cancer. The DAD pattern was associated with a poor outcome. From the perspective of DILD, special attention should be paid when administering antineoplastic agents to patients with thoracic cancer., (© 2022. The Author(s).)

Patients with uncommon EGFR- mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR- mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002.

Background: For decades, concurrent chemo-radiotherapy with cisplatin-based regimen has been a standard therapy for locally advanced stage III non-small-cell lung cancer (NSCLC). We conducted individual-participant-data (IPD) meta-analyses to compare S-1/cisplatin versus other third-generation anti-cancer medications plus cisplatin regimens with the goal of determining whether or not S-1/cisplatin was the ideal choice for treatment accompanied by radiotherapy (RT)., Methods: A thorough search was performed using multiple electronic databases. We integrated the IPD of each trial and analyzed the resulting meta-database. The primary endpoint was the overall survival (OS), and the secondary endpoints included the progression-free survival (PFS), objective response rate (ORR), toxicities, and treatment delivery. Subgroup analyses were conducted based on baseline characteristics. Statistical analyses were stratified by trials., Results: Three randomized control trials (WJOG5008L study, SPECTRA study, and TORG1018 study) were found. Of the 316 patients enrolled in those studies, 159 received S-1/cisplatin (SP), and 157 were assigned to other combination chemotherapy. The median OS for the SP arm was 48.2 months, and that of the non-SP arm was 42.4 months. The combined hazard ratio (HR) for the OS was 0.895 (95% confidence interval [CI] 0.638-1.256), and no heterogeneity was noted among the trials (test for heterogeneity, p = 0.87; I 2  = 0). The median PFS for the SP and non-SP arms was 12.8 and 14.0 months, respectively. The corresponding HR for the PFS was 1.022 (95% CI 0.776-1.347), and there was evidence of moderate heterogeneity among the trials (test for heterogeneity, p = 0.16; I 2  = 0.46). The ORRs were 69.7% (95% CI 62.1-76.7%) and 70.9% (95% CI 63.7-78.1%) in the SP and non-SP arms, respectively. The toxicity profile showed that SP caused significantly fewer instances of grade 3-4 leukopenia and neutropenia than non-SP regimens., Conclusion: No marked differences were detected in the OS, PFS, or ORR between the SP and non-SP arms. SP had significantly less myelosuppression and better treatment compliance as a chemotherapy regimen for concurrent chemoradiation in locally advanced NSCLC than non-SP regimens., (© 2022. The Author(s).)

