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Background Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non‐small cell lung cancer (NSCLC). However, factors associated with long‐term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long‐term survival in NSCLC patients treated with nivolumab, using real‐world data. Methods We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG‐PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long‐term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong‐term survivors and long‐term survivors and performed univariate and multivariate analyses of factors associated with long‐term survival. Results Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG‐PS ≤1 were included in the study. Young age, ECOG‐PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil‐to‐lymphocyte ratio (NLR) change (ΔNLR)

Background The fourth wave of COVID-19 in Osaka Prefecture, Japan, caused a medical crisis. Here, we aim to identify the risk factors for COVID-19 severity and compare patients between the first–third waves and the fourth wave. Methods We performed an observational retrospective study of COVID-19 cases at the National Hospital Organization Kinki-Chuo Chest Medical Center. Results We identified 404 patients (median age: 71.0 years [interquartile range: 56.0–80.0]), of whom 199 (49.1%) had mild disease, 142 (35.2%) had moderate disease, and 63 (15.6%) had severe disease. The overall mortality rate was 5.4% (22/404). Based on multivariate logistic regression analysis, cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were independent risk factors for moderate to severe disease. For every 1 mg/dL increase in C-reactive protein, 10 IU/L increase in lactate dehydrogenase, and 100 ng/mL increase in ferritin, the risk for moderate to severe disease increased by 18.3%, 12.9%, and 8.9%, respectively. Overall disease severity in the fourth wave was higher than in the first–third waves. However, there was no significant difference in mortality. Because of a shortage of beds, four of the 28 severe patients (14.3%) in the fourth wave could not be transferred to the advanced hospital. Conclusions Cardiovascular disease, fever, dyspnea, and several inflammatory biomarkers were risk factors for moderate to severe COVID-19 in our cohort. During the fourth wave, COVID-19 severity worsened, increasing the number of patients who could not be transferred to beds for severe cases, resulting in a medical crisis in Osaka.

Background KRAS-mutated non-small cell lung cancer (NSCLC) accounts for 23–35% and 13–20% of all NSCLCs in white patients and East Asians, respectively, and is therefore regarded as a major therapeutic target. However, its epidemiology and clinical characteristics have not been fully elucidated because of its wide variety of mutational subtypes. Here, we focused on two distinct base substitution types: transversion mutations and transition mutations, as well as their association with environmental factors and clinical outcome. Methods Dataset from the Japan Molecular Epidemiology Study, which is a prospective, multicenter, and molecular study epidemiology cohort study involving 957 NSCLC patients who underwent surgery, was used for this study. Questionnaire-based detailed information on clinical background and lifestyles was also used to assess their association with mutational subtypes. Somatic mutations in 72 cancer-related genes were analyzed by next-generation sequencing, and KRAS mutations were classified into three categories: transversions (G > C or G > T; G12A, G12C, G12R, G12V), transitions (G > A; G12D, G12S, G13D), and wild-type (WT). Clinical correlations between these subtypes have been investigated, and recurrence-free survival (RFS) and overall survival (OS) were evaluated. Results Of the 957 patients, KRAS mutations were detected in 80 (8.4%). Of these, 61 were transversions and 19 were transitions mutations. Both pack-years of smoking and smoking duration had significant positive correlation with the occurrence of transversion mutations (p = 0.03 and p = 0.01). Patients with KRAS transitions had the shortest RFS and OS compared to KRAS transversions and WT. Multivariate analysis revealed that KRAS transitions, along with age and stage, were significant predictors of shorter RFS and OS (HR 2.15, p = 0.01; and HR 2.84, p Conclusions Smoking exposure positively correlated with transversions occurrence in a dose-dependent manner. However, vegetable intake negatively correlated with transitions. Overall, KRAS transition mutations are significantly poor prognostic factors among resected NSCLC patients.

Introduction Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. Methods We conducted a 36-centre, retrospective cohort study in patients with chemo-naive advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. Results The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9–16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6–6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4–10.5) and 9 patients (3.0%, 95% CI 1.4–5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0–6.8) and 7.5 (95% CI 6.5–8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07–3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12–8.20, P = 0.03). Conclusions Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. Trial registration number UMIN000038084

Background Osimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits EGFR activating and EGFR T790M resistance mutations. Osimertinib was found to be more effective than first-generation EGFR-TKIs in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) harboring EGFR-positive mutations in a prior phase III trial. Osimertinib is, therefore, one of the most important standard therapies for EGFR mutation-positive patients. However, there are few reports about osimertinib resistance mechanisms in first-line EGFR-TKI therapy. Understanding first-line osimertinib resistance mechanisms is essential for future therapeutic strategies in patients with NSCLC with EGFR-positive mutations. To clarify the resistance mechanisms of first-line osimertinib, we proposed to analyze circulating tumor (ct) deoxyribonucleic acid (DNA) by the ultra-sensitive next-generation sequencing method. Patients and Methods We aim to collect ctDNA samples from patients with the following key inclusion criteria: histologically or cytologically proven NSCLC, activating EGFR mutation-positive, planned treatment with first-line osimertinib, and written informed consent. Patients with comorbidities, who are deemed unsuitable for participation by an attending physician, would be excluded. We plan to enroll 180 cases and estimate a final analysis of 120 cases following registration and 2-year observation. ctDNA samples are collected at osimertinib treatment initiation, 3 and 12 months later, and disease progression. The key primary endpoint is to clarify the incidence and ratio of osimertinib resistance. The key secondary endpoint is to examine how the quantity of osimertinib resistance-associated mutations detected in ctDNA at treatment initiation influences disease progression.

Undifferentiated pleomorphic sarcoma (UPS) is a new disease in the World Health Organization's classification of tumors of soft tissue and bone published in 2013. Primary mediastinal UPS is rare, especially with pleural effusion. Herein, we describe the pathological findings of pleural effusion followed by mediastinal UPS, which was initially misdiagnosed as epithelial malignant pleural mesothelioma (MPM). The cytopathological findings of the pleural effusion cell block often contribute to the diagnosis of various malignant tumors. However, these findings may lead to misdiagnosis of highly invasive mediastinal tumors such as UPS. A biopsy for primary mediastinal lesions should be performed because MPM rarely mimics mediastinal tumors with pleural effusion., Mediastinal undifferentiated pleomorphic sarcoma (UPS) is rare, especially with pleural effusion. Herein, we describe the pathological findings of pleural effusion followed by mediastinal UPS, cytopathologically mimicking epithelial malignant pleural mesothelioma.

