Publications by authors named "Yusuke Okuma"

106 Publications

Alectinib for Miliary Lung Metastasis in -Positive Lung Adenocarcinoma.

Onco Targets Ther 2021 30;14:2911-2915. Epub 2021 Apr 30.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Background: Miliary pulmonary metastasis characterized by tiny nodules is a rare metastatic pattern in advanced non-small cell lung cancer (NSCLC) and is usually seen in patients harboring an mutation, and amylase-producing lung cancer is highly uncommon and rarely reported in NSCLC patients who have an mutation.

Case: A 32-year-old Japanese female was found to have miliary pulmonary nodules throughout both lung fields on a chest x-ray examination during an annual health check-up. Further examination by computed tomography (CT) revealed diffuse, bilateral, miliary nodules. Blood tests showed no increased tumor marker levels, but there was a significantly increased serum amylase level. A diagnosis of -rearranged adenocarcinoma was made based on the results of a mediastinal lymph node biopsy obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Treatment with alectinib resulted in rapid regression of the CT shadows and a reduction in the patient's serum amylase level.

Conclusion: We have reported a case of -rearranged NSCLC with a miliary pulmonary metastasis pattern that was sensitive to alectinib and in which the serum amylase level decreased in response to treatment with alectinib. Young patients with miliary pulmonary metastasis should be checked for all driver mutations.
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http://dx.doi.org/10.2147/OTT.S300229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096437PMC
April 2021

Feasibility of next-generation sequencing (Oncomine™ DX Target Test) for the screening of oncogenic mutations in advanced non-small-cell lung cancer patients.

Jpn J Clin Oncol 2021 Apr 21. Epub 2021 Apr 21.

Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan.

Background: The Oncomine™ Dx Target Test based on next-generation sequencing has been approved for the screening of oncogenic mutations in advanced non-small-cell lung cancer patients.

Methods: We assessed the tissue sample factors that affect the success rate of Oncomine™ Dx Target Test companion diagnostics and the feasibility of using biopsy specimens for Oncomine™ Dx Target Test companion diagnostics in advanced non-small-cell lung cancer patients.

Results: Ninety-nine biopsy samples were subjected to genetic testing using the Oncomine™ Dx Target Test companion diagnostics to detect v-raf murine sarcoma viral oncogene homologue B1 mutations (Cohort 1), and 136 biopsy samples were examined using Oncomine™ Dx Target Test companion diagnostics for the detection of multiple oncogenic mutations (Cohort 2) between July 2018 and April 2020. We retrospectively collected clinical and pathological data, including tissue size and tumour cell content. The success rate was 77% (76/99) in Cohort 1 and 93% (127/136) in Cohort 2. In Cohort 1, the success rate was significantly associated with the tumour cell content: the success rate was 63% for samples with a tumour cell content of <20%, whereas it was 83% for samples with a tumour cell content of 20% or higher (P = 0.0446). The tissue size also affected the success rate: a success rate of 57% was obtained for tissue sizes <4 mm2, whereas a success rate of 95% was obtained for tissue sizes of 4 mm2 or larger (P < 0.0001). In Cohort 2, the success rate was 100% when tumour specimens with a tissue size of 4 mm2 or larger were used.

Conclusions: Tissue size and tumour cell content were significantly associated with the success rate of Oncomine™ Dx Target Test companion diagnostics.
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http://dx.doi.org/10.1093/jjco/hyab059DOI Listing
April 2021

Premature phase II study of amrubicin as palliative chemotherapy for previously treated malignant pleural mesothelioma.

Thorac Cancer 2021 Apr 8. Epub 2021 Apr 8.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo, Japan.

Background: Treatment options for malignant pleural mesothelioma (MPM) are limited. Anthracyclines are considered key drugs for treating MPM. However, their use is limited by severe cardiac toxicities. Amrubicin (AMR) is a next-generation anthracycline that is commonly used to treat lung cancer. Here, we conducted a phase II trial of this drug in patients with previously treated MPM.

Methods: Eligible patients with MPM having adequate organ function and a performance status of 0-2 were enrolled after disease progression following pemetrexed/platinum therapy. Patients received 35 mg/m AMR on days 1-3 every three weeks until tumor progression or the appearance of unacceptable toxicities. The primary endpoint was the objective response rate. Median progression-free survival (PFS), overall survival (OS), number of treatment cycles, and adverse events were evaluated as secondary endpoints.

Results: This trial was discontinued because of low accrual. From September 2013 to July 2018, five patients with MPM were enrolled. Stable disease (SD) was observed in three patients (60%), and progressive disease was noted in two patients (40%). The median PFS was 2.4 (range, 1.2-11.2) months, and the median OS was 9.1 (range, 6.2-22.0) months. The median number of treatment cycles was three (range, 2-11). Grade 1/2 toxicities were observed in all patients. Grade 3/4 neutropenia was observed in four patients (80%), but there were no cases of febrile neutropenia.

