Publications by authors named "Atsushi Horiike"

75 Publications

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

Medicine (Baltimore) 2021 Jun;100(23):e25774

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine.

Introduction: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.

Patients Concerns: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.

Diagnosis: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.

Interventions: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.

Outcomes: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.

Conclusion: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
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http://dx.doi.org/10.1097/MD.0000000000025774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202549PMC
June 2021

Rare Nivolumab-associated Super Hyper Progressive Disease in Patients With Advanced Gastric Cancer.

In Vivo 2021 May-Jun;35(3):1865-1875

Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.

Background/aim: Rapid tumor growth after administration of immune checkpoint inhibitors is designated hyper progressive disease (HPD). In this study, besides the conventional HPD category, we proposed the "super HPD" category where the disease is naturally rapidly growing.

Patients And Methods: Patients treated for advanced gastric cancer with irinotecan or nivolumab as a third-line treatment were retrospectively compared.

Results: Eighteen and 26 patients were treated with irinotecan or nivolumab, respectively. There were 3 HPD cases (16.7%) in the irinotecan group, 6 cases (23.1%) in the nivolumab group, and the frequency of HPD was not significantly different. Two cases satisfied the super HPD definition only in the nivolumab group. When one of them was analyzed immunologically, the number of regulatory T cells was found to be increased, resulting in a low neutrophil-to-lymphocyte ratio.

Conclusion: Our proposed super HPD was likely to represent a true HPD, with a frequency of 7.7%.
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http://dx.doi.org/10.21873/invivo.12449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193338PMC
June 2021

The Prognostic Impact of Eosinophils and the Eosinophil-to-Lymphocyte Ratio on Survival Outcomes in Stage II Resectable Pancreatic Cancer.

Pancreas 2021 02;50(2):167-175

Division of Medical Oncology, Department of Medicine, School of Medicine.

Objectives: The relationship between eosinophils and cancer prognosis is unknown. Therefore, we analyzed the relationship between circulating eosinophils and the survival of stage IIA and IIB pancreatic cancer patients who underwent surgical resection.

Methods: This study included a retrospective cohort of 67 consecutive patients. Patients were categorized into two different groups based on the optimal cutoff for pretreatment levels of each biomarker, according to the receiver operating characteristic curves.

Results: The Kaplan-Meier method showed that low eosinophil (P = 0.0403), high neutrophil (P = 0.0066), and high monocyte (P = 0.0003) counts were associated with short overall survival (OS). Low lymphocyte-to-monocyte ratio (P = 0.0194) and eosinophil-to-lymphocyte ratio (ELR) (P = 0.0413) were associated with reduced OS. In multivariate analysis, histological differentiation (P = 0.0014), high neutrophils (P = 0.047), high monocytes (P = 0.029), and low eosinophils (P < 0.0001) were correlated with poorer OS. Histological differentiation (P = 0.033), low lymphocyte-to-monocyte ratio (P = 0.029), and low ELR (P = 0.005) were correlated with poor OS and were significant independent prognostic factors of poor outcomes.

Conclusions: Low eosinophils and low ELR were significant independent prognostic factors of poor outcomes.
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http://dx.doi.org/10.1097/MPA.0000000000001731DOI Listing
February 2021

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer.

Int J Oncol 2021 01 12;58(1):57-69. Epub 2020 Nov 12.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer is associated with an exceedingly poor prognosis, warranting the development of novel therapeutic strategies and discovery of prognostic predictors. Given that chemoresistance‑related molecules are reportedly associated with the poor prognosis of pancreatic cancer, the present study aimed to identify molecules that could be efficacious therapeutic targets for pancreatic cancer. First, 10 patient‑derived xenografts (PDXs) were established from patients with pancreatic cancer. Subsequently, after treating tumor tissue generated from the PDXs with standard drugs, next‑generation sequencing (NGS) was performed using these tissues. The results of NGS analysis and immunohistochemical analysis on 80 pancreatic cancer tissues revealed that human epididymis protein 4 (HE4) expression in the anticancer drug‑treated PDX group was higher than that in the untreated PDXs. In addition, chemoresistance ability was observed in tumor cell lines overexpressing HE4. Furthermore, Kaplan‑Meier analysis of tumor tissues from 80 patients with pancreatic cancer was performed and it was found that patients with a high HE4 expression level had a poor survival rate compared with those who had a low HE4 expression level. Multivariate analysis also indicated the high expression level of HE4 was an independent poor prognostic biomarker. Thus, it was concluded that high gene and protein expression levels of HE4 mediate chemoresistance and are independent prognostic factors for pancreatic cancer.
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http://dx.doi.org/10.3892/ijo.2020.5147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721086PMC
January 2021

Phase II study of the combination of S-1 with bevacizumab for patients with previously treated advanced non-squamous non-small-cell lung cancer.