Introduction/Background Durvalumab demonstrated a good efficacy and safety in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in the PACIFIC trial. Although a history of radiation pneumonitis (RP) has been reported to increase the risk of pneumonitis associated with programmed death-1 inhibitors, the safety and efficacy of durvalumab in patients with baseline Grade 1 RP have not been assessed. Therefore, we carried out a multicenter prospective cohort study to evaluate the efficacy and safety of durvalumab in these patients. Patients and Methods This was a multicenter prospective cohort study of 35 patients with Grade 1 RP after CCRT and before durvalumab initiation. This study was a first prespecified analysis for the first 20 patients with the primary objective of assessing the short-term safety; it was assessed 3 months after durvalumab initiation. Results Twenty patients were enrolled in this study between March 1, 2019, and September 3, 2019. Three patients (15%) experienced drug-related Grade ≥3 adverse events, while three patients (15%) had Grade ≥2 pneumonitis/RP within 3 months after durvalumab initiation. Three months after durvalumab initiation, all the patients were alive and four patients (20%) experienced disease progression. Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.).

Background Many previous studies have demonstrated that minor-frequency pretreatment T790M mutation (preT790M) could be detected by ultrasensitive methods in a considerable number of treatment-naïve, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) cases. However, the impact of preT790M in resected cases on prognosis remains unclear. Methods We previously reported that preT790M could be detected in 298 (79.9%) of 373 surgically resected, EGFR-mutated NSCLC patients. Therefore, we investigated the impact of preT790M on recurrence-free survival (RFS) and overall survival (OS) in this cohort by multivariate analysis. All patients were enrolled from July 2012 to December 2013, with follow-up until November 30, 2017. Results The median follow-up time was 48.6 months. Using a cutoff value of the median preT790M allele frequency, the high-preT790M group (n = 151) had significantly shorter RFS (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: 1.01–2.25, P = 0.045) and a tendency for a shorter OS (HR = 1.87, 95% CI: 0.99–3.55, P = 0.055) than the low-preT790M group (n = 222). On multivariate analysis, higher preT790M was independently associated with shorter RFS (high vs low, HR = 1.56, 95% CI: 1.03–2.36, P = 0.035), irrespective of advanced stage, older age, and male sex, and was also associated with shorter OS (high vs low, HR = 2.16, 95% CI: 1.11–4.20, P = 0.024) irrespective of advanced stage, older age, EGFR mutation subtype, and history of adjuvant chemotherapy. Conclusions Minor-frequency, especially high-abundance of, preT790M was an independent factor associated with a poor prognosis in patients with surgically resected, EGFR-mutated NSCLC.

Aim Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms. Patients and methods Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS. Results The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab. Conclusion The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC.

Background To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non‐small‐cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival (RFS) and overall survival (OS). Methods Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations. Results Of 876 patients, 172 had ≥2 somatic mutations. Median follow‐up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488‐2.695), age (≥70 vs, A prospective, multi‐center, molecular epidemiology study of 876 surgically resected non‐small cell lung cancer cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival and overall survival (OS). A smaller number of co‐existing mutations, earlier stage, and younger age were associated with longer recurrence free survival and OS, while epidermal growth factor receptor mutations were significantly associated with improved OS.

Background Nivolumab has promising efficacy for the treatment of non‐small cell lung cancer (NSCLC). Various predictive factors for nivolumab response in those with NSCLC have been reported, including performance status (PS). The objective of this retrospective study was to determine the predictive factors for nivolumab response in those with NSCLC with good PS and those with poor PS. Methods We retrospectively collected pretreatment clinical data of 296 consecutive patients with NSCLC treated with nivolumab. We investigated the relationship between progression‐free survival (PFS) and patient characteristics and analyzed predictive factors associated with good PS (PS 0‐1) or poor PS (PS 2‐4). Results The median age of patients was 70 years; 206 patients were male, and 224 were classified as having good PS (PS 0‐1). The median PFS was 3.0 months, 3.7 months, and 1.2 months for all patients, patients with good PS, and patients with poor PS respectively. Multivariate analysis showed that never smoking (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.15‐2.75), high C‐reactive protein (CRP) (HR, 1.39; 95% CI, 1.00‐1.93), liver metastasis (HR, 1.95; 95% CI, 1.24‐3.07), pleural effusion (HR, 1.45; 95% CI, 1.06‐2.00), and steroid use (HR, 2.85; 95% CI, 1.65‐4.94) were associated with significantly shorter PFS in patients with good PS. A high advanced lung cancer inflammation index (ALI) was significantly associated with longer PFS in patients with poor PS (HR, 0.24; 95% CI, 0.08‐0.79). Conclusions In patients with NSCLC treated with nivolumab, the factors found to be predictive of shorter PFS in patients with good PS were never smoking, high CRP, liver metastasis, pleural effusion, and steroid administration, whereas high ALI was predictive of longer PFS in patients with poor PS., PS was associated with PFS in patients with NSCLC receiving nivolumab treatment. Never smoking, high CRP, liver metastasis, pleural effusion, and steroid use at the commencement of nivolumab treatment were predictive of worse PFS in patients with NSCLC who received nivolumab treatment with good PS, and a high ALI was predictive of better PFS in patients with poor PS.

