Publications by authors named "Yuichiro Ohe"

288 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

Savolitinib ± Osimertinib in Japanese Patients with Advanced Solid Malignancies or EGFRm NSCLC: Ph1b TATTON Part C.

Target Oncol 2021 May 3;16(3):339-355. Epub 2021 May 3.

Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Preliminary data suggest that combining savolitinib, a potent and highly selective MET-tyrosine kinase inhibitor (TKI), with osimertinib, a third-generation, irreversible, oral epidermal growth factor receptor-TKI (EGFR-TKI), may overcome MET-based resistance to EGFR-TKIs.

Objective: To investigate the safety and tolerability of savolitinib in Japanese patients with advanced solid malignancies.

Patients And Methods: In Part C of the phase Ib, multi-arm, open-label, multicenter TATTON study, two cohorts of Japanese adult patients were evaluated across six study centers in Japan. Patients with advanced solid malignancies received oral savolitinib monotherapy 400 mg once daily (qd), escalating to 600 mg; patients with advanced EGFR mutation-positive (EGFRm) non-small-cell lung carcinoma (NSCLC) who progressed on prior EGFR-TKI received oral osimertinib 80 mg+savolitinib 300/400/600 mg qd combination therapy. Primary endpoints: safety/tolerability of savolitinib±osimertinib, and maximum tolerated dose(s) (MTD) definition.

Results: Seventeen patients received monotherapy; 12 received combination. Dose-limiting toxicities (DLTs): with monotherapy, 400 mg, none reported; 600 mg, n = 3/9 evaluable patients (33%) reported DLTs (grade 3 and 4 alanine aminotransferase and aspartate transaminase increased, and grade 4 drug-induced liver injury). With combination: 400 mg, 1/6 (17%) reported DLTs (grade 2 fatigue, nausea, and myalgia); 300 mg, none reported; 600 mg, 3/4 (75%) reported DLTs (grade 2 pyrexia, grade 3 skin reaction, and anaphylactic shock). Grade ≥3 adverse events were reported in 41% of patients receiving monotherapy and 33% receiving combination. TATTON is no longer recruiting patients.

Conclusions: The MTD of savolitinib was 400 mg qd in both cohorts. Data demonstrate an acceptable safety profile for savolitinib alone, or with osimertinib.

Trial Registration: Clinicaltrials.gov; NCT02143466; 21 May 2014.
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http://dx.doi.org/10.1007/s11523-021-00806-5DOI Listing
May 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

Peripheral blood biomarkers predict immune-related adverse events in non-small cell lung cancer patients treated with pembrolizumab: a multicenter retrospective study.

J Cancer 2021 16;12(7):2105-2112. Epub 2021 Feb 16.

Division of Pharmaceutical Care Sciences, Center for Social Pharmacy and Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.

Pembrolizumab is currently the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). However, the association between immune-related adverse events (irAEs) and peripheral blood cell counts remains unclear. We aimed at identifying peripheral blood cell counts that may predict the development of pembrolizumab-induced irAEs. We retrospectively analyzed data on consecutive patients with advanced NSCLC who received pembrolizumab monotherapy as first-line or later-line therapy at the National Cancer Center Hospital and Keio University Hospital. We used data between December 2015 and November 2018. The primary endpoint was the relationship between peripheral blood cell count data and early-onset irAEs during the 6-weeks study period. Receiver operating characteristic (ROC) curve and multivariable logistic regression analyses were performed. In total, 92 patients were evaluated, of whom 45 (48.9%) had at least one irAE during the first 6-weeks after treatment initiation. The ROC curves revealed that the optimal cutoff of pretreatment absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) for onset of irAEs were 1459, 2.320, 1.538, and 165, respectively. Multivariable logistic regression analyses revealed that pretreatment ALC>1450 and LMR>1.6 were significantly associated with a reduced risk for onset of any irAEs, whereas pretreatment NLR>2.3 and PLR>165 were significantly associated with an increased risk. The findings suggest that considering the routine availability of blood cell count data before the initiation of treatment with pembrolizumab, it may be useful in identifying early-onset irAEs during the 6-weeks study period in clinical practice.
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http://dx.doi.org/10.7150/jca.53242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974524PMC
February 2021

A multi-institutional randomized phase III study comparing weekly carboplatin plus nab-paclitaxel and daily low-dose carboplatin as regimens for concurrent chemoradiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG1914.