Conclusions: Despite the absence of the responders, the observation of SD in three patients suggests that AMR could have potential for treating MPM.
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http://dx.doi.org/10.1111/1759-7714.13892DOI Listing
April 2021

Activity and Immune Correlates of Programmed Death-1 Blockade Therapy in Patients With Advanced Large Cell Neuroendocrine Carcinoma.

Clin Lung Cancer 2021 Feb 8. Epub 2021 Feb 8.

Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

Background: The efficacy of anti-programmed death receptor 1 (PD-1) therapy in patients with large cell neuroendocrine carcinoma (LCNEC) remains unclear. We investigated the outcome of anti-PD-1 therapy and its predictive markers by evaluating the immune-related tumor microenvironment.

Patients: We retrospectively reviewed patients with advanced LCNEC treated with systemic chemotherapy. We also evaluated PD ligand 1 (PD-L1) expression (clone: 22C3), CD8-positive tumor-infiltrating lymphocytes (TILs), and the mutational profiles.

Results: Seventy patients were enrolled, and 13 of 70 patients received anti-PD-1 therapy. The progression-free survival (PFS) and objective response rate (ORR) of the anti-PD-1 therapy were 4.2 months and 39%, respectively. The overall survival of patients treated with anti-PD-1 therapy (n = 13) was significantly better than those treated without anti-PD-1 therapy (n = 57) (25.2 months vs 10.9 months; P = .02). Among the 13 patients treated with anti-PD-1 therapy, 10 patients (90%) had PD-L1-negative tumors. Patients with a high density of tumoral CD8-positive TILs (≥38/mm) had a significantly better ORR and PFS than those with a low density of tumoral CD8-positive TILs (ORR: P = .02; PFS: P = .003). Additionally, all 3 patients with TP53 mutation co-occurring with PIK3CA mutation (2 of 8 patients) or RB1 mutation (1 of 8 patients) responded to anti-PD-1 therapy.

Conclusions: Anti-PD-1 therapy was effective regardless of PD-L1 positivity in patients with advanced LCNEC. Our investigation might suggest that the density of tumoral CD8-positive TILs and the presence of co-occurring mutations are predictors of the efficacy of anti-PD-1 therapy in patients with advanced LCNEC.
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http://dx.doi.org/10.1016/j.cllc.2021.02.003DOI Listing
February 2021

A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors.

Clin Cancer Res 2021 May 16;27(9):2571-2583. Epub 2021 Feb 16.

The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%-30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.

Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies ( = 303 unique patients) using a uniform computational approach.

Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis ( < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers ( = 105).

Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4834DOI Listing
May 2021

IMpower132: Atezolizumab plus platinum-based chemotherapy vs chemotherapy for advanced NSCLC in Japanese patients.

Cancer Sci 2021 Apr 9;112(4):1534-1544. Epub 2021 Feb 9.

Chugai Pharmaceutical co., Ltd, Tokyo, Japan.

IMpower132 explored the safety and efficacy of atezolizumab plus pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Key eligibility criteria for the phase 3, open-label, IMpower132 study included age ≥18 y, histologically or cytologically confirmed advanced non-squamous NSCLC per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status of 0/1, and no prior systemic treatment for stage IV NSCLC. Patients received atezolizumab (1200 mg) plus pemetrexed (500 mg/m ) and cisplatin (75 mg/m ) or carboplatin (area under the concentration curve, 6 mg/mL/min) (APP arm) or chemotherapy alone (PP arm). The co-primary study endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS) per RECIST 1.1 in the intention-to-treat population. A subgroup analysis was conducted in Japanese patients. In the Japanese subgroup (n = 101), median OS was 30.8 (95% CI, 24.3 to not estimable) mo in the APP arm (n = 48) and 22.2 (95% CI, 15.7-30.8) mo in the PP arm (n = 53; hazard ratio [HR], 0.63 [95% CI, 0.36-1.14]). PFS was 12.8 (95% CI, 8.6-16.6) mo in the APP arm vs 4.5 (95% CI, 4.1-6.7) mo in the PP arm (HR, 0.33 [95% CI, 0.21-0.58]). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 68.8% of APP arm patients and 44.2% of PP arm patients. Consistent with global study results, atezolizumab plus pemetrexed and platinum-based chemotherapy improved efficacy and was well tolerated in Japanese patients with advanced NSCLC despite a higher incidence of grade 3/4 TRAEs.
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http://dx.doi.org/10.1111/cas.14817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019191PMC
April 2021

Prognostic impact of peripheral blood neutrophil to lymphocyte ratio in advanced-stage pulmonary large cell neuroendocrine carcinoma and its association with the immune-related tumour microenvironment.