Background Although patients with advanced cancer often have poor prognostic awareness, the most effective communication approach for improving prognostic awareness is unclear. In addition, the association between prognostic awareness and preferences for future medical treatment remains unexplored. Materials and Methods We performed a prospective observational study of consecutive patients with advanced or post-operative recurrent non-small cell lung cancer whose disease had progressed after first–line chemotherapy, and their caregivers. We evaluated patterns of clinical discussions about incurability, prognostic awareness, and preference for future medical treatment at baseline and 3 months later. Results We obtained 200 valid responses to the questionnaires at baseline and 147 valid responses 3 months later. In addition, 180 caregivers returned valid responses. A total of 54% of patients and 51% of caregivers had accurate awareness at baseline, and 52% of patients had accurate awareness 3 months later. Multiple logistic regression analysis revealed that patients who were informed about incurability in recent and past discussions were significantly more likely to have accurate awareness 3 months later, compared with those who were only informed recently (adjusted odds ratio 5.08; 95% CI, 1.31-19.78; P = .019). Accurate awareness at 3 months was significantly negatively associated with preference for life-prolonging treatment at 3 months after adjusting for covariates (adjusted odds ratio 0.39; 95% CI, 0.17-0.90; P = .028). Conclusion Patients with advanced cancer who had both recent and past discussions about incurability with their oncologists have more accurate prognostic awareness. Improving prognostic awareness could reduce the preference for life-prolonging treatment.

To investigate the exposure–safety relationships of afatinib in Japanese population, we performed population pharmacokinetics (PK) analysis of afatinib in Japanese advanced non-small cell lung cancer patients harboring epidermal growth factor receptor mutation. Plasma samples were collected at 0.5–1, 2–3, 8–12, and 24 h after oral afatinib (40 mg) administration on day 1 and day 8. Plasma afatinib concentrations were determined using high-performance liquid chromatography. Data was analyzed following the population approach and using the software Phoenix® NLMETM Version 7.0 software (Certara USA, Inc., Princeton, NJ, USA). From 34 patients, a total of 354 afatinib plasma concentration values were available for the population PK analysis. Significant covariates in the population PK model included aspartate aminotransferase and creatinine clearance on CL/F, and age and body mass index on V/F. Results of simulation based on final PK model indicated that hepatic impairment had a significant effect on afatinib levels in plasma after multiple dosing. Afatinib trough plasma concentrations on day 8 were higher in patients with adverse events of grade 3 or higher. The population PK analysis showed that hepatic impairment affected afatinib PK parameters and contributed to the high inter-patient variability and high plasma concentrations of afatinib following multiple treatments.

Objective: Ramucirumab plus docetaxel therapy (RAM/DOC) is currently the standard for previously treated advanced non-small cell lung cancer (NSCLC), irrespective of histology. However, the safety data of anti-angiogenic agents for squamous cell NSCLC (Sq) is lacking, with a higher reported rate of severe hemoptysis in a clinical trial setting. We conducted a multicenter retrospective cohort study to confirm the efficacy and safety of RAM/DOC for Sq in real-world settings.Methods: We retrospectively analyzed previously treated patients with advanced NSCLC who underwent RAM/DOC at four institutions. Clinical data on the initiation of RAM/DOC were collected from medical records. Treatment outcomes of RAM/DOC were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1. Incidence of pulmonary hemorrhage was assessed according to the Common Terminology Criteria for Adverse Events version 5.0.Results: Overall, 237 patients with NSCLC were included and 38 (16%) had squamous cell carcinoma. There were no significant differences in median progression-free survival and overall survival between Sq and non-Sq patients (5.8 months vs. 4.3 months, P=0.0937; 15.2 months vs. 13.4 months, P=0.714, respectively). Of all patients, 13 (5%) developed pulmonary hemorrhage. According to histology, there was no significant difference in pulmonary hemorrhage proportion between Sq and non-Sq cohorts (2/38 vs. 11/199, respectively, P=0.947).Conclusion: For previously treated patients with Sq, efficacy and safety data of RAM/DOC were confirmed in a real-world setting and were similar to non-Sq. Ramucirumab is the only vascular endothelial growth factor-blocker available for Sq.

This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT).We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT.In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months.HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

Background and objective: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations.Methods: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment.Results: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P

Ramucirumab (RAM) plus Docetaxel (DOC) is one of the standard treatments after first-line treatment failure in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the efficacy and safety of RAM plus DOC in older patients. We aimed to clarify these and elucidate the prognostic factors.In this multicenter retrospective study, conducted at four medical facilities in Japan, we evaluated the efficacy and safety data for two groups (65 and ≥ 65 years). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to reveal the prognostic factors for better PFS and OS. Patient characteristics and adverse events (AEs) in both groups were compared using the Mann-Whitney's U and Fisher's exact tests for categorical variables.A total of 237 patients were included, of whom 43% (n = 103), and 57% (n = 134) were aged65, and ≥ 65 years. Median OS was 12.2 (95% CI: 9.4-15.0), and 14.8 months (95% CI: 10.8-18.8), respectively, and there were no significant differences between the groups (p = 0.534). Multivariate analysis identified DOC dose reduction (none vs performed, HR: 2.66, 95% CI: 1.62-4.35, p0.001) as an independent prognostic factor for OS in older patients, and a similar result was shown for the PFS. Grade ≥ 3 all AEs were identified in 42.7% and 56.7% of younger and older patients, respectively, and there was a significant difference between the groups (p = 0.033); however, the difference between the groups disappeared with primary DOC dose reduction (p = 0.526).The efficacy of RAM plus DOC administration in older, pretreated patients with advanced NSCLC was comparable to those of younger patients, whereas RAM plus DOC should be cautiously administered to older patients because of severe toxicity. Moreover, appropriate DOC dose reduction may be recommended for increased survival benefit and safety in such patients.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.

Objectives As first line therapy, pembrolizumab provides longer progression free survival (PFS) and overall survival (OS) than platinum doublets in programmed death ligand 1 (PD-L1)-positive non-small cell lung cancer (NSCLC) with tumor propensity scores (TPS) ≥50%. However, clinical trials do not represent real-world patients. Materials and Methods This multicenter retrospective study conducted across 11 medical centers in Japan analyzed clinical data from patients receiving first-line pembrolizumab for NSCLC between February 1, 2017 and April 30, 2018. The efficacy, safety, and suitability of pembrolizumab monotherapy were evaluated. Results The median age of the 213 enrolled patients was 71 (range: 39–91) years. Among them, 176 (82.6%) were male, 20 (9.4%) were never smokers (median Brinkman index: 900), 172 (80.8%) had an ECOG PS of 0–1, 55 (25.8%) had squamous-cell carcinoma (SQ). PD-L1 TPS were 50–74%, 75–89%, and 90–100% in 97 (45.5%), 47 (22.1%), and 69 (32.4%) patients, respectively. Adverse events (AEs) of grades ≥3 were observed in 39 (18.3%) patients. Pneumonitis was the most common severe AE, occurring in 10 patients (4.7%) including 1 with grade 4 toxicity; no severe AE-related deaths occurred. The overall response rate, median PFS, and median OS was 51.2%, 8.3 months, and 17.8 months, respectively. On multivariate analysis, ECOG PS (0–1 vs. ≥2: HR: 1.69, 95.0% CI: 1.05–2.72; p = 0.03138), CRP/Alb (