Jpn J Clin Oncol 2021 Apr;51(5):836-841

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

Daily low-dose carboplatin plus concurrent thoracic radiotherapy is the standard treatment for elderly patients with unresectable clinical stage (c-Stage) III non-small cell lung cancer (NSCLC) in Japan. However, a phase I study by Omori et al. suggests that weekly carboplatin and nab-paclitaxel plus concurrent thoracic radiotherapy have comparable efficacy outcomes with more manageable adverse events. In December 2020, we initiated a randomized controlled trial in Japan to confirm whether the weekly carboplatin plus nab-paclitaxel regimen is noninferior to the daily low-dose carboplatin regimen for concurrent chemoradiotherapy in elderly patients with unresectable c-Stage III NSCLC. We plan to enroll 166 patients from 50 institutions in 3.5 years. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, response rate, proportion of patients starting maintenance durvalumab therapy, adverse events, site of progression, Functional Assessment of Cancer Therapy-Trial Outcome Index deterioration and Instrumental Activities of Daily Living deterioration.
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http://dx.doi.org/10.1093/jjco/hyab025DOI 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

Usefulness of Simple Original Interstitial Lung Abnormality Scores for Predicting Radiation Pneumonitis Requiring Steroidal Treatment After Definitive Radiation Therapy for Patients With Locally Advanced Non-Small Cell Lung Cancer.

Adv Radiat Oncol 2021 Jan-Feb;6(1):100606. Epub 2020 Oct 31.

Department of Radiotherapy in National Cancer Center Hospital, Tokyo, Japan.

Purpose: Adjuvant durvalumab has become a standard treatment after chemoradiation therapy for patients with locally advanced non-small cell lung cancer (LA-NSCLC). Accordingly, predicting radiation pneumonitis (RP) requiring steroidal treatment (steroid-RP) is of utmost importance because steroidal administration is reported to weaken the effectiveness of immunotherapy. However, grade 2 RP was used as an index of RP in previous studies, but it is an ambiguous definition because it includes not only steroid-RP but also a mild cough requiring only a cough medicine. Therefore, in this study, steroid-RP was used for evaluating RP, and the purpose of this study was to investigate predictive factors of steroid-RP, including original simple interstitial lung abnormality scores (ILASs).

Methods And Materials: A total of 145 patients with LA-NSCLC who received definitive radiation therapy (DRT) in our institution from January 2014 to May 2017 were identified. Original ILASs, performance status, age, respiratory function, Brinkman index, concurrent administration of chemotherapy, and dose-volume histogram metrics of the lung were analyzed to evaluate their association with steroid-RP. Additionally, 3 diagnostic radiologists evaluated the patients' pre-DRT chest computed tomography images and determined the simple ILASs. ILASs were rated as follows: 0: none; 1: abnormality without honeycombing (ground-glass attenuation, fine reticular opacity, and microcysts); and 2: honeycombing.

Results: The median follow-up period was 729 days. Thirty-one patients (21.4%) experienced steroid-RP. In the univariate analysis, lung V5/V10/VS5, Brinkman index, and ILASs were significant predictive factors of steroid-RP. Additionally, multivariate analysis including Brinkman index ≥840, lung V5 ≥37%, and an ILAS ≥1 revealed that only an ILAS ( = .001) was an independent predictive factor of steroid-RP.

Conclusions: The original simple ILAS was an easy-to-use tool and a significant predictive factor of steroid-RP in DRT in patients with LA-NSCLC.
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http://dx.doi.org/10.1016/j.adro.2020.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897760PMC
October 2020

Reply to J. L. Derks et al.