Int J Clin Oncol 2021 Mar 7;26(3):507-514. Epub 2020 Nov 7.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: We assessed the efficacy and safety of bevacizumab and S-1 chemotherapy for patients with previously treated advanced non-squamous non-small-cell lung cancer (NSCLC).

Methods: This was a prospective single-arm study, including patients with non-squamous NSCLC who had received at least one chemotherapy regimen along with a platinum-based regimen. Bevacizumab 15 mg/kg was intravenously administered every 3 weeks, and S-1 40 mg/m was orally administered twice daily from day 1 (evening) through day 15 (morning). The treatment continued for 3 weeks/cycle until disease progression or until unacceptable toxicities occurred. During the lead-in part, six patients were evaluated for dose-limiting toxicity (DLT) rate. In phase II, the primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.

Results: In the lead-in part, we evaluated the safety in the first six patients and observed no DLT. In phase II, a total of 46 patients were enrolled from September 2012 to December 2018. The median follow-up duration was 13.7 months [95% confidence interval (CI) 1.4-72.0]. The ORR was 28.3%. The median PFS and OS were 4.3 (95% CI 2.9-5.9) and 15.0 months (95% CI 9.8-30.3), respectively. The most common adverse events were hypertension (65.2%), diarrhea (47.8%), mucositis oral (45.7%), and proteinuria (43.5%), and the most common grade 3 adverse events were hypertension (23.9%) and proteinuria (6.5%). Grade 4/5 adverse events were not observed.

Conclusion: Bevacizumab and S-1 combination chemotherapy showed high activity and were well tolerated in patients with previously treated advanced non-squamous NSCLC.
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http://dx.doi.org/10.1007/s10147-020-01822-7DOI Listing
March 2021

A Novel System to Detect Circulating Tumor Cells Using Two Different Size-selective Microfilters.

Anticancer Res 2020 Oct;40(10):5577-5582

Division of Protein Engineering, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

Background/aim: Clusters of circulating tumor cells (CTCs) increase metastatic potential compared to single CTC. However, conventional technologies have been unable to generate an accurate analysis of single and cluster CTCs in the peripheral blood. We propose an effective strategy to detect and isolate both single and cluster CTCs using two size-selective microfilters.

Materials And Methods: Five ml of whole blood were collected from 10 patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Single and cluster CTCs were identified using precision microfiltration membranes with two distinct pore sizes together with anti-EpCAM antibody labeling.

Results: Single and cluster CTCs were detected by simultaneously using two size-selective microfilters. The EGFR-L858R mutation was detected in the DNA from cells captured using both microfilters.

Conclusion: Our method can be used to detect and isolate single and cluster CTCs in the whole blood and may facilitate the development of a liquid biopsy strategy.
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http://dx.doi.org/10.21873/anticanres.14570DOI Listing
October 2020

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

Cancer Sci 2020 Dec 16;111(12):4480-4489. Epub 2020 Oct 16.

Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.
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http://dx.doi.org/10.1111/cas.14647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734005PMC
December 2020

Association Between the Efficacy of Pembrolizumab and Low STK11/LKB1 Expression in High-PD-L1-expressing Non-small-cell Lung Cancer.

In Vivo 2020 Sep-Oct;34(5):2997-3003

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

Background/aim: STK11/LKB1 mutation has been suggested as a poorly responding candidate biomarker of the anti-programmed cell death-1 (PD-1) antibody; however, the association between STK11/LKB1 expression and the effects of anti-PD-1 antibodies is uncertain. The aim of the study was to correlate the efficacy of pembrolizumab monotherapy and STK11/LKB1 expression in untreated patients with non-small-cell lung carcinoma (NSCLC) and high PD-ligand 1 expression.

Patients And Methods: From February 2017 to January 2020, we retrospectively analyzed 30 previously untreated patients with NSCLC and a tumor proportion score (TPS) ≥50% treated with pembrolizumab monotherapy. STK11/LKB1 expression in tumor tissue was evaluated by immunohistochemistry.

