Publications by authors named "Yukio Hosomi"

106 Publications

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

A Case of Cytokine Release Syndrome Induced by Immune-checkpoint Inhibitor Therapy for Non-small-cell Lung Cancer.

Intern Med 2021 Mar 29. Epub 2021 Mar 29.

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

Immune-related adverse events, including autoimmune toxicity, may develop as a consequence of immune-checkpoint inhibitor (ICI) cancer therapy. Cytokine release syndrome (CRS) is a severe and life-threatening cytokine-associated toxicity that can develop after adoptive T-cell therapy. We herein report a rare case of severe CRS after ICI therapy for advanced non-small-cell lung cancer. He presented with a prolonged high fever, cardiogenic shock, and disseminated intravascular coagulation after the first course of programed death ligand-1 inhibitor and platinum-based doublet chemotherapy. He recovered by steroid pulse therapy and tocilizumab. CRS is a rare but life-threatening adverse event of ICI therapy and therefore warrants awareness.
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http://dx.doi.org/10.2169/internalmedicine.5922-20DOI Listing
March 2021

A case series on the safety of immunotherapy with reduced blood testing frequency in lung cancer patients.

Int J Clin Oncol 2021 Mar 3. Epub 2021 Mar 3.

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

Background: The necessity of regular blood tests with the administration of immune checkpoint inhibitors has not been investigated. This study examined the safety of omitting a blood test every 2 weeks for patients with lung cancer who were injected an immune checkpoint inhibitor.

Methods: We conducted a retrospective review of the medical records of 201 patients diagnosed with lung cancer and administered with nivolumab or durvalumab between December 1, 2015, and February 30, 2020, in a single hospital. We extracted 16 patients who had treatments without blood testing every 2 weeks.

Results: Adverse events that resulted in discontinued treatment included two cases of interstitial pneumonia, one case of creatinine increase, and one infection. All four cases were detected by chest X-ray or their symptoms.

Conclusions: Our results indicate that immune checkpoint inhibitor administration without a blood test every 2 weeks did not subject patients to more adverse side effects.
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http://dx.doi.org/10.1007/s10147-021-01865-4DOI Listing
March 2021

Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer.

Cancer Med 2021 Jan 14;10(2):626-633. Epub 2020 Dec 14.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.

Cisplatin-based chemoradiotherapy is considered standard treatment for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study examined two regimens of chemotherapy in concurrent chemoradiation. Eligible patients with unresectable, radically irradible LA-NSCLC were randomized to either the SP (S-1 and cisplatin) or DP (docetaxel and cisplatin) arms with concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival (OS) rate at 2 years (the 2-year OS rate). From May 2011 to August 2014, 110 patients were enrolled. Of 106 eligible patients, the 2-year OS rates were 79% (95% CI: 66%-88%) and 69% (95% CI: 55%-80%) the SP and DP arms, respectively. The median progression-free survival was 11.6 months for the SP arm and 19.9 months for the DP arm, while the median survival time was 55.2 months for the SP arm and 50.8 months for the DP arm. Grade 3/4 leukopenia were more frequent in DP arm. The incidences of febrile neutropenia and pneumonitis tended to be higher in DP arm. There were no treatment-related deaths in either arm. The primary endpoint was met in both arms. The SP arm as a future reference regimen will be chosen due to fewer toxicities and better OS.
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http://dx.doi.org/10.1002/cam4.3641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877366PMC
January 2021

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

Cancer Sci 2021 Jan 30;112(1):388-396. Epub 2020 Nov 30.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.
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http://dx.doi.org/10.1111/cas.14730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780021PMC
January 2021

Polypharmacy among older advanced lung cancer patients taking EGFR tyrosine kinase inhibitors.

J Geriatr Oncol 2021 Jan 17;12(1):64-71. Epub 2020 Sep 17.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo 113-0021, Japan.

Objective: Polypharmacy (PP) is a common problem among the older adults and has a potential effect on health-related problems. However, the significance of PP in older advanced non-small cell lung cancer (NSCLC) patients and those on oral molecular-targeted anticancer agents is unclear.

Materials And Methods: This retrospective, nonrandomized study reviewed the records of 334 advanced NSCLC patients who underwent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. PP was defined as ≥ 5 concomitant medications. Potentially inappropriate medication (PIM) use was measured using the updated screening tool of older people's prescriptions (STOPP) ver. 2 criteria. We also estimated survival distributions using the Kaplan-Meier method, compared between-group differences using the log-rank test, explored potential predictors of survival using Cox regression, and performed cluster analysis to identify factors affecting multiple-medication use.