J Clin Oncol 2021 May 4;39(13):1509-1510. Epub 2021 Mar 4.

Hirotsugu Kenmotsu, MD, PhD, Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi-cho Sunto-gun, Japan; Seiji Niho, MD, PhD, Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan; Masahiro Tsuboi, MD, PhD, Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan; Masashi Wakabayashi, ME, and Junko Eba MD, Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan; Hisao Asamura, MD, PhD, Division of Thoracic Surgery, Keio University School of Medicine, Tokyo, Japan; Yuichiro Ohe, MD, PhD, Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; and Shun-ichi Watanabe, MD, PhD, Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1200/JCO.21.00107DOI Listing
May 2021

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs.

Thorac Cancer 2021 03 20;12(5):631-642. Epub 2021 Jan 20.

Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.

Background: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops.

Methods: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor.

Results: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines.

Conclusions: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.
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http://dx.doi.org/10.1111/1759-7714.13839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919131PMC
March 2021

Exacerbation of atrioventricular block associated with concomitant use of amlodipine and aprepitant in a lung cancer patient: A case report.

Int J Clin Pharmacol Ther 2021 Apr;59(4):328-332

Objective: To report a case of second-degree atrioventricular block associated with concomitant use of aprepitant and amlodipine.

Case: A 73-year-old man with lung cancer was treated with aprepitant for prophylactic use for the prevention of nausea and vomiting, concomitantly with cisplatin, gemcitabine, and an investigational drug (anti-epidermal growth factor receptor monoclonal antibody). He was diagnosed with first-degree atrioventricular block and was taking amlodipine for hypertension. During the first cycle of chemotherapy, 5 days after the start of aprepitant, he experienced Wenckebach second-degree atrioventricular block (Mobitz type I), and amlodipine was discontinued. After day 6, the atrioventricular block was not shown. According to the Naranjo adverse drug reaction scale, a score of 7 was obtained (causality: probable). In addition, using the Drug Interaction Probability Scale, a score of 6 was obtained (causality: probable).

Conclusion: The drug-drug interaction between aprepitant and amlodipine was considered to have deteriorated his atrioventricular block, conceivably due to the inhibition of cytochrome P450 (CYP) 3A-mediated metabolism of amlodipine by aprepitant.
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http://dx.doi.org/10.5414/CP203758DOI Listing
April 2021

Proteasome Inhibition Overcomes ALK-TKI Resistance in -Rearranged/-Mutant NSCLC via Noxa Expression.

Clin Cancer Res 2021 Mar 11;27(5):1410-1420. Epub 2020 Dec 11.

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

Purpose: In -rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms.

Experimental Design: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). -rearranged NSCLC cell lines expressing wild-type or mutant were used to evaluate cellular apoptosis induced by ALK-TKIs.

Results: In 90 patients with -rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, comutated patients showed significantly worse progression-free survival (PFS) than wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. -rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from -rearranged NSCLC cells with nonfunctional p53.

Conclusions: These clinical and preclinical results indicate concomitant mutations reduce the efficacy of alectinib for -rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for -rearranged/-mutated NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2853DOI Listing
March 2021

Disease flare of leptomeningeal metastases without radiological and cytological findings after the discontinuation of osimertinib.

Lung Cancer 2021 01 13;151:1-4. Epub 2020 Nov 13.

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

Objectives: Rapid tumor progression occurring after the discontinuation of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is referred to as a disease flare of non-small cell lung cancer (NSCLC). The clinicopathological features of disease flares after osimertinib discontinuation remain unclear.

Results: We report a patient with EGFR-mutated NSCLC who experienced the progression of leptomeningeal metastases as a disease flare shortly after the discontinuation of osimertinib despite the absence of radiological or cytological findings.