Results: Twenty-three (76.7%) of the 30 patients were classified with low-STK11/LKB1 expression. The median progression-free survival and overall survival of patients with low-STK11/LKB1 expression was shorter than those with high-STK11/LKB1 expression, although the results were not statistically significant. The disease progression rate for the low-STK11/LKB1 group was higher than that of the high-STK11/LKB1 group.

Conclusion: STK11/LKB1 expression, as measured by immunohistochemistry, could be a useful biomarker associated with the efficacy of pembrolizumab monotherapy for patients with NSCLC and a TPS ≥50%.
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http://dx.doi.org/10.21873/invivo.12131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652526PMC
June 2021

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

A high number of PD-L1 CD14 monocytes in peripheral blood is correlated with shorter survival in patients receiving immune checkpoint inhibitors.

Cancer Immunol Immunother 2021 Feb 5;70(2):337-348. Epub 2020 Aug 5.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, 6-11-11 Kita-Karasuyama, Setagaya-ku, Tokyo, 157-8577, Japan.

Purpose: Targeting of anti-programmed cell death protein-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) is a standard therapeutic strategy for various cancers. The aim of the present study was to investigate the prognostic effect of pretreatment PD-L1 expression levels in peripheral blood mononuclear cell (PBMC) subsets for patients with several cancer types receiving anti-PD-1 blockade therapies.

Patients And Methods: Thirty-two patients undergoing anti-PD-L1 blockade therapy, including 15 with non-small cell lung cancer, 14 with gastric cancer, 1 with melanoma, 1 with parotid cancer, and 1 with bladder cancer, were recruited for the present study. PD-L1 expression levels in CD3, CD4, CD8, CD45RA and CCR7 T cells; CD20 B cells; CD14 and CD16 monocytes were measured via flow cytometry before treatment. The percentages of PD-L1 cells in respective PBMC subsets were compared with respect to different clinicopathological conditions and the association with overall survival (OS) was assessed.

Results: The percentages of PD-L1 with CD3, CD4 and CD8 T cells including naïve and memory T cell subsets, or CD20 B cells during pretreatment were not markedly correlated with the OS of patients (p > 0.05); however, the percentage of the PD-L1 CD14 monocyte subset was significantly correlated with OS (p = 0.0426).

Conclusion: Increase in pretreatment expression levels of PD-L1 on CD14 monocytes is associated with the OS of patients treated with immune checkpoint inhibitors. Further evaluation of large sample size and each specific cancer type might clarify the predictive role of PBMC in patients.
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http://dx.doi.org/10.1007/s00262-020-02686-6DOI Listing
February 2021

High expression levels of polymeric immunoglobulin receptor are correlated with chemoresistance and poor prognosis in pancreatic cancer.

Oncol Rep 2020 Jul 11;44(1):252-262. Epub 2020 May 11.

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157‑8577, Japan.

Pancreatic cancer has extremely poor prognosis, warranting the discovery of novel therapeutic and prognostic markers. The expression of polymeric immunoglobulin receptor (pIgR), a key component of the mucosal immune system, is increased in several cancers. However, its clinical relevance in pancreatic cancer remains unclear. In the present study, the prognostic value of pIgR in pancreatic cancer patients after surgical resection was assessed and it was determined that the expression of pIgR was correlated with poor prognosis. Ten pancreatic cancer patient‑derived xenograft (PDX) lines were established, followed by next‑generation sequencing of tumor tissues from these lines after standard chemotherapy. Immunohistochemical analysis of chemoresistance‑related molecules using 77 pancreatic cancer tissues was also performed. The expression of pIgR mRNA in the PDX group treated with anticancer drugs was higher than in the untreated group. High pIgR expression in tissue specimens from 77 pancreatic cancer patients was significantly associated with poor prognosis and was revealed to be an independent prognostic factor, predicting poor outcomes. High pIgR mRNA and protein levels were independent prognostic factors, indicating that pIgR could be a novel predictor for poor prognosis of pancreatic cancer patients.
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http://dx.doi.org/10.3892/or.2020.7610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251687PMC
July 2020

Dissociated responses at initial computed tomography evaluation is a good prognostic factor in non-small cell lung cancer patients treated with anti-programmed cell death-1/ligand 1 inhibitors.

BMC Cancer 2020 Mar 12;20(1):207. Epub 2020 Mar 12.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Dissociated responses (DR) are phenomena in which some tumors shrink, whereas others progress during treatment of patients with cancer. The purpose of the present study was to evaluate the frequency and prognosis of DR in non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) inhibitors.