Results: The PP and PIM use prevalence was 38.4% and 31.9%, respectively. The median overall survival (OS) for PP(+) and PP(-) patients was 19.4 and 27.3 months, respectively. Multivariate analysis revealed a significant correlation between PP and OS. The frequency of unexpected hospitalization during EGFR-TKI treatment was higher in PP(+) patients compared to PP(-) patients (49.4% vs. 29.4%; odds ratio = 2.34).

Conclusion: PP is an independent prognostic factor in older advanced NSCLC patients taking EGFR-TKIs. PP can be used as a simple indicator of such patients' comorbidities and symptoms or as a predictive marker of unexpected hospitalization during treatment.
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http://dx.doi.org/10.1016/j.jgo.2020.09.011DOI Listing
January 2021

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

Phase I/II study of erlotinib plus S-1 for patients with previously treated non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0808/0913.

Invest New Drugs 2021 Feb 15;39(1):202-209. Epub 2020 Aug 15.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan.

Introduction In preclinical data, the combination therapy with S-1 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had a synergistic antitumor effect on non-small cell lung cancer (NSCLC), regardless of the EGFR mutation status. Patients and Methods Patients with previously treated NSCLC and adequate organ function regardless of EGFR mutation status were eligible for the phase I study, with wild-type EGFR were eligible for the phase II study. Treatment consisted of erlotinib 150 mg/body orally once every day and S-1 60 mg/m, 70 mg/m, or 80 mg/m (level 0, level 1, or level 2) orally on days 1-14 every three weeks. The primary endpoint for the phase I study was the determination of the recommended dose (RD), the phase II study was the overall response rate (ORR). Results A total of 7 patients with performance-status (PS) 0 or 1 were enrolled as subjects in phase I. Five of these subjects were EGFR-mutation positive. Four subjects were enrolled at S-1 dose level 1 and 3 were enrolled at S-1 dose level 2. No dose-limiting toxicities were observed in these subjects. The RD was decided as erlotinib 150 mg/body and S-1 80 mg/m. In phase I, 5 subjects achieved partial response, and the ORR was 71.4%. A total of 10 patients with PS 0, 1, or 2 EGFR-wild type NSCLC were enrolled in phase II. In phase II, the ORR was 10.0%, and the disease control rate (DCR) was 40.0%. After the enrollment of 10 subjects, enrollment was stopped based on two treatment-related deaths. Conclusion The combination therapy of erlotinib plus S-1 was not feasible in the EGFR wild-type NSCLC at least and early stopped. Trial registration: UMIN-CTR Identifier: 000003421 (2010/03/31, phase I), 000003422 (2010/03/31, Phase II).
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http://dx.doi.org/10.1007/s10637-020-00985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851018PMC
February 2021

Phase I/II study of carboplatin plus weekly nab-paclitaxel in patients aged ≥75 years with squamous-cell lung cancer: TORG1322.

Lung Cancer 2020 08 19;146:182-188. Epub 2020 May 19.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Objectives: This phase I/II study assessed the efficacy and safety of combination therapy with carboplatin (CBDCA) and nab-paclitaxel (nab-PTX) in advanced elderly patients (aged ≥75 years) with advanced squamous cell lung cancer (SqCLC).

Materials And Methods: In this phase I study, the doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL/min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m) on days 1, 8, and 15 every 4 weeks for up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6 m PFS) rate.

Results: A total of 46 patients were enrolled in this study. Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia; at dose level 2, 1/3 patient exhibited grade 3 anorexia as a DLT. The recommended dose was determined to be level 2. Efficacy was then evaluated in 39 patients enrolled in a phase II study. The median number of cycles was 4 (range, 1-6), and the median follow-up time was 17.5 months (range, 5.6-28.9 months). The 6 m PFS rate was 59.4% (90% confidence interval [CI], 44.8%-71.4%), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6-35.4), and the median PFS was 6.8 months (95% CI, 5.4-9.1). The response rate was 54%, and the disease control rate was 92%. Sixteen patients (41%) received immune checkpoint inhibitors post-study. Common grade 3 or 4 toxicities were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%).

Conclusion: Combination chemotherapy consisting of CBDCA with weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly patients (aged ≥75 years) with advanced SqCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.005DOI Listing
August 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

Switching administration of anti-PD-1 and anti-PD-L1 antibodies as immune checkpoint inhibitor rechallenge in individuals with advanced non-small cell lung cancer: Case series and literature review.