Conclusion: If CNS symptoms develop immediately after the discontinuation of osimertinib, the possibility of a CNS disease flare should be considered even if no radiological or cytological findings are present.
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http://dx.doi.org/10.1016/j.lungcan.2020.11.010DOI Listing
January 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

Brigatinib in Japanese Patients With ALK-Positive NSCLC Previously Treated With Alectinib and Other Tyrosine Kinase Inhibitors: Outcomes of the Phase 2 J-ALTA Trial.

J Thorac Oncol 2021 03 25;16(3):452-463. Epub 2020 Nov 25.

Internal Medicine III, Wakayama Medical University, Wakayama, Wakayama Prefecture, Japan. Electronic address:

Introduction: This phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs).

Methods: This single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)-assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1.

Results: We report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%-49%) with median duration of response of 11.8 months (95% CI: 5.5-16.4). Disease control rate was 79% (95% CI: 64%-89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7-9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations.

Conclusions: Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).
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http://dx.doi.org/10.1016/j.jtho.2020.11.004DOI Listing
March 2021

Nurse-led, screening-triggered, early specialised palliative care intervention programme for patients with advanced lung cancer: study protocol for a multicentre randomised controlled trial.

BMJ Open 2020 11 26;10(11):e037759. Epub 2020 Nov 26.

Department of Palliative Medicine, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

Introduction: It has been suggested that palliative care integrated into standard cancer treatment from the early phase of the disease can improve the quality of life of patients with cancer. In this paper, we present the protocol for a multicentre randomised controlled trial to examine the effectiveness of a nurse-led, screening-triggered, early specialised palliative care intervention programme for patients with advanced lung cancer.

Methods And Analysis: A total of 206 patients will be randomised (1:1) to the intervention group or the control group (usual care). The intervention, triggered with a brief self-administered screening tool, comprises comprehensive need assessments, counselling and service coordination by advanced-level nurses. The primary outcome is the Trial Outcome Index of the Functional Assessment of Cancer Therapy (FACT) at 12 weeks. The secondary outcomes include participants' quality of life (FACT-Lung), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7), illness perception (Prognosis and Treatment Perceptions Questionnaire), medical service use and survival. A mixed-method approach is expected to provide an insight about how this intervention works.

Ethics And Dissemination: This study has been approved by the Institutional Review Board of the National Cancer Center Japan (approval number: 2016-235). The findings will be disseminated through peer-reviewed publications and conference presentations and will be reflected on to the national healthcare policy.

Trial Registration Number: UMIN000025491.
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http://dx.doi.org/10.1136/bmjopen-2020-037759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692832PMC
November 2020

Differential Efficacy of Pembrolizumab According to Metastatic Sites in Patients With PD-L1 Strongly Positive (TPS ≥ 50%) NSCLC.

Clin Lung Cancer 2021 Mar 16;22(2):127-133.e3. Epub 2020 Oct 16.

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

Background: Pembrolizumab has shown significantly better efficacy than platinum doublet chemotherapy in patients with programmed cell death ligand 1 (PD-L1) strongly positive (tumor proportion score ≥ 50%) non-small-cell lung cancer (NSCLC). However, the predictors of response to pembrolizumab have not yet been fully elucidated for patients with PD-L1 strongly positive NSCLC.

Patients And Methods: We retrospectively analyzed 145 patients who had been treated with pembrolizumab for PD-L1 strongly positive (TPS ≥ 50%) NSCLC without an EGFR (epidermal growth factor receptor) mutation or ALK rearrangement from February 2017 to March 2020. Various clinical characteristics, including Eastern Cooperative Oncology Group performance status, treatment line, PD-L1 expression, C-reactive protein level, neutrophil/lymphocyte ratio, and metastatic sites, and the clinical outcome of pembrolizumab treatment were examined.