Br J Cancer 2021 Mar 30;124(5):925-932. Epub 2020 Nov 30.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Background: The prognostic value of the neutrophil-to-lymphocyte ratio (NLR) with large cell neuroendocrine carcinoma (LCNEC) patients remains unclear. Thus, we performed a retrospective study to examine the relationship between the pretreatment NLR and clinical outcome in advanced LCNEC patients and the impact of the immune-related tumour microenvironment (TME).

Methods: This retrospective study included 63 advanced LCNEC patients who had received chemotherapy. We collected clinical data and investigated the TME status (CD4, CD8, CD20 and FOXP3).

Results: The overall survival of the patients with a low NLR (<5) was significantly longer than those with a high NLR (≥5) (14.9 vs. 5.2 months; p < 0.001). A multivariate analysis identified a high NLR as a predictor of a poor prognosis (HR, 3.43; 95% CI, 1.73-6.79; p < 0.001). The NLR was inversely correlated with tumoural and stromal CD8-positive tumour-infiltrating lymphocytes (tumoural: r = -0.648, p = 0.005, stromal: r = -0.490, p = 0.046).

Conclusions: A high NLR was associated with a poor prognosis in advanced LCNEC patients. Our study revealed that the NLR can reflect the TME, at least in part, suggesting that the NLR plays an important role not only as a clinical outcome predictor but also as a tumour immune status indicator.
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http://dx.doi.org/10.1038/s41416-020-01188-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921668PMC
March 2021

Impact of chemoradiotherapy on the immune-related tumour microenvironment and efficacy of anti-PD-(L)1 therapy for recurrences after chemoradiotherapy in patients with unresectable locally advanced non-small cell lung cancer.

Eur J Cancer 2020 11 8;140:28-36. Epub 2020 Oct 8.

Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. Electronic address:

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 versus post-CRT median, 470/mm; 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.
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http://dx.doi.org/10.1016/j.ejca.2020.08.028DOI Listing
November 2020

Prognostic factors for patients with metastatic or recurrent thymic carcinoma receiving palliative-intent chemotherapy.

Lung Cancer 2020 10 20;148:122-128. Epub 2020 Aug 20.

Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Thymic malignancies are a model of rare cancer. However, little clinical data is available based on the large database. We aimed to clarify the prognostic factors, particularly the metastatic sites, for thymic malignancies using one of the largest, representative, multi-institutional databases, the NEJ023 database.

Patients And Methods: Patients with Stage IVA/IVB or recurrent thymic carcinoma were enrolled between 1995 and 2014. Clinicopathologic information was evaluated, and the patients were subdivided according to the metastatic organs of involvement (serosal dissemination, liver, lymph node, pulmonary, and bone metastasis). A Kaplan-Meier analysis and multivariate Cox regression were used to evaluate survival.

Results: Two hundred and seventy-nine patients with metastases and a predominantly squamous histology (66.7%) were included. Most patients (53.0%) had serosal dissemination, whereas 26.5%, 21.9%, 19.7%, and 15.8% had pulmonary, lymph node, bone and liver metastases, respectively. Over a median follow-up time of 21.5 months, the median overall survival (mOS) was 30.7 months. When the subjects were grouped according to involved metastatic sites, patients with more than 3 involved metastatic organs had the worst survival outcome. Among patients with isolated involvement, those with bone metastasis had the poorest survival, followed by patients with liver metastasis. Subjects with hypoalbuminemia also had poor survival outcomes. When patients treated with platinum and anthracycline-containing pharmacotherapy were compared with those treated with platinum and non-anthracycline-containing pharmacotherapy, no significant difference was observed. Bone metastasis (P = 0.0005), liver metastasis (P =  0.047), and hypoalbuminemia (P =  0.0021) were identified as prognostic factors in a multivariate analysis.

Conclusion: The site of metastatic involvement affects the survival outcomes of patients with thymic carcinoma, and this result may reflect the sensitivity of metastatic sites to pharmacotherapy. As a next step, controlling liver metastasis with pharmacotherapy could help to improve the prognosis of patients with thymic carcinoma.
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http://dx.doi.org/10.1016/j.lungcan.2020.08.014DOI Listing
October 2020

The Gut Microbiome Associates with Immune Checkpoint Inhibition Outcomes in Patients with Advanced Non-Small Cell Lung Cancer.

Cancer Immunol Res 2020 10 27;8(10):1243-1250. Epub 2020 Jul 27.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo City, Tokyo, Japan.

The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non-small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti-PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3-V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of UCG 13 and When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, UCG 13 and were enriched in patients with favorable ORR and PFS >6 months. UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI..
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0196DOI Listing
October 2020

Phase II trial of S-1 treatment as palliative-intent chemotherapy for previously treated advanced thymic carcinoma.