Methods: This retrospective study included NSCLC patients who received anti-PD-1/L1 inhibitor as second- or later-line treatment. We excluded patients without radiological evaluation. In patients who showed progressive disease (PD) according to the RECIST 1.1 at the initial CT evaluation, we evaluated all measurable lesions in each organ to identify DR independently of RECIST 1.1. We defined DR as a disease with some shrinking lesions as well as growing or emerging new lesions. Cases not classified as DR were defined as 'true PD'. Overall survival was compared between patients with DR and those with true PD using Cox proportional hazards models.

Results: The present study included 62 NSCLC patients aged 27-82 years (median: 65 years). DR and true PD were observed in 11 and 51 patients, respectively. The frequency of DR in NSCLC patients who showed PD to anti-PD-1/L1 was 17.7%. Median overall survival was significantly longer in patients with DR versus true PD (14.0 vs. 6.6 months, respectively; hazard ratio for death: 0.40; 95% confidence interval: 0.17-0.94).

Conclusions: Patients with DR exhibited a relatively favorable prognosis.
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http://dx.doi.org/10.1186/s12885-020-6704-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066771PMC
March 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

Insulinoma-associated Protein 1 (INSM1) Is a Better Marker for the Diagnosis and Prognosis Estimation of Small Cell Lung Carcinoma Than Neuroendocrine Phenotype Markers Such as Chromogranin A, Synaptophysin, and CD56.

Am J Surg Pathol 2020 06;44(6):757-764

Division of Pathology, The Cancer Institute.

To diagnose small cell lung carcinoma (SCLC), neuroendocrine (NE) phenotype markers such as chromogranin A, synaptophysin, and CD56 are helpful. However, because they are dispensable, SCLCs occur without apparent NE phenotypes. Insulinoma-associated protein 1 (INSM1) is a transcription factor for NE differentiation and has emerged as a single practical marker for SCLC. Using the surgical samples of 141 pulmonary NE tumors (78 SCLCs, 44 large cell NE carcinomas, and 19 carcinoids), and 246 non-NE carcinomas, we examined the immunohistochemical expression and prognostic relevance of INSM1 in association with NE phenotype markers. We evaluated its sensitivity and specificity for SCLC diagnosis, as well as its usefulness to diagnose SCLC without NE marker expression and to estimate the prognosis. INSM1 was expressed in SCLCs (92%, 72/78), large cell NE carcinomas (68%, 30/44), and carcinoids (95%, 18/19). In addition, among SCLCs with no expression of NE phenotype markers (n=12), 9 (75%) were positive for INSM1. These data suggest the superiority of INSM1 to the phenotype markers. Only 7% of adenocarcinomas (9/134) and 4% of squamous cell carcinomas (4/112) were positive for INSM1. SCLC with low-INSM1 expression (n=28) had a significantly better prognosis (P=0.040) than the high-INSM1 group (n=50). Our study revealed that INSM1 is highly sensitive and specific to detect SCLC and can estimate prognosis. INSM1 will be a promising marker for SCLC.
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http://dx.doi.org/10.1097/PAS.0000000000001444DOI Listing
June 2020

Drug resistance mechanisms in Japanese anaplastic lymphoma kinase-positive non-small cell lung cancer and the clinical responses based on the resistant mechanisms.

Cancer Sci 2020 Mar 8;111(3):932-939. Epub 2020 Feb 8.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.
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http://dx.doi.org/10.1111/cas.14314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060465PMC
March 2020

Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L).

J Clin Oncol 2020 03 27;38(8):793-803. Epub 2019 Dec 27.

Kyushu University Hospital, Fukuoka, Japan.

Purpose: Patients with non-small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy.

Patients And Methods: Patients with untreated advanced nonsquamous NSCLC without confirmed 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment.

Results: Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank = .069). In the wild-type subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank = .020). The median progression-free survival (PFS) was 5.7 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank < .001). The safety data were consistent with previous reports of treatment regimens.

Conclusion: In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.
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http://dx.doi.org/10.1200/JCO.19.01494DOI Listing
March 2020

Association of High Neutrophil-to-Lymphocyte Ratio With Poor Outcomes of Pembrolizumab Therapy in High-PD-L1-expressing Non-small Cell Lung Cancer.