Results: Patients with higher PD-L1 expression (≥ 75%; n = 90) had a higher objective response rate (ORR) and longer progression-free survival (PFS) compared with those with lower expression (50%-74%; n = 55; ORR, 51% vs. 33%; P = .0305; median PFS, 13.9 months vs. 5.2 months; P = .0111). In addition, 15 patients with liver metastasis (LM) had a significantly lower ORR and shorter PFS than the 130 patients without LM (ORR, 20% vs. 47%; P = .0468; median PFS, 3.4 months vs. 9.4 months; P = .0018). A multivariate analysis indicated that PD-L1 expression and LM were significant predictors of PFS after pembrolizumab treatment (higher PD-L1 expression: hazard ratio, 0.58; 95% confidence interval, 0.38-0.91; P = .0183; presence of LM: hazard ratio, 2.05; 95% confidence interval, 1.03-3.82; P = .0420).

Conclusion: PD-L1 expression and LM status were predictors of the efficacy of pembrolizumab in patients with PD-L1 strongly positive NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.10.002DOI Listing
March 2021

Randomized Phase III Study of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin for Completely Resected High-Grade Neuroendocrine Carcinoma of the Lung: JCOG1205/1206.

J Clin Oncol 2020 12 2;38(36):4292-4301. Epub 2020 Nov 2.

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

Purpose: To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung.

Methods: This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m, days 1-3) plus cisplatin (80 mg/m, day 1) or irinotecan (60 mg/m, days 1, 8, 15) plus cisplatin (60 mg/m, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216).

Results: Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients 4% of 107 patients) and neutropenia (97% 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% 11%) and diarrhea (1% 8%) were more frequently observed in the irinotecan plus cisplatin arm.

Conclusion: Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.
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http://dx.doi.org/10.1200/JCO.20.01806DOI Listing
December 2020

Treatment and relapse of interstitial lung disease in nivolumab-treated patients with non-small cell lung cancer.

Cancer Sci 2021 Apr 24;112(4):1506-1513. Epub 2021 Feb 24.

The Jikei University School of Medicine, Tokyo, Japan.

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.
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http://dx.doi.org/10.1111/cas.14715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019226PMC
April 2021

Neoadjuvant chemotherapy promotes the expression of HER3 in patients with ovarian cancer.

Oncol Lett 2020 Dec 7;20(6):336. Epub 2020 Oct 7.

Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.

HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy [odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48-22.64; P<0.001) and non-HGSC histology (OR, 5.42; 95% CI, 1.99-14.78; P<0.001) as significant predictive factors for HER3-high. In pre-chemotherapy biopsy specimens, 15 patients were HER3-high and 13 were HER3-low. After chemotherapy, eight of 13 patients with HER3-low exhibited a change in status to HER3-high, with a trend toward poorer progression-free survival compared to that of patients whose status remained HER3-low. In conclusion, HER3 overexpression was revealed to be common among patients with ovarian cancer, especially in those with non-HGSC histology. In addition, HER3 expression may be promoted by chemotherapy. These findings suggested that patients with ovarian cancer are good candidates for emerging HER3-targeting therapies.
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http://dx.doi.org/10.3892/ol.2020.12200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583842PMC
December 2020

Association between serum level soluble programmed cell death ligand 1 and prognosis in patients with non-small cell lung cancer treated with anti-PD-1 antibody.

Thorac Cancer 2020 12 27;11(12):3585-3595. Epub 2020 Oct 27.

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

Background: Programmed cell death ligand 1 (PD-L1) is known to have soluble forms aside from its membrane-bound forms. The aim of this study was to evaluate the predictive and prognostic values of serum soluble PD-L1 (sPD-L1) in patients with non-small cell lung cancer (NSCLC) who were treated with anti-PD-1 antibody.

Methods: A total of 233 patients were enrolled in this study. We assessed the level of serum sPD-L1 before anti-PD-1 antibody treatment (pembrolizumab or nivolumab) and evaluated the correlation with PD-L1 expression on tumor cells, the response to anti-PD-1 antibody treatment, and patient outcome.