Thorac Cancer 2020 07 18;11(7):1927-1933. Epub 2020 May 18.

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

Background: Based on several phase III studies, immune checkpoint inhibitors (ICIs) are essential and promising drugs for the treatment of non-small cell lung cancer (NSCLC). However, in patients previously treated with ICI, the efficacy and safety of rechallenging the same or another type of ICI inhibitor remain unclear. Moreover, clinical data about the efficacy of switching the administration of anti-programmed death-1 (PD-1) antibodies (e.g. nivolumab, pembrolizumab) and anti-programmed death-ligand 1 (PD-L1) antibodies (e.g. atezolizumab) as ICI rechallenge are limited. Thus, the current study aimed to evaluate the efficacy and safety of such treatment strategy in NSCLC patients.

Methods: We retrospectively reviewed the medical records of 17 patients with advanced or recurrent NSCLC who received both anti-PD-1 and anti-PD-L1 antibodies during their clinical courses.

Results: Among the 17 patients, one (5.9%) and nine (52.9%) achieved partial response and stable disease, respectively, after ICI rechallenge. The median progression-free survival of ICI rechallenge in these patients was 4.0 (range: 0.4-8.0) months, and the median overall survival from the start of the initial ICI was 31.0 (range: 7.6-46.8) months. Of the 10 patients who developed immune-related adverse events (irAEs) during the first ICI treatment, five presented with these events after the readministration of ICI. Among them, four experienced relapsed irAEs and two patients had pneumonitis, which is a grade 3 or higher irAE. Almost all irAEs during the rechallenge treatment were manageable.

Conclusions: Switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be a treatment option for some NSCLC patients.

Key Points: • Significant findings of the study In this study, switching the administration of anti-PD-1 and anti-PD-L1 antibodies as ICI rechallenge could be an effective and safe treatment option for some patients with advanced or recurrent NSCLC. • What this study adds Switching the administration of ICI may increase the efficacy of readministration. However, the mechanism is unknown. Thus, further accumulation of cases is required, and extensive investigations must be conducted to elucidate the mechanism and benefits of such treatment.
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http://dx.doi.org/10.1111/1759-7714.13483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327670PMC
July 2020

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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http://dx.doi.org/10.1001/jamaoncol.2020.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226294PMC
July 2020

Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 05 14;6(5):e196828. Epub 2020 May 14.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.

Importance: Few clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.

Objective: To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.

Design, Setting, And Participants: This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.

Interventions: Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.

Main Outcomes And Measures: The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.

Results: Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.

Conclusion And Relevance: Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.

Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.
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http://dx.doi.org/10.1001/jamaoncol.2019.6828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068674PMC
May 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

A phase I and extension study of S-1 and carboplatin for previously untreated patients aged 75 years or more with advanced non-small cell lung cancer -TCOG 1101.

Int J Clin Oncol 2020 May 14;25(5):867-875. Epub 2020 Feb 14.

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

Purpose: Combination carboplatin and S-1 is active in the treatment of non-small cell lung cancer (NSCLC). However, data on this combination for elderly patients with NSCLC are insufficient.

Methods: Eligibility criteria were no prior chemotherapy, Stage IIIB or IV NSCLC, performance status 0-1, age ≥ 75 years, and adequate hematological, hepatic, and renal functions. Carboplatin was administered on day 1 and S-1 was administered orally, twice a day, between days 1 and 14, repeated every 3 weeks. In phase I, the primary purpose was determination of the recommended dose. Starting doses of carboplatin and S-1 were area under the curve (AUC) of 4 and 80 mg/m/day, respectively. In the extension study, the effects and tolerability of this combination therapy of recommended dose were confirmed.

Results: A total of 10 patients were entered into phase I and 14 patients were entered into the extension study. The recommended doses for this drug combination are AUC 5 for carboplatin and 80 mg/m/day every 3 weeks for S-1. With carboplatin and S-1 combination therapy at the recommended dose, the response rate was 30.0% [95% confidence interval (CI) 12-54%] and the disease control rate was 90.0% (95% CI 68-99%). Thrombocytopenia and neutropenia were major adverse events.

Conclusions: The recommended doses for this combination therapy are carboplatin AUC 5 and S-1 80 mg/m/day every 3 weeks, and this combination is effective with tolerable toxicities for advanced NSCLC patients ≥ 75 years old.
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http://dx.doi.org/10.1007/s10147-020-01629-6DOI 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

Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study.