Anticancer Res 2019 Dec;39(12):6851-6857

Department of Thoracic Medical Oncology, the Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

Background: This study aimed to determine whether the neutrophil-to-lymphocyte ratio (NLR) reflected poor treatment benefits in patients with tumor proportion score (TPS) ≥50% and who under went first-line pembrolizumab monotherapy.

Patients And Methods: This study retrospectively analyzed patients with untreated stage III/IV or recurrent non-small cell lung cancer (NSCLC) with TPS ≥50% and who received pembrolizumab monotherapy at two hospitals between February 2017 and April 2019. The NLR was calculated from pre-treatment complete blood counts.

Results: A total of 51 previously untreated patients with NSCLC who had TPS ≥50% and who underwent pembrolizumab monotherapy were evaluated. Multivariate analysis revealed that high NLR, Eastern Cooperative Oncology Group performance status (PS) ≥2, stage IV or recurrent cancer, and TPS=50-74% were significantly and independently associated with poor progression-free survival. Moreover, high NLR and PS ≥2 were significantly associated with short overall survival.

Conclusion: A high pre-treatment NLR was associated with significantly short progression-free and overall survival in previously untreated patients with NSCLC with high expression of programmed cell-death ligand 1 treated with pembrolizumab monotherapy.
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http://dx.doi.org/10.21873/anticanres.13902DOI Listing
December 2019

Updated Survival Data for a Phase I/II Study of Carboplatin plus Nab-Paclitaxel and Concurrent Radiotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer.

Oncologist 2020 06 24;25(6):475-e891. Epub 2019 Oct 24.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Lessons Learned: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen.

Background: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC).

Methods: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS).

Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period.

Conclusion: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2019-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288639PMC
June 2020

Efficacy of anti-PD-1 therapy for recurrence after chemoradiotherapy in locally advanced NSC LC.

Int J Clin Oncol 2020 Jan 10;25(1):67-73. Epub 2019 Sep 10.

Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake 3-8-31, Koto, Tokyo, 1358550, Japan.

Purpose: Chemoradiotherapy (CRT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Recently, anti-PD-1 antibody therapy became a key treatment for stage IV NSCLC as the combination of immune checkpoint inhibitors (ICIs) and platinum doublet chemotherapy. However, the efficacy and toxicity of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC are not well examined.

Methods: Patients who received anti-PD-1 therapy for recurrence after CRT were identified in our clinical database. The safety and efficacy of anti-PD-1 therapy were retrospectively analyzed.

Results: From March 1, 2013 to April 30, 2018, there were 20 patients who received anti-PD-1 therapy for recurrence after CRT. The median duration from CRT to initial anti-PD-1 therapy was 9.3 months. 12 patients (60%) were alive and 7 patients (35%) were still receiving anti-PD-1 therapy at the data cutoff point (median follow-up, 13.5 months). The ORR for anti-PD-1 therapy was 45.0%. Median progression-free survival (PFS) and overall survival (OS) from initiation of anti-PD-1 therapy was 8.4 months and 26.2 months, respectively. PFS in patients who had a short interval from last CRT to initial anti-PD-1 therapy seemed to have better outcomes (duration from last CRT to initial anti-PD-1 therapy < 9.3 months vs. ≥ 9.3 months; median PFS, 17.0 months vs. 4.9 months). Grade 3 or 4 immune-related adverse events occurred in 5% of patients. Only grade 1 pneumonitis was observed.

Conclusion: The efficacy of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC might better than in stage IV NSCLC. The duration from CRT to initial anti-PD-1 therapy might be related to efficacy.
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http://dx.doi.org/10.1007/s10147-019-01537-4DOI Listing
January 2020

Barcode sequencing identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating tumor DNA of lung cancer patients.