Introduction: The accelerated development of lung cancer treatments has resulted in a single global study that is sufficient for a new agent and indication to be approved. Not all new treatments predominate globally, and differences in standards of care may influence the efficacy of treatments in the real world., Methods: The results from Japanese domestic trials and global trials that included a subset population of Japanese patients were evaluated for 18 genomic targeted agents and immune therapies approved after 2000. The results were collected from drug applications that were reviewed for treatment approval in Japan., Results: Japan is one of the first countries to approve and fully reimburse new agents around the world. Alectinib and nivolumab, which were first developed by Japanese pharmaceutical companies, were evaluated in an independent domestic trial, which resulted in their early approval. For most other indications, 1.1-15.8% of the patients who participated in pivotal registration studies were Japanese, and their treatment results were comparable to those of the overall population. Overall survival was less likely to be improved by four agents for which the post-protocol therapy might have been different in Japan than in other countries., Conclusions: Overall, a positive result in a global trial was emulated in Japanese patients and led to the approval of a new standard treatment in Japan. Early approvals were attained by either participating in the global registrational study or conducting a domestic phase II study. The higher efficacy of new agents may be an issue in the future, as Japanese patients had early access to the new agent and may receive better treatment after the trial., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: A history of radiotherapy and chemoradiotherapy (CRT) reportedly increases the efficacy of the PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC). We investigated the efficacy of anti-PD-(L)1 therapy after CRT failure and how CRT changes the status of PD-L1 expression on tumours and on tumour-infiltrated lymphocytes (TILs)., Methods: We retrospectively reviewed patients with unresectable locally advanced NSCLC (LA-NSCLC) who were treated with CRT between 2007 and 2018 and evaluated the efficacy of the PD-(L)1 blockade after CRT failure. We also compared the PD-L1 (clone: 22C3) expression levels and the tumoral and stromal distributions of CD8-positive TILs using paired formalin-fixed, paraffin-embedded specimens obtained before and after CRT., Results: We identified 422 patients and 65 patients who had relapsed after CRT received anti-PD-(L)1 therapy. The objective response rate (ORR) and the progression-free survival (PFS) after anti-PD-(L)1 therapy were 48% and 8.7 months (95% CI, 4.5-13), respectively. The RR and PFS did not differ according to the pre-CRT PD-L1 expression levels. PD-L1 expression changed in 16 of the 18 patients between before and after CRT, but a specific trend was not seen (increased, 9 patients; decreased, 7 patients; no change, 2 patients). In contrast, the density of tumoral CD8-positive TILs increased after CRT treatment (pre-CRT median, 110/mm 2 versus post-CRT median, 470/mm 2 ; p = 0.025)., Conclusions: Anti-PD-(L)1 therapy was effective in patients with LA-NSCLC who had progressed after CRT regardless of their pre-CRT PD-L1 expression. The efficacy of anti-PD-(L)1 therapy for patients with NSCLC with CRT failure was superior to that of standard second-line treatment for patients with advanced NSCLC., Competing Interests: Conflict of interest statement TY reports grants from ONO Pharmaceutical, during the conduct of the study, grants and personal fees from AstraZeneca, grants and personal fees from Bristol-Myers Squibb, grants from Takeda, personal fees from Chugai, personal fees from Novartis, grants from MSD, grants from Abbvie, outside the submitted work;. YM reports grants from National Cancer Center Research and Development Fund, grants from Grant-in-Aid for Scientific Research on Innovative Areas, grants from Hitachi, Ltd., grants from Hitachi High-Technologies, personal fees from Olympus, personal fees from AstraZeneca, personal fees from Novartis, personal fees from COOK, and personal fees from AMCO INC., outside the submitted work. YO reports personal fees from AstraZeneca K.K., personal fees from Nippon Boehringer Ingelheim, personal fees from Ily-Lilly K.K., personal fees from MSD K.K., personal fees from Chugai Pharma Co., Ltd, personal fees from Ono Pharma Co., Ltd, and personal fees from Bristol Myers Squibb, outside the submitted work;. YG reports grants and personal fees from Eli Lilly, grants and personal fees from Chugai, grants and personal fees from Taiho Pharmaceutical, personal fees from Boehringer Ingelheim, grants and personal fees from Pfizer, grants and personal fees from Novartis, personal fees from AstraZeneca, grants and personal fees from MSD, grants and personal fees from Guardant Health, grants and personal fees from Ono Pharmaceutical, grants from Kyorin, grants from Dai-ichi Sankyo, and personal fees from Illumina, outside the submitted work. HH reports grants and personal fees from BMS, grants and personal fees from MSD, grants and personal fees from Chugai, grants and personal fees from Taiho, grants and personal fees from Astra Zeneca, grants from Astellas, grants from Merck Serono, grants from Genomic Health, grants and personal fees from Lilly, grants and personal fees from Ono, outside the submitted work. NY reports grants from Chugai, grants from Taiho, grants from Eisai, grants from Lilly, grants from Quintiles, grants from Astellas, grants from BMS, grants from Novartis, grants from Daiichi-Sankyo, grants from Pfizer, grants from Boehringer Ingelheim, grants from Kyowa-Hakko Kirin, grants from Bayer, grants from ONO PHARMACEUTICAL CO., LTD, grants from Takeda, personal fees from ONO PHARMACEUTICAL CO., LTD, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Lilly, personal fees from BMS, personal fees from Eisai, personal fees from Otsuka, personal fees from Takeda, personal fees from Boehringer Ingelheim, personal fees from Cimic, grants from Janssen Pharma, grants from MSD, grants from Merck, personal fees from Sysmex, grants from GSK, grants from Sumitomo Dainippon, outside the submitted work. YO reports grants and personal fees from AstraZeneca, grants and personal fees from Bristol-Myers Squibb, personal fees from Boehringer Ingelheim, grants and personal fees from Chugai, personal fees from Celtrion, personal fees from Amgen, grants and personal fees from Eli Lilly, from Janssen, grants and personal fees from Kyorin, grants and personal fees from Nippon Kayaku, grants and personal fees from Novartis, grants and personal fees from ONO Pharmaceutical, grants and personal fees from Pfizer, grants from Ignyta, grants and personal fees from Taiho, and grants and personal fees from Takeda, outside the submitted work. NM reports grants and personal fees from Ono, personal fees from BMS, personal fees from MSD, personal fees from AstraZeneca, grants and personal fees from Roche Diagnostics, personal fees from Novartis, personal fees from Taiho, personal fees from Chugai, personal fees from Miraca Life Science, personal fees from Beckton Dickinson Japan, and personal fees from Covidien Japan Inc, outside the submitted work. All other authors have nothing to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma., Methods: This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777., Findings: Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events., Interpretation: The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma., Funding: Center for Clinical Trials, Japan Medical Association., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC., Methods: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001)., Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred., Interpretation: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC., Funding: Ignyta/F Hoffmann-La Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m 2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC 0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m 2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

ABP 215 (MVASI™) is the first approved biosimilar to Avastin ® (bevacizumab). It is approved in the USA and the European Union (EU) for all bevacizumab indications in these jurisdictions except for ovarian cancer in the USA due to orphan drug exclusivity. ABP 215 was shown to be structurally, functionally and clinically (pharmacokinetic, efficacy and safety) similar to the bevacizumab reference product; the pharmacokinetic study was conducted in healthy adult men (n = 202); safety and efficacy were evaluated in patients with advanced nonsquamous non-small-cell lung cancer (n = 642). Together, these results comprise the totality of evidence that provides scientific justification for extrapolation to all approved indications of the reference product and supports the clinical value of ABP 215 as an additional treatment option.

We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Epidermal growth factor receptor inhibitors (EGFRI), EGFR tyrosine kinase inhibitors (TKI) and anti-EGFR antibodies commonly develop skin toxicities including acneiform eruption (AfE). However, precise skin changes and risk factors for severe AfE are still unclear. The objective of the current study was elucidation of the useful parameters for early and sensitive detection of the skin changes by EGFRI. Transepidermal water loss (TEWL), skin surface hydration, skin surface lipid levels and erythema/melanin index were serially measured for 2 weeks in 19 EGFR-TKI afatinib/erlotinib-treated patients and for 8 weeks in 20 anti-EGFR antibody cetuximab-treated patients. The TEWL levels of the cheek in the patients who developed AfE of grade 2 and more (AfE ≥ Gr2) were already elevated at 7 days after the initiation of afatinib/erlotinib therapy compared with those before therapy as well as in patients with grade 1 or less (AfE ≤ Gr1). In patients treated with cetuximab, the skin surface hydration on the cheek in AfE ≥ Gr2 patients significantly decreased compared with that of AfE ≤ Gr1 patients at the 2nd and 6th week. Baseline skin surface lipid levels and erythema index on the cheek of patients with AfE ≥ Gr2 were significantly higher than those with AfE ≤ Gr1. The small sample size of the present study, especially for logistic regression analysis, is a limitation. In conclusion, instrumental evaluation declared rapid inflammatory changes of the skin by EGFRI and elucidated oily skin as a risk for severe AfE., (© 2018 Japanese Dermatological Association.)