Cancer Med 2020 10 19;9(20):7418-7427. Epub 2020 Aug 19.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival following palliative-intent chemotherapy. Sunitinib, everolimus, and pembrolizumab have been proposed as active agents based on previous phase II trials. In this phase II study, TC patients previously treated with platinum-based chemotherapy were enrolled. The patients received S-1 orally twice daily at a dose of 40-60 mg/m for 4 weeks, followed by 2 weeks off until the progression of the disease or the presence of unacceptable toxicities. The primary endpoint was the objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size of 26 patients was planned to reject the ORR of 10% under the expectation of 30% with a power of 0.80 and a type I error of 0.05 (one-sided). Twenty-six patients were recruited between 2013 and 2016; 23 patients had squamous cell carcinoma and 10 had an ECOG performance status of 0. One patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (90% confidence interval [CI], 18.3-46.9) and an 80.8% disease control rate (90% CI, 65.4-90.3). The median PFS was 4.3 months (95% CI, 2.3-10.3 months) and median OS was 27.4 months (95% CI, 16.6-34.3). Adverse events of grade ≥ 3 included neutropenia (12%), skin rash (8%), elevated alanine aminotransferase, and fatigue (4%). No treatment-related death was observed. S-1 confirmed clinical activity with tolerability in patients with previously treated TC. (UMIN000010736).
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http://dx.doi.org/10.1002/cam4.3385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571815PMC
October 2020

Bridging over troubled waters: the doubling time and histological subtypes of thymic epithelial tumors.

J Thorac Dis 2020 Jul;12(7):3886-3889

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

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http://dx.doi.org/10.21037/jtd.2020.03.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399412PMC
July 2020

Durvalumab Consolidation Treatment after Chemoradiotherapy for an HIV-Positive Patient with Locally Advanced Non-Small Cell Lung Cancer.

Case Rep Oncol 2020 May-Aug;13(2):747-753. Epub 2020 Jun 26.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Due to antiretroviral therapy, human immunodeficiency virus (HIV) patients and non-HIV patients have a similar life expectancy. The leading cause of death among HIV patients is lung cancer. However, clinical toxicities with immune checkpoint inhibitors, including durvalumab, in HIV-positive patients with non-small cell lung cancer (NSCLC) remain unknown. We report a 45-year-old Japanese HIV patient, who was safely treated with durvalumab consolidation therapy after concurrent chemoradiotherapy (CCRT) for locally advanced NSCLC without significant toxicities until his disease progressed. This case demonstrates the safety of durvalu-mab consolidation therapy for HIV-positive patients after CCRT for locally advanced NSCLC.
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http://dx.doi.org/10.1159/000507390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383185PMC
June 2020

Efficacy of anti-PD-1 antibodies in NSCLC patients with an EGFR mutation and high PD-L1 expression.

J Cancer Res Clin Oncol 2021 Jan 23;147(1):245-251. Epub 2020 Jul 23.

Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Introduction: Several studies have demonstrated that non-small cell lung cancer patients (NSCLCs) harboring epidermal growth factor receptor (EGFR) mutations have poor clinical outcomes in response to treatment with programmed death-1 (PD-1) inhibitors. However, it remains unclear whether EGFR-mutated NSCLCs with a high programmed death-ligand-1 (PD-L1) expression (tumor proportion score ≥ 50%) respond to PD-1 inhibitors.

Methods: We retrospectively investigated the NSCLCs who had received PD-1 inhibitors between January 2016 and December 2018 to assess the efficacy of PD-1 inhibitors in patients with an EGFR mutation and high PD-L1 expression.

Results: There were 153 patients with a high PD-L1 expression level, and the median progression-free survival (mPFS) was 5.3 months [95% confidence interval (CI) 1.3-12.4 months] in the patients with EGFR mutations (n = 17) and 8.3 months (95% CI 6.0-11.7 months) in those with wild-type EGFR (n = 136; hazard ratio (HR) 1.62; 95% CI 0.83-2.87). Among the 110 patients in the low PD-L1 expression group, the mPFS was 1.6 months (95% CI 1.3-5.9 months) in the patients with EGFR mutations (n = 18) and 3.8 months (95% CI 2.5-5.9 months) in those with wild-type EGFR (n = 92; HR 2.59; 95% CI 1.48-4.31). The HR for PFS in the group with EGFR mutations and high PD-L1 expression was 0.97 (95% CI 0.56-1.59) compared to the group with wild-type EGFR and low PD-L1 expression.