J Clin Oncol 2020 01 4;38(2):115-123. Epub 2019 Nov 4.

Tohoku University School of Medicine, Sendai, Japan.

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor combined with cytotoxic chemotherapy is highly effective for the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, little is known about the efficacy and safety of this combination compared with that of standard therapy with EGFR- tyrosine kinase inhibitors alone.

Methods: We randomly assigned 345 patients with newly diagnosed metastatic NSCLC with EGFR mutations to gefitinib combined with carboplatin plus pemetrexed or gefitinib alone. Progression-free survival (PFS), PFS2, and overall survival (OS) were sequentially analyzed as primary end points according to a hierarchical sequential testing method. Secondary end points were objective response rate (ORR), safety, and quality of life.

Results: The combination group demonstrated a better ORR and PFS than the gefitinib group (ORR, 84% 67% [ < .001]; PFS, 20.9 11.9 months; hazard ratio for death or disease progression, 0.490 [ < .001]), although PFS2 was not significantly different (20.9 18.0 months; = .092). Median OS in the combination group was also significantly longer than in the gefitinib group (50.9 38.8 months; hazard ratio for death, 0.722; = .021). The rate of grade ≥ 3 treatment-related adverse events, such as hematologic toxicities, in the combination group was higher than in the gefitinib group (65.3% 31.0%); there were no differences in quality of life. One treatment-related death was observed in the combination group.

Conclusion: Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR mutations with an acceptable toxicity profile, although its OS benefit requires further validation.
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http://dx.doi.org/10.1200/JCO.19.01488DOI Listing
January 2020

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

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Mol Clin Oncol 2019 Oct 23;11(4):349-353. Epub 2019 Jul 23.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa 240-8555, Japan.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20-30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92-133 days], and the median number of ZA administrations was 4 (range, 2-41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156-264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.
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http://dx.doi.org/10.3892/mco.2019.1903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713944PMC
October 2019

Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.

Lung Cancer 2019 09 8;135:188-195. Epub 2019 Jul 8.

Sylvester Comprehensive Cancer Center at the University of Miami, 1475 NW 12th Ave, Miami, FL 33136, USA. Electronic address:

Objectives: Most lung cancer diagnoses occur in elderly patients, who are underrepresented in clinical trials. We present a pooled analysis of safety and efficacy in elderly patients (≥75 years) who received pembrolizumab (a programmed death 1 inhibitor) for advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1)‒positive tumors.

Methods: The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894) studies. In KEYNOTE-010, patients were randomized to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel, as second- or later-line therapy. In KEYNOTE-024 and KEYNOTE-042, patients were randomized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy. Overall survival (OS) was estimated by the Kaplan-Meier method, and safety data were summarized in elderly patients (≥75 years).

Results: The analysis included 264 elderly patients with PD-L1-positive tumors (PD-L1 tumor proportion score [TPS] ≥1%); among these, 132 had PD-L1 TPS ≥ 50%. Pembrolizumab improved OS among elderly patients with PD-L1 TPS ≥ 1% (hazard ratio [HR], 0.76 [95% CI, 0.56-1.02]) and PD-L1 TPS ≥ 50% (HR, 0.40 [95% CI, 0.25-0.64]). Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50% (from KEYNOTE-024 and KEYNOTE-042) compared with chemotherapy (HR, 0.41 [95% CI, 0.23‒0.73]). Pembrolizumab was associated with fewer treatment-related adverse events (AEs) in elderly patients (overall, 68.5% vs 94.3%; grade ≥3, 24.2% vs 61.0%) versus chemotherapy. Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy (overall, 24.8% vs 6.7%; grade 3‒4: 9.4% vs 0%; no grade 5 events).

Conclusions: In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors, pembrolizumab improved OS versus chemotherapy, with a more favorable safety profile. Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall populations in the individual studies.
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http://dx.doi.org/10.1016/j.lungcan.2019.07.004DOI Listing
September 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

Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: A multicenter, open-label single-arm phase II trial.

Lung Cancer 2019 08 3;134:274-278. Epub 2019 Jun 3.

Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.

Objectives: The efficacy of nivolumab against metastatic non-small cell lung cancer (NSCLC) has been demonstrated; however, pneumonitis is relatively common and is a potentially life-threatening immune-related adverse event. Patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis and are generally excluded from clinical trials. Additionally, to date, a multicenter prospective trial for previously-treated NSCLC patients with IIP has not been performed. To fulfill this unmet medical need, we conducted a multicenter, open-label single-arm phase II trial to evaluate the efficacy and safety of nivolumab in NSCLC patients with mild IIP.