Background: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care., Methods: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study., Results: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient)., Conclusions: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised., Clinical Trial Registration: NCT02296125 (ClinicalTrials.gov).

Introduction: Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI-sensitizing mutations., Methods: Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety., Results: The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41-0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25-1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively., Conclusion: In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Nivolumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has been shown to yield a durable response and significant prolongation of the survival in some patients with non-small-cell lung cancer (NSCLC). However, identification of patients who are likely to respond to nivolumab remains difficult at present., Materials and Methods: We conducted a retrospective analysis of the clinical data of 87 consecutive patients with advanced NSCLC seen in clinical practice who received nivolumab monotherapy at the National Cancer Center Hospital in Japan between January 2016 and July 2016 (discovery cohort). In addition, we also collected the clinical data of 75 patients who were administered nivolumab monotherapy between August 2016 and March 2017 (validation cohort). For this study, we focused on the changes in the lymphocyte-to-monocyte ratio (LMR) observed after nivolumab monotherapy., Results: In the discovery cohort, increase (≥10%) of the LMR at 4 weeks after the start of nivolumab monotherapy relative to the pretreatment LMR was positively correlated with an objective response (objective response rate (ORR); 39.4% vs 11.8%, p = 0.0065). When this cutoff value of ≥10% was used, increase of the LMR was significantly associated with a prolonged progression-free survival (PFS) (median PFS [mPFS]; 7.3 months vs 2.5 months, p = 0.0049) and overall survival (OS) (median survival time; 15.6 months vs 8.9 months, p = 0.014). In the validation cohort also, increase of the LMR was significantly associated with higher ORR (50.0% vs 20.0%, p = 0.015) and prolonged PFS (mPFS; not reached vs 3.1 months, p = 0.0092). On the other hand, no such correlation was observed among patients treated with docetaxel., Conclusion: A rapid increase of the LMR was significantly associated with the effects of nivolumab monotherapy in our study cohort. Therefore, early change of the LMR may be used as a novel effective surrogate marker to decide on continuation of anti-PD-1 therapy., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The Guidelines of the Japan Society of Clinical Oncology recommend standard triple antiemetic therapy with aprepitant, a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone for patients receiving highly emetogenic chemotherapy. Recently, a Phase III study demonstrated the significance of adding of olanzapine (10 mg) to standard triple antiemetic therapy. Olanzapine is associated with somnolence, and we have previously conducted a randomized Phase II study to evaluate the efficacy and safety of 10 mg and 5 mg olanzapine. Lower dose of olanzapine reduced the incidence of somnolence. Therefore, we conducted a randomized, double blind, placebo-controlled, Phase III study to evaluate the efficacy of olanzapine (5 mg) combined with standard triple antiemetic therapy for cisplatin-based highly emetogenic chemotherapy. This study initiated in Feb 2017. A total of 690 patients are planned to be enrolled over a period of 2 years. This study has been registered at the UMIN Clinical Trials Registry as UMIN000024676.

Introduction: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective., Patients and Methods: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed., Results: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ + T-cell and CD4 + regulatory T-cell (CD25 + CD127 low ) counts before discontinuation correlated significantly with successful therapy discontinuation., Conclusion: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC)., Methods: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival., Results: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%)., Conclusions: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