Conclusions: PD-1 inhibitors can serve as one of the treatment options for NSCLCs with an EGFR mutation and high PD-L1 expression.
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http://dx.doi.org/10.1007/s00432-020-03329-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810613PMC
January 2021

Eltrombopag olamine for refractory immune-related thrombocytopenia induced by pembrolizumab in a non-small cell lung cancer patient.

Lung Cancer 2020 08 30;146:362-365. Epub 2020 May 30.

Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.

Objectives: Immune checkpoint inhibitors (ICIs) have shown antitumor activity against a wide variety of malignancies. ICI-induced immune-related thrombocytopenia is a rare immune-related adverse event (irAE). Little is known about the treatment of refractory immune-related thrombocytopenia in non-small cell lung cancer (NSCLC) patients treated with pembrolizumab.

Results: We report the case of a patient with advanced NSCLC complicated by pembrolizumab-induced refractory immune-related thrombocytopenia who showed remarkable improvement in the thrombocytopenia in response to eltrombopag olamine treatment.

Conclusion: Eltrombopag olamine can be a viable treatment option for refractory pembrolizumab-induced immune-related thrombocytopenia in an NSCLC patient.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.015DOI Listing
August 2020

Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial.

Lancet Oncol 2020 06;21(6):843-850

Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. Electronic address:

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.
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http://dx.doi.org/10.1016/S1470-2045(20)30162-5DOI Listing
June 2020

Polypharmacy as a prognostic factor in older patients with advanced non-small-cell lung cancer treated with anti-PD-1/PD-L1 antibody-based immunotherapy.

J Cancer Res Clin Oncol 2020 Oct 27;146(10):2659-2668. Epub 2020 May 27.

Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1Tsukiji, Chuo, Tokyo, 105-0045, Japan.

Purpose: Polypharmacy is a common problem among older adults. However, its prevalence and impact on the clinical outcomes of anticancer treatment, such as survival and adverse events, in older patients with advanced cancer have not been well investigated.

Methods: We retrospectively reviewed data from Japanese patients treated with an immune checkpoint inhibitor (ICI) for advanced or recurrent non-small-cell lung cancer (NSCLC) between 2016 and 2019.

Results: Among 157 older (aged ≥ 65 years) patients, the prevalence of polypharmacy, defined as ≥ 5 medications, was 59.9% (94/157). The prevalence of potentially inappropriate medication use, according to the screening tool of older people's prescription (STOPP) criteria version 2, was 38.2% (60/157). The median progression-free survival (PFS) in patients with and without polypharmacy was 3.7 and 5.5 months, respectively (P = 0.0017). The median overall survival (OS) in patients with and without polypharmacy was 9.5 and 28.1 months, respectively (P < 0.001). Multivariate analysis revealed marked associations between polypharmacy and OS, but no significant associations between polypharmacy and PFS. Polypharmacy was not associated with immune-related adverse events but was associated with higher rate of unexpected hospitalizations during ICI treatment (59.6% vs. 31.7%, P < 0.001).

Conclusion: Polypharmacy is an independent prognostic factor in older patients with advanced NSCLC treated with ICI. Also, polypharmacy could be utilized as a simple indicator of patients' comorbidities and symptoms or as a predictive marker of unexpected hospitalizations during ICI treatment.
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http://dx.doi.org/10.1007/s00432-020-03252-4DOI Listing
October 2020

Efficacy of immune checkpoint inhibitor monotherapy for patients with massive non-small-cell lung cancer.

J Cancer Res Clin Oncol 2020 Nov 27;146(11):2957-2966. Epub 2020 May 27.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo, 113-8677, Japan.

Purpose: Baseline tumor size (BTS) and the presence of massive lesions are important for predicting the clinical course of cancer. However, their impact on survival and clinical response in patients with advanced NSCLC undergoing immune checkpoint inhibitor (ICI) treatment has been scarcely investigated.

Methods: We retrospectively reviewed 294 patients who underwent ICI therapy for advanced or recurrent non-small-cell lung cancer (NSCLC) between January 2016 and July 2019.

Results: Of these 294 patients, 284 (96.6%) had at least one measurable lesion. Of these, 263 patients treated with ICI monotherapy were included in the analysis. The median total and maximum target lesion diameters were 96.5 mm and 49.1 mm, respectively. Median progression-free survival (PFS) with massive lesions (max BTS > 50 mm, group A) and without massive lesions (max BTS ≤ 50 mm, group B) was 2.5 months (95% CI 1.8-3.7) and 6.7 months (95% CI 5.1-9.7), respectively. Median overall survival (OS) for groups A and B was 9.5 months (95% CI 5.5-12.3) and 20.0 months (95% CI 13.3-32.0), respectively. The multivariate analysis revealed marked associations between the presence of massive lesions and both PFS and OS.