Results: The median serum sPD-L1 concentration was 67.7 (range, 25 to 223) pg/mL. A weak correlation between serum sPD-L1 and tumor PD-L1 expression was observed. The disease control rate in the high sPD-L1 group (≥90 pg/mL) was significantly lower than that in the low sPD-L1 group (<90 pg/mL) (37% vs. 57%, P = 0.0158). The progression-free survival (PFS) and overall survival (OS) in the high sPD-L1 group were significantly shorter than those in the low sPD-L1 group (median PFS, 57 days vs. 177 days, P = 0.011; median OS, 182 days vs. not reached, P < 0.001). The high level of serum sPD-L1 was independently associated with a shorter PFS (hazard ratio [HR], 1.910; P = 0.061) and OS (HR, 2.073; P = 0.034) in multivariate analysis.

Conclusions: The serum sPD-L1 level, which was only weakly correlated with the tumor PD-L1 expression level, was an independent predictive and prognostic biomarker for NSCLC patients receiving anti-PD-1 antibody.

Key Points: SIGNIFICANT FINDINGS OF THE STUDY: The disease control rate in the high sPD-L1 group was significantly lower than that in the low sPD-L1 group. The progression-free survival (PFS) and overall survival (OS) in the high sPD-L1 group were significantly shorter than those in the low sPD-L1 group. The high level of serum sPD-L1 was independently associated with a shorter PFS and OS in multivariate analysis.

What This Study Adds: This study demonstrated that serum sPD-L1 level was an independent predictive and prognostic biomarker for NSCLC patients receiving anti-PD-1 antibody.
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http://dx.doi.org/10.1111/1759-7714.13721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705908PMC
December 2020

Radiographic features and poor prognostic factors of interstitial lung disease with nivolumab for non-small cell lung cancer.

Cancer Sci 2021 Apr 24;112(4):1495-1505. Epub 2021 Feb 24.

The Jikei University School of Medicine, Tokyo, Japan.

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.
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http://dx.doi.org/10.1111/cas.14710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019215PMC
April 2021

Clinical outcomes of pembrolizumab therapy in advanced-NSCLC patients with poor performance status (≥3) and high PD-L1 expression (TPS ≥50%): A case series.

Thorac Cancer 2020 12 21;11(12):3618-3621. Epub 2020 Oct 21.

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

Pembrolizumab is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression tumor proportion score (TPS) ≥50%. The benefit of pembrolizumab in patients with advanced NSCLC and poor performance status (PS ≥3) is limited, even when the tumor is PD-L1-expression-positive. We retrospectively reviewed a total of four NSCLC cases with high PD-L1 expression (TPS ≥50%) and poor PS. The only patient with very high PD-L1 expression (TPS 100%) responded to pembrolizumab, but none of the three patients with high PD-L1 expression (50%-80%) responded to pembrolizumab. In conclusion, pembrolizumab can serve as a treatment option for patients with poor PS, if PD-L1 expression TPS is 100%.
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http://dx.doi.org/10.1111/1759-7714.13713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705620PMC
December 2020

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

Feasibility study of cryobiopsy for practical pathological diagnosis of primary lung cancer including immunohistochemical assessment.

Jpn J Clin Oncol 2021 Feb;51(2):271-278

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

Background: Precision medicine in non-small cell lung cancer requires attainment of a sufficient amount of high-quality tumor tissue. Transbronchial cryobiopsy has emerged as a new diagnostic method for non-neoplastic lung disease with a better potential to assess morphology compared with conventional methods. However, the influence of cryobiopsy on specimen quality, particularly detection of protein expression, is unknown. We performed a comparative immunohistochemical study in specimens obtained by cryobiopsy versus conventional sampling to evaluate the feasibility of cryobiopsy for lung cancer diagnosis.

Methods: Pairs of artificial biopsy specimens, collected using a cryoprobe or conventional scalpel, were obtained from 43 surgically resected primary lung tumors. Formalin-fixed, paraffin-embedded blocks were prepared in an ISO15189-certified laboratory. Immunohistochemical staining of thyroid transcription factor-1, p40, Ki67 and programmed death-ligand 1 (22C3) was performed. The H-scores for thyroid transcription factor-1 and p40, labeling index for Ki67 and tumor proportion score for programmed death-ligand 1 were assessed. Pearson's correlation coefficients between two sampling types were calculated.