Purpose: Data on the treatment of non-small cell lung cancer (NSCLC) in real-world clinical practice in Japan are limited. This large-scale, retrospective cohort study examined data on patients' characteristics and systemic therapies for advanced or recurrent NSCLC in routine practice in Japan., Methods: This study used an electronic health records-based database of health claims and Diagnosis Procedure Combination data from 215 consenting hospitals in Japan. Records from April 2008 to September 2015 were analyzed. Regimens were examined by histology, age, sex, and therapeutic line. Logistic regression analysis was performed to predict which clinical and demographic factors affected patients' probability of receiving first- or second-line therapy or completing first-line platinum-based chemotherapy., Findings: Among 16,413 patients, 67.9%, 39.2%, and 22.3% received first-, second-, and third-line systemic treatment, respectively. Treatment was more common in patients aged <75 versus ≥75 years (76.0% vs 51.6%), in female versus male patients (71.6% vs 65.4%), and in patients with nonsquamous versus squamous disease (75.6% vs 61.9%). More than 30 systemic regimens were administered. The most common first-line therapy was platinum-based chemotherapy (nonsquamous, 53.6%; squamous, 73.7%). Non-platinum-based chemotherapy use increased in the second-line setting, but platinum-based chemotherapy use remained high (nonsquamous, 33.9%; squamous, 38.6%). Tyrosine kinase inhibitors were used in 32.0% and 29.4% of patients with nonsquamous NSCLC in the first- and second-line settings, respectively. Switches from first- to second-line platinum-based chemotherapy and from first- to second-line tyrosine kinase inhibitors occurred. Forty-two percent of the patients died during hospitalization. In the logistic regression analysis, factors associated with a decreased likelihood of receiving first-line therapy were male sex, squamous histology, age >75 years, treatment at a general (vs cancer-specific) hospital, worse scores on certain activities of daily living, presence of chronic pulmonary disease, worse Hugh-Jones classification, and positive smoking status. The likelihood of completing first-line platinum-based chemotherapy was increased with greater body mass index, better activities of daily living scores, absence of chronic pulmonary disease, and better Hugh-Jones classification. The likelihood of continuing with second-line therapy was decreased with older age and recurrence of NSCLC., Implications: Systemic treatment patterns for advanced or recurrent NSCLC in Japan were varied. Nearly 30% of all patients and approximately half of elderly patients did not receive systemic treatment. Treatment rates declined with subsequent therapeutic lines. Generally, guidelines were followed with first-line treatment administration, but not with second-line administration. These results underscore the need for better guideline adherence and more optimal treatment in and elderly patients and in those receiving later-line treatment in Japan., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy., Clinical Trial Registration Number: JapicCTI-132072., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: RET rearrangements are rare oncogenic alterations in non-small-cell lung cancer (NSCLC). Vandetanib is a multitargeted tyrosine kinase inhibitor exhibiting RET kinase activity. We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET-rearranged NSCLC., Methods: In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily. RET-positive patients were screened using a nationwide genomic screening network of about 200 participating institutions. Primary endpoint was the independently assessed objective response in eligible patients. This study is registered with UMIN-CTR, number UMIN000010095., Findings: Between Feb 7, 2013, and March 19, 2015, 1536 patients with EGFR mutation-negative NSCLC were screened, of whom 34 were RET-positive (2%) and 19 were enrolled. Among 17 eligible patients included in primary analysis, nine (53% [95% CI 28-77]) achieved an objective response, which met the primary endpoint. In the intention-to-treat population of all 19 patients treated with vandetanib, nine (47% [95% CI 24-71]) achieved an objective response. At the data cutoff, median progression-free survival was 4·7 months (95% CI 2·8-8·5). The most common grade 3 or 4 adverse events were hypertension (11 [58%]), diarrhoea (two [11%]), rash (three [16%]), dry skin (one [5%]), and QT prolongation (two [11%])., Interpretation: Vandetanib showed clinical antitumour activity and a manageable safety profile in patients with advanced RET-rearranged NSCLC. Our results define RET rearrangement as a new molecular subgroup of NSCLC suitable for targeted therapy., Funding: The Ministry of Health, Labour and Welfare of Japan and the Practical Research for Innovation Cancer Control from the Japan Agency for Medical Research and Development, AMED., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Aim: Limited sampling points for both amrubicin (AMR) and its active metabolite amrubicinol (AMR-OH) were simultaneously optimized using Akaike's information criterion (AIC) calculated by pharmacokinetic modeling., Methods: In this pharmacokinetic study, 40 mg/m(2) of AMR was administered as a 5-min infusion on three consecutive days to 21 Japanese lung cancer patients. Blood samples were taken at 0, 0.08, 0.25, 0.5, 1, 2, 4, 8 and 24 h after drug infusion, and AMR and AMR-OH concentrations in plasma were quantitated using a high-performance liquid chromatography. The pharmacokinetic profile of AMR was characterized using a three-compartment model and that of AMR-OH using a one-compartment model following a first-order absorption process. These pharmacokinetic profiles were then integrated into one pharmacokinetic model for simultaneous fitting of AMR and AMR-OH. After fitting to the pharmacokinetic model, 65 combinations of four sampling points from the concentration profiles were evaluated for their AICs. Stepwise regression analysis was applied to select the sampling points for AMR and AMR-OH to predict the area under the concentration-time curves (AUCs) at best., Results: Of the three combinations that yielded favorable AIC values, 0.25, 2, 4 and 8 h yielded the best AUC prediction for both AMR (R(2) = 0.977) and AMR-OH (R(2) = 0.886). The prediction error for AUC was less than 15%., Conclusion: The optimal limited sampling points of AMR and AMR-OH after AMR infusion were found to be 0.25, 2, 4 and 8 h, enabling less frequent blood sampling in further expanded pharmacokinetic studies for both AMR and AMR-OH., (© 2016 John Wiley & Sons Australia, Ltd.)

Although several clinical trials have demonstrated the benefits of platinum-combined adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC), predictive biomarkers for the efficacy of such therapy have not yet been identified. Selection of patients with high metastatic ability in the early stage of non-small cell lung cancer (NSCLC) has the potential to predict clinical benefit of adjuvant chemotherapy (ADJ).In order to develop a predictive biomarker for efficacy of ADJ, we reanalyzed patient data using a public database enrolled by JBR.10, which was a clinical trial to probe the clinical benefits of ADJ in stage-IB/II patients with NSCLC. The patients who were enrolled by JBR.10 were classified into 2 subgroups according to expression of the ACTN4 transcript: ACTN4 positive (ACTN4 (+)) and ACTN4 negative (ACTN4 (-)). In the ACTN4 (+) group, overall survival (OS) was significantly higher in the ADJ subgroup compared with the observation subgroup (OBS), indicating a significant survival benefit of ADJ. However, no difference in OS was found between ADJ and OBS groups in ACTN4 (-). Although ACTN4 expression level did not correlate with the chemosensitivity of cancer cell lines for cytotoxic drugs, the metastatic potential of A549 lung adenocarcinoma cells was significantly reduced by ACTN4 shRNA in in vitro assays and in an animal transplantation model. The clinical and preclinical data suggested that ACTN4 is a potential predictive biomarker for efficacy of ADJ in stage-IB/II patients with NSCLC, by reflecting the metastatic potential of tumor cells., Competing Interests: The authors declare that they have no competing interests.

Purpose: Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure., Methods: AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state., Results: Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure., Conclusions: Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.