Conclusion: The presence of massive lesions (max diameters > 50 mm) is an independent prognostic factor in advanced NSCLC treated with ICI monotherapy. Although overall response rates were similar between groups A and B, the disease control rate was significantly poorer for group A. Max BTS might be useful for predicting clinical outcomes for patients undergoing immunotherapy as a parameter reflecting their tumor burden.
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http://dx.doi.org/10.1007/s00432-020-03271-1DOI Listing
November 2020

A randomized phase III study comparing continuation and discontinuation of PD-1 pathway inhibitors for patients with advanced non-small-cell lung cancer (JCOG1701, SAVE study).

Jpn J Clin Oncol 2020 Jul;50(7):821-825

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

The development of PD-1 pathway inhibitors has dramatically altered the treatment of advanced/recurrent non-small-cell lung cancer patients. However, the prognostic significance of their ongoing usage is controversial, especially for patients who have not progressed for a period of time. If discontinuation has no negative impact on survival, suspension may reduce side effects from toxicity and help alleviate the economic burdens on health insurance systems and patients. This randomized controlled trial enrolls patients who have responded well to PD-1 pathway inhibitors for >12 months. The aim is to confirm the non-inferiority of discontinuation of PD-1 pathway inhibitors, relative to continuation, in terms of overall survival. A total of 216 patients will be enrolled over 3 years. This trial has been registered in the Japan Registry for Clinical Trials as jRCT1031190032 (https://jrct.niph.go.jp/). An ancillary study examining the prognostic and predictive role of circulating tumor DNA using Guardant360® is planned.
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http://dx.doi.org/10.1093/jjco/hyaa054DOI Listing
July 2020

High Serum OX40 and OX40 Ligand (OX40L) Levels Correlate with Reduced Survival in Patients with Advanced Lung Adenocarcinoma.

Oncology 2020 25;98(5):303-310. Epub 2020 Feb 25.

Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Introduction: Interaction of OX40 and OX40 ligand (OX40L) is associated with immune activation. OX40-OX40L axis is also suggested to play a role in immunity against several solid malignancies.

Objective: In this study, serum OX40 and OX40L levels in patients with advanced lung adenocarcinoma were assessed and their correlation with survival and clinicopathologic parameters was determined.

Methods: Serum samples were collected from patients with advanced lung adenocarcinoma, then OX40 and OX40L were quantified via enzyme-linked immunosorbent assay. Immunohistochemical (IHC) analysis of OX40 and OX40L in resected primary lesions was also performed. The association between OX40 and OX40L levels and clinicopathologic status and patient survival was retrospectively analyzed.

Results: A total of 56 patients were analyzed. Median serum OX40 and OX40L levels were 156.2 pg/mL and 186.6 pg/mL, respectively. IHC analysis in 5 patients indicated high positivity of OX40 in tumor-infiltrating lymphocytes and of OX40L in tumor cells in mucinous adenocarcinoma. Patients with a high OX40 level (≥152.2 pg/mL) had poorer prognosis than those with a low serum OX40 level (median survival, 7.36 vs. 21.19 months, respectively, p = 0.04). Patients with a high OX40L level (≥207.3 pg/mL) had poorer prognosis than those with a low serum OX40L level (median survival, 7.36 vs. 14.26 months, respectively, p = 0.04). In the subset of patients treated with immune checkpoint inhibitors (ICIs) (n = 12), those with a high OX40L level were found to have longer survival from ICI initiation than those with a low OX40L level (p = 0.023).

Conclusions: High OX40 and OX40L levels are associated with poor prognosis and may reflect the immune-exhausted status against lung adenocarcinoma.
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http://dx.doi.org/10.1159/000505975DOI Listing
May 2020

The efficacy of immune checkpoint inhibitors in advanced non-small-cell lung cancer with liver metastases.

J Cancer Res Clin Oncol 2020 Mar 11;146(3):777-785. Epub 2019 Dec 11.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo, Tokyo, 113-0022, Japan.

Objectives: Although liver metastasis has been known to be associated with poor prognosis, only a few studies have shown an association between liver metastasis and treatment outcomes with immune checkpoint inhibitors (ICI). Furthermore, factors associated with prognosis have remained unclear. The present study therefore evaluates the efficacy of nivolumab, pembrolizumab, and atezolizumab among patients with non-small cell lung cancer (NSCLC) who had liver metastasis and identifies factors correlated with prognosis.

Materials And Methods: A total of 215 patients with advanced and recurrent NSCLC who received ICI therapy at a single center were retrospectively reviewed. A total of 41 patients (19.1%) had liver metastasis upon initiation of ICI therapy. Overall, 125, 64, and 26 patients were treated with nivolumab, pembrolizumab, and atezolizumab, respectively.