Background/aim Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group). Materials and methods This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions. Results We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195). Conclusion Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Objective Pleomorphic carcinoma (PC) is a rare pulmonary epithelial malignant tumor with a poor prognosis. The objective of the present study was to investigate the programmed death-ligand 1 (PD-L1) expression in PC and its correlation between the clinicopathological factors and prognosis. Methods Clinical and pathological data of 35 patients with surgically resected PC encountered from 2002 to 2016 at our institution were collected. The PD-L1 expression on tumor cells was evaluated via immunohistochemistry (clone 22C3). We examined the correlation between the PD-L1 expression and patients' clinicopathological factors and their prognosis. Results A high PD-L1 expression (≥50%) was seen in 21 (60%) patients, and parietal-pleural invasion was significantly correlated with a high PD-L1 expression (p=0.012). The 5-year overall survival and relapse-free survival were 68.2% and 43.2%, respectively. Tumor size ≥50 mm (p=0.021), lymph node metastasis (p=0.023), and a high PD-L1 expression (p=0.047) were correlated with a short relapse-free survival. Since lymph node metastasis was an independent risk factor of a poor overall survival (p=0.012), patients with a high PD-L1 expression also tended to have a worse overall survival than those with low levels (p=0.081). Conclusion A high PD-L1 expression is frequently seen in PC. The PD-L1 expression is associated with parietal-pleural invasion and might indicate a poor prognosis.

The most frequent mechanism of resistance after 1st/2nd-generation (G) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is secondary point mutation Thr790Met (T790M) in EGFR. Afatinib followed by osimertinib (Afa group) may provide better outcomes for T790M-positive non-small cell lung cancer (NSCLC) than 1st-G EGFR-TKI followed by osimertinib (1st-G group). We studied 111 consecutive NSCLC patients with T790M mutation treated with osimertinib after progression following 1st/2nd-G EGFR-TKI between March 28, 2016 and March 31, 2018. We analyzed the ratio of T790M to EGFR-activating mutation (T790M ratio) in post EGFR-TKI resistance re-biopsy tissue using droplet digital polymerase chain reaction. And investigated whether afatinib purified the T790M mutation more than 1st-G EGFR-TKI. Among 60 patients with preserved re-biopsy tissue, we analyzed 38 having adequate DNA content. The response rate in Afa group was 81.8% (n = 11) and 1st-G group was 85.2% (n = 27). The mean T790M ratio in total population was 0.3643. The ratio in those with response to osimertinib was significantly higher than in the non-responders (0.395, 0.202; p = 0.0231) and was similar in Afa and 1st-G group (0.371, 0.362; p = 0.9693). T790M ratio significantly correlated with osimertinib response and was similar between the 1st/2nd-G EGFR-TKIs in 1st/2nd-G EGFR-TKI-refractory tumors.

Background Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved. Methods We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions. Results Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR. Conclusions Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Objectives Vascular endothelial growth factor plays an important role in the pathogenesis of malignant pleural effusion (MPE). We previously showed the efficacy of bevacizumab (Bev) plus carboplatin (CBDCA)/paclitaxel (PTX) in the treatment of non-small lung cell cancer (NSCLC) with MPE. However, the toxicities were a little severe, and the efficacy was not satisfied sufficiently. Therefore, we conducted a phase II study for NSCLC with MPE to evaluate the efficacy and safety of Bev plus CBDCA/nab-PTX, which is a new combination therapy. Methods Chemotherapy-naive non-squamous (SQ) NSCLC patients with MPE participated in the study. A single aspiration (not allowing chest tube drainage) was allowed before chemotherapy. Patients received a maximum of six cycles of Bev (15 mg/kg, day1) plus CBDCA (AUC 6, day1)/nab-PTX (100 mg/m

ObjectiveTo investigate whether smoking duration alone can replace pack-years to predict the risk of oncogenic mutations in non-small cell lung cancer (NSCLC).DesignA cross-sectional study using the baseline dataset from the Japan Molecular Epidemiology for Lung Cancer Study.SettingForty-three medical institutions nationwide in Japan.ParticipantsFrom July 2012 to December 2013, 957 patients with newly diagnosed stage I–IIIB NSCLC who underwent surgery were enrolled, and molecular analyses were performed on 876 samples (from 441 ever-smokers and 435 never-smokers).Main outcomes measuredWe calculated the area under the receiver operating characteristic curve (AUC) values using logistic regression to compare between the predictive values of smoking duration and pack-years for mutational frequencies in the v-Ki-ras2 Kirsten rat sarcoma (KRAS), tumour suppressor p53 (TP53), and epidermal growth factor receptor (EGFR) genes and for cytosine-to-adenine base substitution (C>A).ResultsFor predicting KRAS mutations, the AUC values for smoking duration and pack-years were 0.746 (95% CI 0.682 to 0.800) and 0.759 (95% CI 0.700 to 0.810), respectively (p=0.058). For predicting KRAS mutations in smokers, the AUC values for smoking duration and pack-years were 0.772 (95% CI 0.697 to 0.833) and 0.787 (95% CI 0.714 to 0.845), respectively (p=0.036). There were no significant differences between the AUC values for smoking duration and pack-years in terms of predicting TP53 and EGFR mutations and C>A. Pack-years was a significantly better predictor of KRAS mutations than smoking duration.ConclusionSmoking duration was not significantly different from pack-years in predicting the likelihood of smoking-related gene mutations. Given the recall bias in obtaining smoking information, smoking duration alone should be considered for further investigation as a simpler alternative to pack-years.