Background: Thymic carcinoma is a rare neoplasm of the thymus, and information regarding its genetic profile and optimal medical treatment is limited. We sought to characterize the genetic profile of thymic carcinoma and to evaluate the efficacy of various medical treatments, including treatment with tyrosine kinase inhibitors (TKIs), cytotoxic agents, and immune checkpoint inhibitors., Methods: We retrospectively reviewed medical records of 64 consecutive patients with thymic carcinoma at the National Cancer Center Hospital between April 1973 and March 2014. We analyzed treatment course of patients who underwent medical treatment involving investigational drugs. For patients with available tissue samples, targeted sequencing of 50 cancer-related genes using next-generation sequencing was performed., Results: Thirty-six patients had received chemotherapy. Median progression-free survival in patients receiving first-line chemotherapy was 7.07 months (95% confidence interval, 5.67-8.93). Median survival time was 32.6 months (95% confidence interval, 23.2-43.4). As second- or later-line chemotherapy, a total of 13 patients were treated with 24 investigational drugs, including 8 multi-targeted TKIs, 5 cytotoxic agents, and 2 immune checkpoint inhibitors. Six (24%) of the patients treated with investigational drugs maintained disease control for at least 6 months. Tissue samples of 52 patients (81.3%) were available for targeted sequencing, consisting of 52 formalin-fixed, paraffin-embedded (FFPE) and 16 fresh frozen tissue samples. The genetic alterations of TP53, KRAS, FBXW7, and NRAS were detected in 7 patients (13.5%), and no KIT mutations were noted., Conclusions: Multi-targeted TKIs exhibited potential clinical efficacy for previously-treated thymic carcinoma. The frequency of genetic alterations in this study was low, with no apparent relationship with the efficacy of chemotherapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated., Patients and Methods: In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore., Result: ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity., Conclusions: Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection., Registration Number: JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center)., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: Pulmonary pleomorphic carcinoma (PPC) follows an aggressive clinical course and outcomes are disappointing. Due to its rarity, however, the clinicopathological and molecular characteristics of this disease remain unclear., Methods: We retrospectively evaluated the efficacy of chemotherapy and molecular targeted therapy in 16 patients with PPC who received chemotherapy or EGFR-TKI. We also investigated the status of EGFR mutation, KRAS mutation and ALK expression., Results: On histologic review of the malignant epithelial component, adenocarcinoma was identified in seven cases (43.8%), large cell carcinoma in four (25.0%), and squamous cell carcinoma in two (12.5%). For the sarcomatoid component, 14 cases (87.5%) had both spindle cell tumor and giant cell and 2 (12.5%) had giant cell. Eleven patients received cytotoxic chemotherapy as first-line but did not achieve an objective response, although one patient who received docetaxel as second-line achieved a partial response. We also found that one patient achieved long stable disease of about 9 years without progression after receiving cisplatin and gemcitabine treatment. EGFR mutation, KRAS mutation and ALK expression were investigated in 14 patients whose tumor specimens were available. EGFR mutation was observed in 2 (14.3%) and KRAS mutation in 3 (21.4%), while no patient was positive for ALK expression. One patient harboring EGFR exon 19 deletion was treated with gefitinib after postoperative recurrence and achieved a complete response of about 35 months., Conclusions: Although advanced PPC showed a poor response to chemotherapy, one patient with EGFR mutation achieved an extended complete response. We therefore recommend the evaluation of driver gene alteration such as EGFR in the treatment of advanced PPC.

Objective: Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer., Methods: Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate., Results: From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia., Conclusions: While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Docetaxel and gefitinib play key roles in the treatment of non-small-cell lung cancer (NSCLC), and their combination could be of interest. Both drugs are mainly metabolized by CYP3A4, and drug-drug interactions are a major concern. This phase I dose-finding study was designed to assess the tolerability and drug-drug interactions in this combination using full pharmacokinetic (PK) samplings., Methods: Docetaxel was intravenously administered on days 1 and 22 at a dose of 45 or 60 mg/m(2). Gefitinib (250 mg/day) was orally administrated starting on day 2. Ten PK samplings of docetaxel were performed on days 1 and 22. Seven PK samplings of gefitinib were performed on day 18 ± 3 and on day 22., Results: Twelve patients with advanced or metastatic NSCLC were enrolled without considering EGFR mutation status. The major toxicity was neutropenia. Two patients withdrew from this study due to dose-limiting toxicities; however, the toxicity profiles in this combination were generally acceptable. The docetaxel AUC0-24 and C max did not differ whether administered alone or with gefitinib, and the geometric mean ratios (GMRs) of AUC0-24 and C max (co-administrated/administrated alone) were 0.95 (90 % CI 0.85-1.06) and 0.95 (90 % CI 0.85-1.05), respectively. Furthermore, the GMRs of the steady state gefitinib AUC0-24 and C max were 0.93 (90 % CI 0.84-1.03) and 0.98 (90 % CI 0.88-1.09), respectively., Conclusion: The tolerability of 60 mg/m(2) docetaxel with 250 mg/day gefitinib was confirmed, and we observed no drug-drug interaction in this combination.

Background: The EGFR T790M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation (EGFR-mutated lung cancer). In preclinical models, the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790M resistance mutations., Methods: We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors. The study included dose-escalation cohorts and dose-expansion cohorts. In the expansion cohorts, prestudy tumor biopsies were required for central determination of EGFR T790M status. Patients were assessed for safety, pharmacokinetics, and efficacy., Results: A total of 253 patients were treated. Among 31 patients enrolled in the dose-escalation cohorts, no dose-limiting toxic effects occurred at the doses evaluated. An additional 222 patients were treated in five expansion cohorts. The most common all-cause adverse events were diarrhea, rash, nausea, and decreased appetite. The overall objective tumor response rate was 51% (95% confidence interval [CI], 45 to 58). Among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response, the response rate was 61% (95% CI, 52 to 70). In contrast, among 61 patients without centrally detectable EGFR T790M who could be evaluated for response, the response rate was 21% (95% CI, 12 to 34). The median progression-free survival was 9.6 months (95% CI, 8.3 to not reached) in EGFR T790M-positive patients and 2.8 months (95% CI, 2.1 to 4.3) in EGFR T790M-negative patients., Conclusions: AZD9291 was highly active in patients with lung cancer with the EGFR T790M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01802632.).