Results: Among the included patients, those with liver metastasis had shorter overall survival (OS) [hazard ratio (HR), 2.04; 95% CI 1.33-3.13] and progression-free survival (PFS) (HR, 1.89; 95% CI 1.29-1.71) compared to those without the same. Patients with liver metastasis had a response rate (RR) of 22.5%. Among patients with liver metastasis, inferior OS was associated with low albumin, poor Eastern Cooperative Oncology Group performance status, driver mutation, and number of liver metastasis (≥ 5). Moreover, patients with liver metastasis who had good Royal Marsden Hospital (0-1) and Gustave Roussy Immune (0-1) scores showed significantly longer OS and PFS.

Conclusion: Despite the poor outcomes with ICI treatment in patients with advanced and recurrent NSCLC who had liver metastasis, some characteristics among patients with liver metastasis may be associated with prognosis.
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http://dx.doi.org/10.1007/s00432-019-03104-wDOI Listing
March 2020

Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

Oncologist 2020 04 26;25(4):e668-e674. Epub 2019 Nov 26.

Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Background: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma.

Material And Methods: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records.

Results: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively).

Conclusion: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study.

Implications For Practice: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.
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http://dx.doi.org/10.1634/theoncologist.2019-0593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160416PMC
April 2020

Retrospective analysis of docetaxel in combination with ramucirumab for previously treated non-small cell lung cancer patients.

Transl Lung Cancer Res 2019 Aug;8(4):450-460

Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram.

Methods: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018.

Results: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041).

Conclusions: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients.
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http://dx.doi.org/10.21037/tlcr.2019.08.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749132PMC
August 2019

High Serum Soluble CD27 Level Correlates with Poor Performance Status and Reduced Survival in Patients with Advanced Lung Cancer.

Oncology 2019 18;97(6):365-372. Epub 2019 Sep 18.

Department of Pathology, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan.

Introduction: Soluble CD27 (sCD27) is associated with somatic immune reaction status. Moreover, sCD27 level is associated with the prognosis of patients with prostate cancer who receive immunotherapy.

Objective: In this study, we assessed sCD27 levels in patients with advanced lung cancer and determined their correlation with survival and clinicopathologic parameters.

Methods: Serum samples were collected from patients with advanced lung cancer, and sCD27 was quantified via enzyme-linked immunosorbent assay. The association between sCD27 levels and clinicopathologic status and patient survival was retrospectively analyzed.

Results: Of 96 patients analyzed, 73 had adenocarcinoma, 7 had squamous cell carcinoma, and 15 had small cell carcinoma. Median serum sCD27 level was 36.54 U/mL (range, undetectable-104.47); this is lower than that previously reported for patients with lung cancer, including those with localized stages. Patients with squamous cell carcinoma had higher sCD27 levels (p = 0.010). Age, performance status, and serum albumin levels were significantly correlated with serum sCD27 level. Patients with high serum sCD27 levels (≥32.52 U/mL; n = 58) had poorer prognosis than those with low serum sCD27 levels (<32.52 U/mL, n = 38; median survival, 7.3 vs. 21.8 months, respectively, p< 0.0001).

Conclusions: High sCD27 level is associated with poor prognosis and may reflect the immune-exhausted status of patients with advanced lung cancer.
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http://dx.doi.org/10.1159/000502441DOI Listing
December 2019

Management of non-small cell lung cancer harboring epidermal growth factor receptor mutations in the era of first-line osimertinib.

J Thorac Dis 2019 Jul;11(7):2664-2668

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan.

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http://dx.doi.org/10.21037/jtd.2019.06.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687974PMC
July 2019

Impact of clinical features on the efficacy of osimertinib therapy in patients with T790M-positive non-small cell lung cancer and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors.

J Thorac Dis 2019 Jun;11(6):2350-2360

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital, Bunkyo, Tokyo, Japan.

Background: Osimertinib exhibits good efficacy in patients with T790M-positive non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Compared with the clinical trials, in real-world clinical practice, osimertinib must be administered to older patients and those with poor Eastern Cooperative Oncology Group performance status (ECOG-PS). Therefore, we investigated the association between osimertinib efficacy/safety and PS score, age, and other clinical features in patients with T790M-positive NSCLC.

Methods: We reviewed all patients with T790M-positive NSCLC and acquired resistance to initial EGFR-TKIs who were administered osimertinib between March 2016 and January 2018 at the Tokyo Metropolitan Cancer and Infectious Diseases Center in Komagome Hospital, Japan.