This study evaluated the efficacy and safety of nivolumab treatment beyond progressive disease (PD) in non-small cell lung cancer (NSCLC). Medical records of consecutive patients with advanced NSCLC who received nivolumab between December 2015 and December 2018 were reviewed. Clinical outcomes of three groups of eligible patients who received nivolumab as a second-line treatment after PD were compared based on Response Evaluation Criteria in Solid Tumors v1.1. We conducted subgroup analyses in patients with and without new lesions at first PD. Twenty-eight patients continued nivolumab treatment beyond PD (TBP). Post PD, 46 patients switched to other anti-cancer treatment (OAT), and 21 received no further anti-cancer treatment (NAT). There were no significant differences in overall survival (OS) or survival post progression (SPP) between TBP and OAT groups (OS: 15.6 vs. 13.4 months, P = .40, SPP: 12.2 vs. 9.3 months, P = .42). Subgroup analyses indicated that among patients without new lesions at first PD, SPP was longer in the TBP than in the OAT groups (12.6 vs. 9.3 months, P = .22, HR: 0.64; 95% CI 0.31‒1.31). The frequency of immune-related adverse events leading to discontinuation during nivolumab beyond PD was equivalent to that for pre-PD (10.7 vs. 12.6%). No significant benefits were associated with continuation of nivolumab for advanced NSCLC patients. Continuation of nivolumab beyond PD could be a more useful option in patients without new lesions at first PD. Treatment-related toxicities require attention during nivolumab treatment not only before PD but also beyond PD.

Background Pembrolizumab is effective as first-line therapy against advanced non-small cell lung cancer (NSCLC) in patients with programmed death ligand-1 (PD-L1) expression levels ≥50% [1]. However, it is not effective in all patients, and the factors predicting responses among this population remain unknown. Methods We retrospectively analyzed patients with NSCLC and a PD-L1 tumor proportion score (TPS) > 50%, who received first-line monotherapy with pembrolizumab from February 1, 2017 to April 30, 2018. The study included 11 hospitals, which participated in the Hanshin Oncology clinical Problem Evaluation group (HOPE). We analyzed the differences between responders and non-responders in terms of age, sex, performance status score, degree of progression, histological type, smoking history, expression of PD-L1, use of steroids prior to treatment, metastasis site, and laboratory data. Results A total of 205 patients were included in this study. Of those, 108 patients exhibiting complete or partial response were defined as responders. Those exhibiting progressive disease (N = 52) were defined as non-responders. In the univariate analysis, Eastern Cooperative Oncology Group performance status score ≥ 2 (p = 0.0832), stage IV disease or recurrence (p = 0.0487), PD-L1 TPS 50–89% (p = 0.0657), use of steroids prior to the administration of pembrolizumab (p = 0.0243), malignant pleural effusion (p = 0.0032), and baseline C-reactive protein (CRP) levels > 1.0 mg/dL (p = 0.0390) were significantly associated with non-response to treatment. In the multivariate analysis, use of steroids prior to the administration of pembrolizumab (odds ratio [OR]: 5.86; 95% confidence interval [CI]: 1.32–31.8; p = 0.0200), malignant pleural effusion (OR: 2.68; 95% CI: 1.15–6.35; p = 0.0228), and baseline CRP > 1.0 mg/dL (OR: 2.17; 95% CI: 1.03–4.68; p = 0.0402) were significantly associated with non-response to treatment. Conclusion In real-world patients with NSCLC and a PD-L1 TPS ≥50%, use of steroids prior to treatment, malignant pleural effusion, and baseline CRP levels > 1.0 mg/dL reduced the response of first-line monotherapy with pembrolizumab.

Background: Compared to conventional cytotoxic chemotherapy, immune checkpoint inhibitors have shown a significant efficacy in the treatment of lung cancer. Although interstitial lung disease (ILD) is an important adverse event in immunotherapy, risk factors for ILD remain unclear. Patients and Methods: In this multicenter cohort study (UMIN000025908), 201 patients who were treated with nivolumab were retrospectively reviewed. Associations between the incidence of ILD and patient characteristics were evaluated. ILD grade and progression-free survival were analyzed according to the presence or absence of imaging findings of airway obstruction adjacent to lung tumors (IAOT). Results: In the multivariate analysis, the odds ratio (OR) of ILD for patients with a history of radiation pneumonitis or IAOT was 3.96 (p=0.012) and 6.59 (p=0.004), respectively. ILD occurred in six (37.5%) out of 16 patients with IAOT and 19 (10.3%) out of 185 patients without IAOT. Three out of the six patients with ILD and IAOT had ILD of grade 4 or more. The median progression-free survival of patients with and without IAOT was 0.9 and 3.2 months, respectively (p

Nivolumab has been associated with unique adverse events known as immune-related adverse events. Although interstitial lung disease (ILD) is a life-threatening immune-related adverse event, the risk of ILD during nivolumab treatment is unclear. In this report, we encountered three patients with stage IV non-small cell lung cancer with signs of lung obstruction caused by tumor-mediated compression on imaging who developed acute ILD within 10 days of commencing nivolumab treatment. The first case involved a 74-year-old Japanese female never-smoker, the second a 67-year-old Japanese female never-smoker, and the third a 75-year-old Japanese female current-smoker. The first patient was administered nivolumab as third-line chemotherapy, the second was administered nivolumab as fifth-line chemotherapy, and the third was administered nivolumab as second-line chemotherapy. Regardless of aggressive treatments for ILD, 2 of 3 patients died. The findings of these cases suggest that obstructive findings in the lungs, which easily cause infections, may be an important risk factor for nivolumab-induced ILD.