Interstitial lung disease (ILD) occurrence and risk factors were investigated in the Japanese non-small-cell lung cancer, post-marketing, large-scale surveillance study, POLARSTAR. All patients with unresectable, recurrent/advanced non-small-cell lung cancer who were treated with erlotinib in Japan between December 2007 and October 2009 were enrolled. Primary endpoints were patterns of ILD and risk factors for onset of ILD and ILD-related death. Overall survival, progression-free survival, and occurrence of adverse drug reactions were secondary endpoints. Interstitial lung disease was confirmed in 429 (4.3%) patients. Concurrent/previous ILD (hazard ratio, 3.19), emphysema or chronic obstructive pulmonary disease (hazard ratio, 1.86), lung infection (hazard ratio, 1.55), smoking history (hazard ratio, 2.23), and period from initial cancer diagnosis to the start of treatment (<360 days; hazard ratio, 0.58) were identified as significant risk factors for developing ILD by Cox multivariate analysis. Logistic regression analysis identified Eastern Cooperative Oncology Group performance status 2-4 (odds ratio, 2.45 [95% confidence interval, 1.41-4.27]; P = 0.0016), ≤50% remaining normal lung area (odds ratio, 3.12 [1.48-6.58]; P = 0.0029), and concomitant honeycombing with interstitial pneumonia (odds ratio, 6.67 [1.35-32.94]; P = 0.02) as poor prognostic factors for ILD death. Median overall survival was 277 days; median progression-free survival was 67 days. These data confirm the well-characterized safety profile of erlotinib. Interstitial lung disease is still an adverse drug reaction of interest in this population, and these results, including ILD risk factors, give helpful information for treatment selection and monitoring. Erlotinib efficacy was additionally confirmed in this population. (POLARSTAR trial ML21590.)., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Objective: Magnesium supplementation has been reported to have a nephroprotective effect on cisplatin-induced renal dysfunction, but little evidence exists regarding the effect of magnesium preloading before cisplatin administration. We started to include magnesium preloading (8 mEq) in cisplatin-containing treatment regimens in January 2011. The aim of the present study was to evaluate whether magnesium preloading reduces cisplatin-induced nephrotoxicity., Methods: We retrospectively reviewed 496 thoracic malignancy patients treated with cisplatin (≥60 mg/m²)-containing regimens as a first-time chemotherapy between January 2009 and December 2011. We compared the incidence of Grade ≥2 serum creatinine elevation according to the Common Terminology Criteria for Adverse Events, version 4.0, between magnesium preloading group (n = 161 [32%]) and non-magnesium preloading group (n = 335 [68%]) during the first cycle and all cycles., Results: The median number of administered cycles was four in both groups. The incidence of Grade ≥2 serum creatinine elevation in magnesium preloading group was significantly lower during both the first cycle and all cycles than in the non-magnesium preloading group (4.9 versus 19.1% during the first cycle, and 14.2 versus 39.7% during all the cycles). A multivariate analysis indicated that magnesium preloading significantly reduced cisplatin-induced nephrotoxicity throughout the entire period from after the first administration (odds ratio: 0.262, 95% confidence interval: 0.106-0.596 during the first cycle, and odds ratio: 0.234, 95% confidence interval: 0.129-0.414 during all cycles)., Conclusions: Magnesium preloading before cisplatin administration significantly reduced cisplatin-induced nephrotoxicity.

Objectives: We conducted an open-label, multicenter, single-arm study to confirm the efficacy and safety of amrubicin (AMR), a topoisomerase II inhibitor, for treating refractory small-cell lung cancer (SCLC)., Patients and Methods: Patients with chemotherapy-refractory SCLC received 40 mg/m(2) AMR for 3 consecutive days, every 21 days. The primary endpoint was the overall response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety., Results: Between November 2009 and February 2011, 82 patients were enrolled. Each patient received a median of four treatment cycles (range, 1-22 cycles). ORR was 32.9% [P<0.0001 by the exact binomial test for the null hypothesis that ORR ≤ 10%; 95% confidence interval (CI), 22.9-44.2%]. The median PFS and OS periods were 3.5 months (95% CI, 3.0-4.3 months) and 8.9 months (95% CI, 7.6-11.3 months), respectively. Significant differences in ORR (21.4% v 45.0%; P=0.034), PFS (median, 2.9 v 5.1 months; P=0.0009), and OS (median, 7.9 v 13.1 months; P=0.0128) were observed between patients previously treated with etoposide and others. Neutropenia was the most common grade 3 or 4 adverse events (93.9%), and febrile neutropenia developed in 26.8% patients. No treatment-related death occurred., Conclusions: AMR monotherapy can be considered an effective and safe treatment option for refractory SCLC. Previous chemotherapy with etoposide may influence AMR efficacy., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) differs in patients with lung adenocarcinoma harboring EGFR-activating mutations. Although lung adenocarcinoma with EGFR-activating mutations has heterogeneous morphologic features, the predictive role of histologic subtype of lung adenocarcinoma with regard to the effectiveness of EGFR-TKIs in patients with EGFR-activating mutations has not been well defined., Methods: Among 134 postoperative recurrence patients with lung adenocarcinoma harboring EGFR-activating mutation (L858R or exon 19 deletion) treated with EGFR-TKIs, we retrospectively analyzed 61 patients treated with EGFR-TKIs as first-line chemotherapy. All the tumors were classified according to the new histologic classification proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) into the following subtypes: lepidic, papillary, acinar, micropapillary, or solid predominant subtype. We evaluated the correlation between the histologic subtype and the clinical efficacy of EGFR-TKIs., Results: In overall response rate, adenocarcinoma with solid predominant subtype is significantly worse than with non-solid predominant subtype (61 vs. 88 %, P = 0.03). The median progression-free survival (PFS) and overall survival after EGFR-TKI treatment were significantly shorter for the patients with solid predominant subtype than for those with non-solid predominant subtype (median PFS of 7.7 vs. 13.5 months, P = 0.002, and median OS of 21.5 vs. 31.0 months, P = 0.028)., Conclusions: This study indicated that among patients with lung adenocarcinoma harboring activating EGFR mutations treated with EGFR-TKIs, solid predominant subtype according to IASLC/ATS/ERS classification is a response predictor for EGFR-TKI.