Cancer Sci 2019 Oct 19;110(10):3350-3357. Epub 2019 Aug 19.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Most patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) will inevitably develop acquired resistance induced by treatment with EGFR tyrosine kinase inhibitors (EGFR-TKI). The mechanisms of resistance to EGFR-TKI are multifactorial, and the detection of these mechanisms is critical for treatment choices in patients who have progressed after EGFR-TKI therapy. We evaluated the feasibility of a molecular barcode method using next-generation sequencing to detect multifactorial resistance mechanisms in circulating tumor DNA and compared the results with those obtained using other technologies. Plasma samples were collected from 25 EGFR mutation-positive NSCLC patients after the development of EGFR-TKI resistance. Somatic mutation profiles of these samples were assessed using two methods of next-generation sequencing and droplet digital PCR (ddPCR). The positive rate for EGFR-sensitizing mutations was 18/25 (72.0%) using ddPCR, 17/25 (68.0%) using amplicon sequencing, and 19/25 (76.0%) using molecular barcode sequencing. Rate of the EGFR T790M resistance mutation among patients with EGFR-sensitizing mutations was shown to be 7/18 (38.9%) using ddPCR, 6/17 (35.3%) using amplicon sequencing, and 8/19 (42.1%) using molecular barcode sequencing. Copy number gain in the MET gene was detected in three cases using ddPCR. PIK3CA, KRAS and TP53 mutations were detected using amplicon sequencing. Molecular barcode sequencing detected PIK3CA, TP53, KRAS, and MAP2K1 mutations. Results of the three assays were comparable; however, in cell-free DNA, molecular barcode sequencing detected mutations causing multifactorial resistance more sensitively than did the other assays.
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http://dx.doi.org/10.1111/cas.14153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778626PMC
October 2019

Correlation between thyroid transcription factor-1 expression, immune-related thyroid dysfunction, and efficacy of anti-programmed cell death protein-1 treatment in non-small cell lung cancer.

J Thorac Dis 2019 May;11(5):1919-1928

Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Recent studies have suggested a correlation between immune-related thyroid dysfunction (irTD) and the superior efficacy of anti-programmed cell death protein-1 (anti-PD-1) treatment in non-small cell lung cancer (NSCLC). Embryologically, the lung and thyroid are similar in origin, and thyroid transcription factor-1 (TTF-1) expresses in both organs, including NSCLC. We explored our hypothesis that TTF-1 expression in NSCLC might correlate with irTD incidence and anti-PD-1 treatment efficacy.

Methods: We identified 132 patients with NSCLC treated with anti-PD-1 antibody at our hospital between December 2015 and June 2017. We evaluated TTF-1 expression in tumor by immunohistochemistry using a mouse monoclonal antibody (clone 8G7G3/1, 1:100, Dako). IrTD was defined as two or more successive abnormal levels of thyroid-stimulating hormone (TSH) during anti-PD-1 treatment. We retrospectively assessed correlations between TTF-1 expression in tumor, irTD incidence, and anti-PD-1 treatment efficacy.

Results: Of 132 patients, 67 (51%) and 65 (49%) were positive and negative for TTF-1, respectively. We observed irTD in 19 patients (6 positives and 13 negatives for TTF-1). The incidence of irTD was 9% and 20% in TTF-1-positive and TTF-1-negative NSCLCs, respectively (P=0.086). Particularly, in non-squamous (NSQ) cell carcinomas, the irTD incidence was significantly higher in patients negative for TTF-1 (30%) than in those positive for TTF-1 (9%; P=0.010), and TTF-1 expression was identified as a significant risk factor for irTD on multivariate logistic regression analysis [odds ratio (OR), 0.18; 95% confidence interval (CI), 0.05-0.59; P=0.005]. Furthermore, longer median progression-free survival (10.3 months) was observed in patients with TTF-1-negative NSCLC with irTD compared to those with TTF-1-positive NSCLC with irTD, TTF-1-positive NSCLC without irTD, and TTF-1-negative NSCLC without irTD (4.2, 1.4, and 2.4 months, respectively).

Conclusions: TTF-1 expression in NSCLC might correlate with irTD and anti-PD-1 treatment efficacy.
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http://dx.doi.org/10.21037/jtd.2019.04.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588787PMC
May 2019

Correlation between serum adenosine deaminase activity and efficacy of anti-programmed cell death-1 antibody.

Lung Cancer 2019 07 27;133:4-9. Epub 2019 Apr 27.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address:

Objective: Serum adenosine deaminase (ADA) activity is a marker of immune reaction to several diseases. We evaluated changes in serum ADA in patients with lung cancer undergoing chemotherapy or anti-programmed cell death-1 (PD-1) therapy to examine the correlation between serum ADA and the therapy efficacy.

Materials And Methods: We assessed 50 patients with advanced lung cancer receiving chemotherapy or anti-PD-1 therapy. Serum ADA was measured before and on day 7 of the first treatment cycle and day 0 of subsequent cycles. Correlations between ADA change and efficacy of treatment were evaluated.