Programmed death‐ligand 1 (PD‐L1) expression status is inadequate for indicating nivolumab in patients with non–small cell lung cancer (NSCLC). Because the baseline advanced lung cancer inflammation index (ALI) is reportedly associated with patient outcomes, we investigated whether the pretreatment ALI is prognostic in NSCLC patients treated with nivolumab. We retrospectively reviewed the medical records of all patients treated with nivolumab for advanced NSCLC between December 2015 and May 2016 at three Japanese institutes. Multivariate logistic regression and Cox proportional hazards models were used to assess the impact of the pretreatment ALI (and other inflammation‐related parameters) on progression‐free survival (PFS) and early progression (i.e., within 8 weeks after starting nivolumab). A total of 201 patients were analyzed; their median age was 68 years (range, 27–87 years), 67% were men, and 24% had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher. An ECOG performance status ≥2, serum albumin

Background Cisplatin and pemetrexed are very effective against advanced non-squamous non-small cell lung cancer (NSCLC) without EGFR mutations. Erlotinib plus bevacizumab are highly effective against advanced NSCLCs with activating EGFR mutations. We performed this phase I ‘Quartet Trial’ to determine the safety and efficacy of all 4 agents as a first-line treatment for non-squamous NSCLC patients harboring activating EGFR mutations. Patients and Methods Patients received escalating quartet-agent doses every 3 weeks for 4 cycles. We examined the dose-limiting toxicity (DLT) to determine the maximum tolerated dose (MTD) and recommended dose (RD). Results Ten patients (3 men and 7 women) with a median age of 69 years were enrolled. Four and 6 patients had exon 19 and 21 mutations, respectively; 8 received maintenance therapy without unexpected or cumulative toxicities. One of 6 patients experienced grade 3 vagal reflex at 60 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab, which was designated the RD. Four patients experienced no DLT with 75 mg/m2 cisplatin plus 500 mg/m2 pemetrexed with 150 mg erlotinib and 15 mg/kg bevacizumab (designated the MTD); however, 3 underwent dose reduction due to severe toxicities (grade 3 gastrointestinal hemorrhage, skin rash, nausea, and febrile neutropenia) during induction chemotherapy. The most frequent DLT-phase adverse events were nausea, anorexia, and fatigue. The overall response rate was 100%. Furthermore, the progression-free and overall survival rates were 17.9 and 32.0 months, respectively. Conclusions This quartet chemotherapy regimen was tolerable and effective in our patient population (UMIN000012536).

Epidermal growth factor receptor (EGFR) mutations have been used as the strongest predictor of effectiveness of treatment with EGFR tyrosine kinase inhibitors (TKIs). Three most common EGFR mutations (L858R, exon 19 deletion, and T790M) are known to be major selection markers for EGFR-TKIs therapy. Here, we developed a multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction. Serial-dilution experiments with genomic DNA harboring EGFR mutations revealed linear performance, with analytical sensitivity ~ 0.01% for each mutation. All 33 EGFR-activating mutations detected in formalin-fixed paraffin-embedded (FFPE) tissue samples by the conventional method were also detected by this multiplex assay. Owing to the higher sensitivity, an additional mutation (T790M; including an ultra-low-level mutation, Highlights • An ultrasensitive multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction was developed. • This multiplex mutation detection of common mutations of EGFR is a feasible alternative. • A rare pretreatment EGFR mutation (T790M) with a mutant allele frequency below 0.1% was detected via this multiplex assay. Three most common EGFR mutations (L858R, exon 19 deletion, and T790M) are known to be major selection markers for EGFR-TKI therapy. In this article, we developed a multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction with 0.01% sensitivity. All 33 EGFR-activating mutations detected in FFPE samples by the conventional method were also detected by this multiplex assay. Owing to the higher sensitivity, an additional mutation was detected in the same reaction. Results of this proof-of-principle study on clinical samples indicate clinical utility of multiplex ddPCR for screening for multiple EGFR mutations.

Introduction Previous studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes. Patients and Methods We prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS). Results In the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts. Conclusion Our results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.

Although sex hormones are thought to play an important role in the carcinogenesis of non-small cell lung cancer (NSCLC) in never-smokers, the causative mechanism remains unknown. Passive smoking (PS) is common among East Asian women and has been suggested to be a potential cause of the disease.We systematically evaluated the expression of estrogen receptor (ER), the prevalence of PS, and genetic mutations using tumor samples from a prospectively registered cohort of never-smokers with lung cancer. The study enrolled 92 never-smokers with NSCLC. Expression of ERa, ERP, and progesterone receptor (PR) was examined via immunohistochemical staining (IHC). Detailed PS information was obtained through a standardized questionnaire. The cumulative dose of PS (CPS) was evaluated as a sum of the number of exposure years at home and/or in the work place.Nuclear expression of ERa, ERP, and PR was detected in 0, 14, and 3 cases, respectively. ERP was more frequently overexpressed in earlier stage cancer (p=0.043). Ninety patients (97.9%) had a PS history, and the median CPS was 47.5 years (range, 0-103 years). There was no significant correlation between the amount of PS -and ERP expression (p=0.101). Twelve patients (85.7%) had Epidermal growth factor receptor ,EGFR) mutations in 14 .tumors expressing ERP, and a trend towards an association between ERP expression and EGFR mutations (p =0.067) was -observed.Nuclear expression of ERP was more frequently observed in early stage NSCLC in never-smokers.

Nivolumab has become the standard second-line chemotherapy for non-small cell lung cancer. A 73-year-old man with stage IV non-small cell lung cancer received 6 cycles of chemotherapy with nab-paclitaxel/carboplatin/bevacizumab followed by 11 cycles of nab-paclitaxel/bevacizumab; however, treatment was stopped due to pneumothorax. One year after therapy started, a nodule appeared in the left upper lung and increased in size. Mycobacterium abscessus subsp. massiliense disease was diagnosed by a sputum analysis. After short antibiotic treatment, nivolumab was administered. Two months after nivolumab treatment, the nodule improved along with a good tumour response. The effectiveness of nivolumab for chronic infectious diseases, such as M. abscessus disease, should be investigated.