Objective: A generic cisplatin formulation has replaced the brand-name formulation since November 2003 in our hospital. We retrospectively assessed the renal toxicity caused by the brand-name and generic cisplatin formulations., Methods: The medical records of patients with thoracic malignancy who were treated at our hospital between November 2000 and April 2008 were reviewed. In total, 1296 eligible patients received 80 mg/m(2) of cisplatin: 499 patients were treated with the brand-name cisplatin formulation before November 2003 (Group 1) and 797 patients were treated with the generic formulation after November 2003 (Group 2). We compared the maximum serum creatinine level after chemotherapy in the two groups., Results: The patient characteristics, including age, sex and performance status, and pretreatment serum creatinine levels were well balanced between the two groups. More patients received four cycles of chemotherapy in Group 2 (P < 0.0001). The median (range) of the maximum serum creatinine levels during all the chemotherapy cycles were 1.1 (0.5-4.1) mg/dl and 1.1 (0.5-4.4) mg/dl in Groups 1 and 2, respectively (P = 0.0237). The incidence of grade 0 serum creatinine elevations decreased from 47% to 39%, while that of grade 1 serum creatinine elevations increased from 32% to 41% (P = 0.0094). The incidence rates of grade 2 or 3 serum creatinine elevations were similar (21 vs. 20%). The time to serum creatinine elevation was also similar in Groups 1 and 2 (P = 0.161)., Conclusion: Although grade 1 maximum serum creatinine level was more common in the generic cisplatin formulation group, this was attributed to the larger number of patients receiving four cycles of chemotherapy in this group.

Background: Severe hematological toxicity has been frequently observed during amrubicin monotherapy for patients with lung cancer despite the favorable anti-tumor response. The purpose of this retrospective study was to identify pretreatment factors associated with severe hematological toxicity., Methods: The medical records of lung cancer patients treated with amrubicin monotherapy were reviewed, and univariate and multivariate analyses were conducted., Results: From January 2003 to December 2006, the medical records of 103 patients were extracted. Grade 4 neutropenia was frequently observed in females (male, 66% and female, 90%, P = 0.036 in a univariate analysis). In a multivariate analysis, female gender (P = 0.019), body weight loss (P = 0.021) and amrubicin dose (P = 0.028) were significantly correlated with Grade 4 neutropenia., Conclusion: Gender could be considered as one of the important predictive factors associated with Grade 4 neutropenia in patients receiving amrubicin monotherapy.

Background: It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC., Methods: This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m(2) per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665., Findings: 200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3-33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5-33·6) and 16·9 months (13·4-20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47-0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3-4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3-4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group., Interpretation: For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population., Funding: Ministry of Health, Labour, and Welfare of Japan., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

It was recently recognized that some chronic myeloid leukemia patients with a complete molecular response could sustain that response after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase chronic myeloid leukemia patients who could discontinue imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated chronic myeloid leukemia patients, we identified 50 who had discontinued imatinib for at least six months; of these we analyzed 43. Molecular recurrence was detected in 19 patients, and a complete molecular response rate was estimated to be 47% following imatinib discontinuation. Based on multivariate regression analysis, imatinib dose intensity and prior interferon-α administration were independently predictive of molecular recurrence within 12 months. The depth of the molecular response should be a factor influencing long-term sustained complete molecular response after discontinuation of imatinib. Additionally, an immunological mechanism modified by interferon-α might control chronic myeloid leukemia stem cells.

Aim: To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib., Materials & Methods: Japanese non-small-cell lung cancer patients treated with gefitinib from a prospective pharmacoepidemiological cohort with a nested case-control study component ('CCS'; 52 ILD cases, 139 controls) and a retrospective study (28 ILD cases, 55 controls) were genotyped for nearly 500,000 SNPs. Associations between genotype and ILD were evaluated using Fisher's exact test and logistic regression modeling, and false discovery rate analysis was used to adjust for the large number of statistical tests., Results: The CCS data provided some false discovery rate evidence that the significance of top-ranking SNPs exceeded levels expected by chance, suggesting some genuine associations. However, replication analyses using retrospective study data were not supportive and there was little evidence of strong genetic associations from a combined analysis. Adjustment of CCS analyses for clinical variables provided little additional convincing evidence. Significant gene-gene interactions between SNP pairs using CCS data were not confirmed in retrospective study replication analyses., Conclusion: Although it is not possible to exclude genetic influences in ILD etiology, common sequence variation is unlikely to explain a major component of ILD risk. Our top results may provide a useful hypothesis-generating starting point for further research.

We retrospectively examined the results of antiemetic therapy with granisetron and dexamethasone; with granisetron, dexamethasone and aprepitant; and with palonosetron, dexamethasone and aprepitant, in patients who received chemotherapy with cisplatin at 50 mg/m2 or more for the first time. Vomiting was dramatically reduced by the concomitant administration of aprepitant. There was no difference in this effect when palonosetron was used instead of granisetron as a serotonin receptor antagonist. There was also no significant difference in the percentage of patients without nausea among the 3 groups. The results of this study indicate that vomiting in patients receiving chemotherapy can be controlled using aprepitant in combination with two other drugs.