Results: The thyroid transcription factor-1 and p40 H-scores showed perfect correlations between the cryobiopsy and conventional scalpel-obtained specimens (R2 = 0.977 and 0.996, respectively). Ki67 labeling index and PD-L1 tumor proportion score also showed strong correlations between the two sample types (R2 = 0.896 and 0.851, respectively). Five cases (11.6%) exhibited differences in tumor proportion score category between sample types, potentially because of intratumoral heterogeneity.

Conclusions: Immunohistochemical expression of certain tumor markers showed a high concordance between cryobiopsy and conventional scalpel sampling. Cryobiopsy is feasible for pathological diagnostics including PD-L1 evaluation.
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http://dx.doi.org/10.1093/jjco/hyaa174DOI Listing
February 2021

Real-World Evaluation of Factors for Interstitial Lung Disease Incidence and Radiologic Characteristics in Patients With EGFR T790M-positive NSCLC Treated With Osimertinib in Japan.

J Thorac Oncol 2020 12 11;15(12):1893-1906. Epub 2020 Sep 11.

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

Introduction: Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed.

Methods: Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included.

Results: Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment.

Conclusions: The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.
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http://dx.doi.org/10.1016/j.jtho.2020.08.025DOI Listing
December 2020

Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512).

Support Care Cancer 2021 May 11;29(5):2327-2334. Epub 2020 Sep 11.

Department of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan.

Purpose: This FAEISS study was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong steroid levels for the treatment of facial acneiform rash induced by epidermal growth factor receptor (EGFR) inhibitors (EGFRIs), in comparison with strategies employing serially ranking-UP from weak steroid levels. This article reports the primary results of the non-small cell lung cancer (NSCLC) part of the trial.

Methods: Patients with EGFR-mutated advanced NSCLC treated with erlotinib or afatinib were enrolled in the first registration. All patients received preemptive therapy with oral minocycline and heparinoid moisturizer from the initiation of an EGFR inhibitor. Enrolled patients who developed facial acneiform rash within 2 weeks were randomized at second registration to either a ranking-UP (WEAK) group or a ranking-DOWN group. The primary endpoint was incidence of grade ≥ 2 facial acneiform rash over 8 weeks.

Results: Fifty-one patients were enrolled at the first registration and received EGFRIs (n = 30 for afatinib, n = 21 for erlotinib). However, 35 patients did not develop facial acneiform rash within 2 weeks; one patient discontinued preemptive treatment. Fifteen patients (29.4%) were enrolled in the second registration; nine were assigned to the WEAK group and six to the DOWN group. There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice; p = 0.8417). No patients developed severe facial acneiform rash within 10 weeks.

Conclusion: In NSCLC patients who received EGFRIs, preemptive therapy of oral minocycline and heparinoid moisturizer reduced facial acneiform rash incidence.

Trial Registration: UMIN000024113.
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http://dx.doi.org/10.1007/s00520-020-05765-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981297PMC
May 2021

COVID-19 pneumonia in a patient with adult T-cell leukemia-lymphoma.

J Clin Exp Hematop 2020 Dec 3;60(4):174-178. Epub 2020 Sep 3.