Background Radiotherapy (RT) is an effective treatment for elderly patients with locally advanced non-small-cell lung cancer (NSCLC); however, no clinical trials have investigated combination RT with pemetrexed (PEM) in chemotherapy-naive patients ≥71 years old. We conducted a phase I/II study to evaluate the appropriate PEM dose, efficacy, and safety of PEM plus RT in elderly patients. Methods Patients ≥71 years with performance status (PS) scores of 0–2 who had pathologically confirmed stage IIIA/IIIB NSCLC received PEM (500 mg/m2 on day 1 of a 28-day cycle, 4 courses) and RT (a single 2 Gy daily fraction on 5 consecutive days weekly from day 1; 60 Gy total). The primary endpoint was the objective response rate (ORR); the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results Forty-one patients with a median age of 79 years were enrolled; 31 were men. Eighteen patients had squamous cell carcinoma, 27 had stage IIIA disease, and 38 had PS scores 0–1. The ORR was 80.5%, while the median OS and PFS rates were 24.9 and 6.9 months, respectively. Two treatment-related deaths occurred owing to RT-related pneumonitis and severe infection, respectively. Common hematological AEs were leucopenia and neutropenia; common non-hematological AEs were anorexia and constipation. Three patients developed PEM-induced interstitial lung disease; however, most AEs were RT-related. Conclusions Combination PEM and RT shows promising efficacy but relatively severe RT-related toxicities. Therefore, this treatment should be prescribed to elderly patients with caution. UMIN 000005036 .

BACKGROUND/AIM We investigated whether the efficacy and type of pre-nivolumab chemotherapy influence outcomes in non-small cell lung cancer patients following nivolumab treatment. PATIENTS AND METHODS In this multicenter study, 199 patients treated with nivolumab were retrospectively reviewed. We analyzed the relationships between the clinical response to nivolumab and to chemotherapy administered immediately beforehand. RESULTS Patients who achieved objective responses to pretreatments showed higher disease control rates with nivolumab than patients who did not (64% vs. 47%, p=0.03), as did those who achieved disease control with pretreatments (62% vs. 35%, p

Background/aim Nivolumab has a promising efficacy for patients with non-small-cell lung cancer (NSCLC) as second-line or later treatment, and after radiotherapy as abscopal effect. However, the effects of radiation pneumonitis history before nivolumab have not been clarified. Therefore, we retrospectively analyzed the correlation of a history of radiation pneumonitis before nivolumab with onset of interstitial lung disease (ILD) and progression-free survival (PFS) after nivolumab treatment in patients with previously treated NSCLC. Patients and methods A total of 201 patients treated with nivolumab were retrospectively reviewed. We collected clinical data of patients at the time of starting nivolumab and we evaluated ILD incidence and PFS in relation to patient characteristics, including radiation pneumonitis history. Results The median age was 68 years; 135 patients were men, 157 had a smoking history, and 153 had performance status of 0 or 1. Thirty-four patients experienced radiation pneumonitis before nivolumab, and 50 patients received radiotherapy to the chest (31 patients received curative radiotherapy). The overall median PFS was 2.8 months and the overall ILD rate was 12.4%. Higher ILD incidence was observed in the group with a history of radiation pneumonitis (26.5%) compared to the group without radiation pneumonitis (9.6%). The median PFS was 3.6 and 2.3 months, respectively. On multivariate analysis, a history of radiation pneumonitis was also significantly correlated with good PFS (p=0.023). Conclusion Although increasing the risk of ILD, a history of radiation pneumonitis before nivolumab also contributes to the prolongation of PFS after nivolumab.

Background/aim Although immune checkpoint inhibitors play an important role in the therapy of lung cancer, they are associated with various immune-related adverse events and predictive factors of them are unclear. In this study, we investigated predictive factors of nivolumab-induced hypothyroidism which is one of the adverse events in patients with lung cancer. Patients and methods Patients with non-small-cell lung cancer who were administered nivolumab at our hospital between December 2015 and May 2016 were retrospectively enrolled. The thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were analyzed. Results Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The TPO and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism. Conclusion TPO and thyroglobulin antibody levels at baseline may be predictive of hypothyroidism.

The increased risk for early death owing to anti-programmed cell death 1 inhibitors is a major disadvantage that requires special management. We evaluated the frequency, causes, and risk factors of early death during nivolumab treatment for non-small cell lung cancer (NSCLC) in a Japanese clinical setting.The medical records of patients with NSCLC who started receiving nivolumab between December 17, 2015 and July 31, 2016 in 3 Japanese institutes were collected. Early death was defined as any death within 3 months from the start of nivolumab treatment, irrespective of its cause. Treatment response was evaluated using the Response Evaluation Criteria In Solid Tumors criteria, version 1.1.A total of 201 patients with NSCLC were enrolled, and 38 (18.9%) died within the first 3 months. Thirty-one (81.6%) patients who experienced early death developed progressive disease, whereas 14 (36.8%) patients who experienced early death demonstrated nivolumab-induced immune-related adverse events, which required corticosteroid intervention, including interstitial lung disease in 7 (18.4%) patients. Multivariate logistic regression demonstrated that an Eastern Cooperative Oncology Group performance status score ≥ 2 (odds ratio [OR], 5.66; 95% confidence interval [CI], 2.01-15.61; P .001), C-reactive protein-to-albumin ratio0.3 (OR, 10.56; 95% CI, 3.61-30.86; P .001), and the response to prior treatment (OR, 2.07; 95% CI, 1.03-4.14; P = .041) were independent predictors for early death.Disease progression and immune-related adverse events are 2 major causes of early death with nivolumab in patients with NSCLC. An Eastern Cooperative Oncology Group performance status score ≥ 2, pretreatment C-reactive protein-to-albumin ratio0.3, and poor response to prior treatment were associated with early death.

Background Afatinib is an effective first-line treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC). However, few reports have addressed the influence of cerebrospinal fluid (CSF) penetration rate on the efficacy of afatinib in patients with central nervous system metastases. Therefore, we conducted a prospective multicenter trial to evaluate the CSF penetration rate and efficacy of afatinib in patients with EGFR mutation-positive NSCLC with leptomeningeal carcinomatosis. Patients and methods Eleven patients with histologically-proven EGFR mutation-positive NSCLC with leptomeningeal carcinomatosis were enrolled in the study between April 2014 and November 2015. They were treated with afatinib (40 mg/day), and blood and CSF levels of afatinib were analyzed on day 8. The primary endpoint was CSF penetration rate. Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results The median age of patients was 66 years. Five patients harbored an exon 19 deletion, three harbored a p.L858R point mutation, and three harbored an uncommon exon 18 mutation. The levels of afatinib in blood and CSF (mean±SD) were 233.26±195.40 nM and 3.16±1.95 nM, respectively. The CSF penetration rate was 2.45±2.91%. The ORR was 27.3% (three out of 11 patients), and two out of these three responders had uncommon EGFR mutations. The median PFS and OS were 2.0 and 3.8 months, respectively. Conclusion The median CSF penetration rate of afatinib was higher than previously reported. Afatinib was effective against leptomeningeal carcinomatosis particularly in patients with NSCLC harboring uncommon EGFR mutations. The criteria for selecting a specific EGFR tyrosine kinase inhibitor for therapy of NSCLC should include its ability to penetrate CSF and its efficacy against specific mutation types.