Background: Amrubicin is a novel anthracycline agent that is well known to exert significant activity against small cell lung cancer (SCLC), but the adverse pulmonary effects of amrubicin are less well known. We investigated the incidence of acute interstitial lung disease (ILD) in SCLC patients who had been treated with amrubicin., Methods: Medical records were used to retrospectively investigate a total of 100 cases of SCLC patients treated with single-agent amrubicin therapy at the National Cancer Center Hospital East between June 2003 and March 2008. The patients' radiographic records and clinical data were reviewed to identify patients who had developed acute ILD after being treated with amrubicin., Results: After receiving amrubicin, seven of the 100 SCLC patients subsequently developed pulmonary infiltrates, and they were identified as cases of acute ILD associated with amrubicin. Of the seven patients who developed ILD, six were treated with corticosteroids, and the ILD improved in three of them, but the other three patients died of respiratory failure. The incidence of ILD was 33% (4/12) among the patients with pre-existing pulmonary fibrosis (PF) and 3% (3/88) among the patients without PF, and the difference between the two groups was statistically significant (P = 0.0036)., Conclusions: The results of this study indicated that amrubicin may cause severe ILD and that pre-existing PF was associated with a higher rate of ILD among SCLC patients treated with amrubicin. We recommend not administering amrubicin in the treatment of SCLC patients with pre-existing PF.

Purpose: Nedaplatin is a second-generation platinum showing favorable activity against non-small cell lung cancer (NSCLC). Dose-limiting toxicity (DLT) is thrombocytopenia, predicted by creatinine clearance (Ccr). This study was conducted to determine the recommended dose, and evaluate the toxicities, pharmacokinetics and efficacy for elderly NSCLC patients., Methods: Patients > or =70 years were stratified into two groups based on renal functions: Group A, Ccr > or = 60 and Group B, 40 < or = Ccr < 60. The initial doses were 80 and 60 mg/m(2) in Groups A and B, respectively. The doses were escalated in 20-mg/m(2) increments to 100 mg/m(2) until DLT., Results: Chemotherapy-naïve 39 elderly patients (Group A/Group B: 22/17) received a total of 83 cycles. Major toxicities were hematological. In Group A, one of the 15 patients at 100 mg/m(2) experienced DLT (neutropenia) and the recommended dose was determined at 100 mg/m(2). In Group B, three of the five patients had DLTs (leukopenia, neutropenia, thrombocytopenia and febrile neutropenia) at 100 mg/m(2), and the recommended dose was determined at 80 mg/m(2). The percentage decreases of neutrophil were well correlated with total and free-Pt AUCs. Partial responses were observed in 13 (33%) of the 39 patients, and 12 of the 13 patients who responded had a squamous cell carcinoma., Conclusions: Nedaplatin was administered simply and feasibly by stratifying renal function and exerted favorable antitumor activity for elderly patients with NSCLC, especially on squamous cell carcinoma.

We examined the diagnostic accuracy of the cumulative smoking dose for identifying the epidermal growth factor receptor (EGFR) exon 19 deletion and L858R mutation among Japanese patients with non-small-cell lung cancer (NSCLC). EGFR mutations in exon 19 and exon 21 were determined in 1001 NSCLC patients. A receiver-operating characteristic (ROC) curve methodology was applied to estimate the diagnostic accuracy. EGFR mutations were detected in 314 patients (31.4%). A cumulative smoking dose of less than 13 pack-years (PY) was the optimal cut-off point for predicting a positive EGFR mutation status, producing a balance between the sensitivity (73.5%) and the specificity (77%). The area under the ROC curve was 0.77, indicating that the smoking dose had a moderate diagnostic accuracy. The median survival time or the median progression-free survival time of patients who had smoked less than 13 pack-years (PY) were 18.6 and 6.3 months, respectively, while those of patients with equal to or more than 13 PY were 9.6 and 2.4 months, respectively. The overall survival (OS) and progression-free survival (PFS) rates were significantly different between the two groups (OS: hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.51-0.80, P = 0.0001) (PFS: HR = 0.58, 95% CI = 0.47-0.71, P < 0.0001). Our study indicated that the smoking dose predicted EGFR mutations with a moderate diagnostic accuracy. Thus, patients who have smoked less than 13 PY might be candidates for gefitinib treatment when EGFR mutation status cannot be determined.

The purpose of this study was to identify the risk factors for skeletal-related events (SREs) in patients with advanced non-small cell lung cancer (NSCLC). SREs were defined as pathologic fractures, spinal cord compression, requirement for radiation therapy, other radiological intervention, or surgery to the bone, and hypercalcemia of malignancy. Time-to-the first SRE and SRE-free survival, and their associations with the patient characteristics were evaluated retrospectively in 642 patients with metastatic NSCLC who received systemic chemotherapy. A total of 118 (18.4%) patients developed SREs during or after the initial chemotherapy. Of these, 107 required radiotherapy to the bone, 5 developed hypercalcemia of malignancy, 3 developed compression fracture of the vertebrae, 2 required surgical treatment of the bone, and 1 underwent radiofrequency ablation therapy to the bone. The first SRE occurred within 12 months in 80 (67.8%) of the 107 patients. The results of multivariate analysis revealed that male sex, performance status (PS) of 2-3 and multiple bone metastases were risk factors for the first SRE, with hazard ratios (HRs) (95% confidence interval [CI]) to the reference of 1.44 (0.98-2.11), 2.21 (0.97-5.03) and 4.43 (2.91-6.76), respectively. SRE-free survival showed a similar trend. The HRs (CI) of male sex, PS of 2 and multiple bone metastases were 1.64 (1.30-2.06), 3.72 (2.31-5.98) and 1.80 (1.40-2.31), respectively. In conclusion, the presence of multiple bone metastases was significantly associated with the development of SRE in patients with advanced NSCLC treated by systemic chemotherapy. Male sex and poor performance status may be additional risk factors for the development of SREs in these patients.

Purpose: This study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma., Patients and Methods: Overall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis., Results: EGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50)., Conclusion: EGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.