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

Although some patients with COVID-19 develop only mild symptoms, fatal complications have been observed among those with comorbidities. As patients with cancer are immunocompromised, they are thought to have a high risk of severe illness associated with COVID-19. We report a COVID-19 patient with adult T-cell leukemia-lymphoma (ATL) who was treated using favipiravir. A 69-year-old woman with lymphoma-type ATL was treated using cyclophosphamide, doxorubicin, vincristine, prednisolone and mogamulizumab (M-CHOP) with substantial efficacy. However, in cycle 4 of M-CHOP therapy, she developed fever with mild cough. The patient was admitted to the hospital and CT revealed bilateral ground-glass opacities. SARS-CoV-2 was detected by RT-PCR and the patient was diagnosed with COVID-19. Considering severe immunosuppression caused by ATL, we initiated favipiravir therapy. Subsequently, the fever improved without antipyretics and her C-reactive protein level decreased rapidly. SARS-CoV-2 PCR tests were negative on days 17 and 18 of favipiravir therapy, and the patient was discharged without residual disease on the final CT. This is the first documented case of COVID-19 in a patient with ATL. Although severe immunosuppression caused by ATL was present, severe COVID-19 pneumonia did not develop. The immunosuppressed condition caused by hematological malignancy may not always be a risk factor for severe illness associated with COVID-19. Further accumulation of data regarding COVID-19 in patients with hematological malignancies is warranted to clarify the risk factors for severe illness, the best-in-class antiviral agent, and the optimal treatment strategy in this population.
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http://dx.doi.org/10.3960/jslrt.20030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810254PMC
December 2020

Efficacy of Selpercatinib in Fusion-Positive Non-Small-Cell Lung Cancer.

N Engl J Med 2020 08;383(9):813-824

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D., E.R.) and New York University Langone Medical Center (V.V.), New York, and Roswell Park Comprehensive Cancer Center, Buffalo (G.K.D.) - all in New York; Dana-Farber Cancer Institute (G.R.O.) and Massachusetts General Hospital (J.G.), Boston; National Cancer Centre Singapore, Singapore (D.S.W.T.); the Chinese University of Hong Kong, Hong Kong, China (H.H.F.L.); Sarah Cannon Research Institute, Nashville (M.J.); University of California, San Francisco-Helen Diller Family Comprehensive Cancer Center, San Francisco (C.E.M.), University of California, San Diego, Moores Cancer Center, La Jolla (L.B.), and City of Hope Comprehensive Cancer Center, Duarte (K.L.R.) - all in California; University of Bern, Bern, and Cantonal Hospital of Lucerne, Lucerne - both in Switzerland (O.G.); Institut Gustave Roussy, Villejuif (B.B.), Hospital La Timone, Marseille (F.B.), and Centre Léon Bérard, Lyon (P.A.C.) - all in France; Severance Hospital, Yonsei University Health System (B.C.C.), and Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), Seoul, and Seoul National University Bundang Hospital, Seongnam (Y.J.K.) - all in South Korea; Soroka University Medical Center, Beer-Sheva, Israel (N.P.); University of North Carolina-Chapel Hill, Chapel Hill (J. Weiss); National Cancer Center Hospital (Y.O.) and Cancer Institute Hospital of the Japanese Foundation for Cancer Research (M. Nishio), Tokyo, National Hospital Organization Kyushu Cancer Center, Fukuoka (T. Seto), Tottori University Hospital, Tottori (T. Sakamoto), Hyogo Cancer Center, Akashi (M.S.), Okayama University Hospital, Okayama (K.O.), and National Cancer Center Hospital East, Chiba (K.G.) - all in Japan; University of Chicago, Chicago (J.P.); the Ohio State University Comprehensive Cancer Center, Columbus (M.H.S.), and Cleveland Clinic, Cleveland (N.A.P.); Istituto Nazionale Tumori-National Cancer Institute, Università degli Studi di Milano, Milan (F.D.B.); Vall d'Hebron Institute of Oncology, Hospital Universitario Vall d'Hebron, Barcelona (E.G.); Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany (J. Wolf); Peter MacCallum Cancer Institute, Melbourne, VIC, Australia (B.S.); Sarah Cannon Research Institute at HealthONE, Denver (G.F.); Loxo Oncology, Stamford, CT (K.E., M. Nguyen, B.N., E.Y.Z., L.Y., X.H., E.O., S.M.R.); and the University of Texas M.D. Anderson Cancer Center, Houston (V.S.).

Background: fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with advanced fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety.

Results: In the first 105 consecutively enrolled patients with fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.

Conclusions: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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http://dx.doi.org/10.1056/NEJMoa2005653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506467PMC
August 2020