Background This study was designed to determine the recommended dose of carboplatin–pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC). Patients and methods Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. Results The combination of carboplatin at an area under the concentration–time curve (AUC) of 5, and 500 mg/m2 pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68–216 days) and the median overall survival time was 461 days (95% CI 168–754 days). Conclusions This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m2) every 3 weeks, in chemotherapy-naive, elderly (≥75 years old) patients with advanced nonsquamous NSCLC.

Purpose Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors. Patients and Methods This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non–small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction–based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire. Results From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive. Conclusion The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC.

Malignant pleural mesothelioma (MPM) is an uncommon, fatal neoplasm induced by asbestos exposure. Brain metastases from MPM are extremely rare, with most such cases diagnosed only at the time of autopsy. This report describes what we believe to be the first case of MPM metastasizing to the brain after a subarachnoid hemorrhage, as well as the subsequent surgical removal of the brain metastasis.

Malignant effusion is associated with high serum and plasma levels of vascular endothelial growth factor (VEGF). There are no biomarkers of outcome for bevacizumab treatment in patients with malignant pleural effusion (MPE). We previously reported that carboplatin-paclitaxel plus bevacizumab was effective for patients with advanced non-squamous non-small cell lung cancer (NSCLC) and MPE, although we did not evaluate the relationship between treatment outcomes and plasma or pleural effusion levels of VEGF. Therefore, this study evaluated whether plasma or pleural effusion VEGF might predict bevacizumab treatment outcome.We enrolled 23 patients with NSCLC and MPE between September 2010 and June 2012. Plasma VEGF levels were measured in 19 patients and pleural VEGF levels were measured in 22 patients.Compared to patients with a low plasma VEGF level, patients with a high level exhibited significantly shorter overall survival (OS: 13.8 vs. 6.5 months, p=0.04), progression-free survival (PFS: 8.7 vs. 4.8 months, p0.01), and period to re-accumulation of MPE (pPFS: 9.7 vs. 6.2 months, p=0.02). Compared to patients with a low VEGF level in pleural effusion, patients with a high VEGF level exhibited significantly shorter OS (19.6 vs. 6.9 months, p0.01) and pPFS (9.6 vs. 6.7 months, p=0.04), although there was no significant difference in their PFS (6.6 vs. 5.9 months, p=0.18).VEGF levels in the plasma and pleural effusion may predict the outcome of bevacizumab treatment in patients with NSCLC and MPE.

It remains to be determined in elderly patients with advanced non-small-cell lung cancers (NSCLCs) if there is a benefit of chemotherapy in patients aged 80 or older.Using a database from the Japan National Hospital Organization Study Group for Lung Cancer from 1990 to 2005, 3 cohorts based on the age of diagnosis were examined in patients with stage IIIB and IV NSCLC. Cohort 1 was for 70- to 74-year-old patients, cohort 2 for 75- to 79-year old, and cohort 3 for 80 years and older (80+). Multivariate analysis of survival for each cohort was performed using the Cox regression method using the following covariates: age, PS, histology, stage, smoking status, and chemotherapy.There were 1617 patients in cohort 1, 1349 in cohort 2, and 1010 in cohort 3. The number of patients treated with chemotherapy were 991 (61%) in cohort 1, 648 (48%) in cohort 2, and 286 (28%) in cohort 3. Multivariate analysis for overall survival (OS) showed that chemotherapy was a significant prognostic factor among cohort 1 (hazard ratio [HR], 0.540; 95% confidence interval [CI], 0.481-0.607; P.0001) and cohort 2 (HR, 0.715; 95% CI, 0.632-0.810; P.0001) and showed a benefit trend among cohort 3 (HR, 0.869; 95% CI, 0.742-1.018; P = .0940).After adjustment for PS, a trend of survival benefit of chemotherapy remained in patients aged 80 or older.

Background Because of the number of elderly patients with NSCLC is increasing, it is becoming a public health problem world wide. In elderly patients with advanced NSCLC, mono-chemotherapy is the standard treatments. But little information is available for patients aged ≥80 regarding the management of advanced NSCLC. Purpose The purpose of the present study is to evaluate the efficacy and safety of chemotherapy for patients aged ≥80. Methods 110 patients aged ≥75 with advanced NSCLC were retrospectively reviewed. Data was collected from the electronic medical records of our hospital from January 2005 to August 2008. The patient population was divided into three age groups: patients aged ≥80 who received chemotherapy (group A), patients aged 75–79 who received chemotherapy (group B), and patients aged ≥75 who received only best supportive care (group C). Date cut-off of this study was on 20th June, 2009. We evaluated and compared the survival and the toxicity between three groups. Results Among 110 patients, there were 21 patients in group A, 55 patients in group B, 34 patients in group C. Among group C, there were 8 patients aged 75–79 and the main reasons for BSC were poor PS in 7 patients, and there were 26 patients aged ≥80 and the main reason for BSC were age itself in 17 patients. Response rate and disease control rate were similar in group A and group B (16.4% vs. 23.8%, and 57.1% vs. 49.1%). MST was 237 days in group A with PS 0–2 and was 232 days in group C with PS 0–2. Median PFS and MST were 86 and 237 days in group A with PS 0–2 and was 107 and 263 days in group B. Toxicity profile of group A seems to be acceptable: over grade 3 leucopenia was observed 33%; over grade 3 neutropenia was 52%; but no febrile neutropenia; over grade 3 non-hemotological toxicity was observed 14%. Conclusion There was no obvious difference between patients aged ≥80 and 75–79 in terms of safety and efficacy of chemotherapy. Patients aged ≥80 with advanced NSCLC who have good PS might be good candidates for the chemotherapy.