Results: In total, 31 patients, including 8 young (<65 years) and 23 elderly (≥65 years) patients, were included in the study. Of these, 10 (32.3%) patients had poor PS scores. The progression-free survival (PFS) was significantly shorter in young patients was than elderly patients [3.5 6.4 months, P=0.041; hazard ratio (HR), 2.41]. The overall survival (OS) of the young patients tended to be shorter than that of the elderly patients (5.3 19.4 months, P=0.067; HR, 2.58). The PFS (9.1 5.5 months; P=0.071; HR, 0.38) and the OS (not reached 6.6 months, P=0.061; HR, 0.39) were shorter in patients with poor ECOG-PS than those with good ECOG-PS. The toxic effects of osimertinib were manageable. By multivariate analysis, both age and ECOG-PS were independent predictors of osimertinib efficacy.

Conclusions: Poor ECOG-PS and younger age were associated with lower efficacy of osimertinib in T790M-positive NSCLC.
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http://dx.doi.org/10.21037/jtd.2019.06.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626778PMC
June 2019

Correlation between the qualification for bevacizumab use and the survival of patients with non-small cell lung cancer harboring the epidermal growth factor receptor mutation: a retrospective analysis.

J Cancer Res Clin Oncol 2019 Oct 26;145(10):2555-2564. Epub 2019 Jul 26.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo, 113-8677, Japan.

Purpose: Previously, the combination of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and bevacizumab (BEV) was investigated. A subgroup analysis of the IMpower150 trial, which investigated the combination of atezolizumab, carboplatin, paclitaxel, and bevacizumab (ABCP), demonstrated the benefit of ABCP in patients harboring EGFR mutations. This study aims to assess the prognostic significance of the qualification for BEV use and the proportion of patients who potentially benefit from BEV-containing combination therapy before and after initial EGFR-TKI treatment.

Methods: We retrospectively analyzed the data of 297 patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations who had received EGFR-TKIs. We performed statistical analyses using the Kaplan-Meier method and the Cox regression adjusted for risk factors.

Results: Of the 297 patients, 203 (68%) were eligible to receive BEV ("BEV fit") at the time of EGFR-TKI initiation. Among the "BEV unfit" patients at baseline (n = 70), 14 (20%) became eligible to receive ABCP ("ABCP fit") at the time of EGFR-TKI failure. The median overall survival (OS) of the "BEV fit" and "BEV unfit" patients was 26.2 [95% confidence interval (CI) 23.7-31.2] and 19.1 (95% CI 15.0-25.1) months, respectively (P < 0.001). The multivariate analysis revealed a marked correlation between survival and the qualification for BEV use.

Conclusions: The qualification for BEV use at baseline is independently related to the OS. Some patients harboring EGFR mutations, including those who were "BEV unfit" at baseline, could be eligible for the ABCP regimen after EGFR-TKI treatment.
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http://dx.doi.org/10.1007/s00432-019-02985-1DOI Listing
October 2019

Radiographic Assessment of Objective Responses Using the ITMIG-Modified Criteria in Thymic Carcinoma.

Oncology 2019 15;97(5):264-269. Epub 2019 Jul 15.

Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.

Introduction: Pleural metastases are common among patients with thymic carcinoma. Accurate and consistent measurement of pleural lesions is often difficult because of their unique locations and growth patterns. To minimize intraobserver variability, the International Thymic Malignancies Interest Group (ITMIG) proposed modified criteria for measurement of tumor response for thymic epithelial tumors.

Methods: We conducted a retrospective review of the medical records of advanced or recurrent thymic carcinoma patients treated with chemotherapy between 1980 and 2016 in our institution. The best objective responses were assessed using the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) and the ITMIG-modified criteria.

Results: A total of 26 patients were included in the present study. According to the RECIST criteria, 1 (3.8%) patient showed complete response (CR), and 13 (50.0%), 10 (38.5%), and 2 (7.7%) showed partial response (PR), stable disease (SD), and progressive disease (PD), respectively. All 26 patients had the same best overall response using the ITMIG criteria. The median time to progression (TTP) according to the RECIST criteria and the ITMIG-modified criteria was 5.5 months (95% confidence interval [CI] 3.8-8.6) and 7.0 months (95% CI 3.8-9.3), respectively (p = 0.993).

Conclusion: The ITMIG-modified criteria showed a high concordance rate with RECIST 1.1 criteria in response assessment of thymic carcinoma.
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http://dx.doi.org/10.1159/000501104DOI Listing
November 2019

Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202).

Jpn J Clin Oncol 2019 Aug;49(8):749-754

Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo.

Background: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine.

Methods: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1-14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4-6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL).

Results: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9-8.7), 21.4 months (95% CI: 14.7-not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen.

Conclusions: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.
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http://dx.doi.org/10.1093/jjco/hyz064DOI Listing
August 2019

The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV.

Int J Clin Oncol 2019 Jul 2;24(7):731-770. Epub 2019 May 2.

Shizuoka Cancer Center, Shizuoka, Japan.

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.
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http://dx.doi.org/10.1007/s10147-019-01431-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545178PMC
July 2019