Materials And Methods: Eligible patients had previously-treated, inoperable NSCLC with mild IIPs. Mild IIP was defined as a predicted vital capacity of at least 80% and possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern by chest high-resolution computed tomography. Primary end point was the 6 months PFS rate and secondary end point was the safety of this therapy.

Results: Eighteen patients were enrolled in this trial. Six months PFS rate was 56%, response rate was 39%, and disease control rate was 72%. There were no treatment-related deaths. One drug-related grade 3/4 nonhematologic event (grade 3 neurotoxicity) was observed. Two patients had grade 2 pneumonitis which improved by corticosteroid therapy.

Conclusions: Nivolumab could be an effective therapy for NSCLC patients with mild IIPs.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.001DOI Listing
August 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

A single-arm phase II trial of weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy after standard of chemotherapy for previously treated advanced non-small cell lung cancer.

Cancer Chemother Pharmacol 2019 08 16;84(2):351-358. Epub 2019 Apr 16.

Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital, Honkomagome 3-18-22, Bunkyo, Tokyo, 113-0021, Japan.

Background: Few studies have investigated the clinical efficacy of third- and later-line of chemotherapy after standard chemotherapy for previously treated advanced non-small cell lung cancer (NSCLC). We prospectively evaluated the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) following standard chemotherapies for previously treated advanced NSCLC.

Methods: The eligible patients having adequate organ functions with performance status 0-2 were enrolled after completing standard chemotherapy. They received weekly nab-paclitaxel 100 mg/m intravenously on days 1, 8, and 15 every 3 weeks. The primary end point was objective response rate (ORR). Median progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated as secondary end points.

Results: This trial was discontinued because of late accrual. Twenty two patients were enrolled from April 2013 and February 2019. The total ORR was 22.7% [95% CI 7.8-45.4] and disease control rate (DCR) was 81.8% [95% CI 59.7-94.8]. Median PFS was 3.4 months [95% CI 2.3-4.1] and median OS was 7.4 months [95% CI 4.2-10.7]. Median follow-up interval was 6.7 months hematological AEs of Grade 3/4 included anemia (18%), leukopenia (18%), and neutropenia (32%), while the most frequent nonhematological AEs were fatigue (50%) and peripheral neuropathy (36.4%). Severe AEs related to treatment were observed in only one patient.

Conclusion: Nab-paclitaxel may be a safe and effective later-line chemotherapeutic option for previously treated advanced NSCLC after standard of chemotherapies based on other trials.
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http://dx.doi.org/10.1007/s00280-019-03843-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647220PMC
August 2019

Single-arm, multicentre, phase II trial of nivolumab for unresectable or recurrent thymic carcinoma: PRIMER study.

Eur J Cancer 2019 05 13;113:78-86. Epub 2019 Apr 13.

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

Introduction: Thymic carcinoma (TC) is a rare cancer with a poor prognosis and limited treatment options, especially after relapse.

Methods: In this open-label, two-stage, multicentre, single-arm and phase II trial, the main eligibility criteria were unresectable or recurrent TC, an Eastern Cooperative Oncology Group-performance status of 0 or 1, progression after at least one chemo(radio)therapy and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary end-point was response rate (RR) as evaluated by central review using Response Evaluation Criteria In Solid Tumours (RECIST), version 1.1. The planned sample size was 15 for each stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%.

Results: Between July 1 and August 16 2016, 15 patients were accrued in the first stage. Response was assessable in all patients, and 13 had squamous histology. Median follow-up time was 14.1 months (range: 2.4-17.5). The median number of nivolumab received was eight (range: 3-33). RR was 0% (95% confidential interval [CI]: 0-21.8). Eleven patients had stable disease (SD) including five patients with SD for 24 or more weeks. Median progression-free survival was 3.8 months (95% CI: 1.9-7.0). Two patients experienced immune-related serious adverse events (grade III aspartate aminotransferase (AST) increase and grade II adrenal insufficiency). Because the early termination criteria (less than one responder) were fulfilled during the first stage, the patient accrual was terminated.

Conclusions: Despite the small number of patients, nivolumab was unable to produce tumour shrinkage by RECIST in previously treated unresectable or recurrent TC.
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http://dx.doi.org/10.1016/j.ejca.2019.03.012DOI Listing
May 2019