Results: Of the 50 patients, 20 were treated with chemotherapy and 30 were treated with anti-PD-1 therapy. Serum ADA decreased significantly between baseline and day 7 of the first cycle in patients undergoing chemotherapy, regardless of response (partial response [PR] or stable disease [SD]: -23% [-38 to +32; p =  0.002]; progressive disease [PD]: -12% [-42 to +6; p =  0.500]). Conversely, in patients undergoing anti-PD-1 therapy, serum ADA increased significantly between baseline and 7 days after the first dose and before subsequent doses in patients who had PR or SD. (day 7 of first cycle: +6% [-10 to +34; p =  0.034], day 0 of second cycle: 8% [-5 to +37; p =  0.002], day 0 of third cycle: 9% [-3 to +55; p =  0.002]). However, serum ADA did not significant change in PD patients undergoing anti-PD-1 therapy. Furthermore, early increases in serum ADA were associated with longer progression-free survival in patients receiving anti-PD-1 therapy (p =  0.006).

Conclusion: Changes in serum ADA could be used to predict clinical benefit from anti-PD-1 therapy in patients with lung cancer. The association between changes in serum ADA and the efficacy of ant-PD-1 therapy thus remains inconclusive and requires further study.
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http://dx.doi.org/10.1016/j.lungcan.2019.04.022DOI Listing
July 2019

Lung Adenocarcinoma with Lynch Syndrome and the Response to Nivolumab.

Intern Med 2019 15;58(10):1479-1484. Epub 2019 May 15.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Japan.

Lynch syndrome is caused by mutations in mismatch repair genes that lead to microsatellite instability (MSI). An increased number of mutation-associated neoantigens have been observed in patients with high-frequency MSI (MSI-H) cancer; in addition, membranous programmed death ligand-1 (PD-L1) tends to be expressed at higher levels in MSI-H cancers than in microsatellite-stable cancers. MSI-H cancer patients are therefore considered to be susceptible to immune checkpoint blockade. We herein report for the first time a case of lung adenocarcinoma with Lynch syndrome and the response to nivolumab.
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http://dx.doi.org/10.2169/internalmedicine.1673-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548921PMC
June 2019

Improvement in the survival of patients with stage IV non-small-cell lung cancer: Experience in a single institutional 1995-2017.

Lung Cancer 2019 05 21;131:69-77. Epub 2019 Mar 21.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Japan. Electronic address:

Objectives: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice.

Materials And Methods: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation.

Results: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E.

Conclusion: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.
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http://dx.doi.org/10.1016/j.lungcan.2019.03.008DOI Listing
May 2019

Genetic Profiling of Non-Small Cell Lung Cancer at Development of Resistance to First- or Second-Generation EGFR-TKIs by CAPP-Seq Analysis of Circulating Tumor DNA.

Oncologist 2019 08 25;24(8):1022-1026. Epub 2019 Apr 25.

Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Patients with non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually acquire resistance to these drugs. The identification of various resistance mechanisms for determination of subsequent treatment for these patients will require a method for simultaneous detection of multiple genetic alterations with high sensitivity. We performed cancer personalized profiling by deep sequencing (CAPP-Seq) with circulating tumor DNA obtained from patients with NSCLC who acquired resistance to first- or second-generation EGFR-TKIs. Plasma samples from 27 patients were analyzed, and 24 samples underwent CAPP-Seq successfully. Original activating mutations were detected in 23 patients, with the remaining patient showing amplification. With regard to known mechanisms of EGFR-TKI resistance, the T790M mutation of was detected in 17 of the 24 patients, amplification in 9 patients (6 of whom also harbored T790M), amplification in 2 patients (1 of whom also harbored T790M), and amplification in 4 patients (all of whom harbored T790M). Our results thus show that CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations in circulating tumor DNA obtained from patients with NSCLC at the time of disease progression during treatment with first- or second-generation EGFR-TKIs. Patients positive for the T790M mutation of were also found to constitute a molecularly heterogeneous population. KEY POINTS: CAPP-Seq is applicable to clinical samples for the identification of multiple somatic mutations.The T790M mutation of is associated with amplification of , , or in NSCLC patients resistant to EGFR-TKIs.T790M-positive patients are molecularly heterogeneous, and genetic alterations coexisting with T790M may differ between patients treated with first-generation or second-generation EGFR-TKIs.
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http://dx.doi.org/10.1634/theoncologist.2019-0101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693714PMC
August 2019

Epithelial-to-Mesenchymal Transition Is a Mechanism of ALK Inhibitor Resistance in Lung Cancer Independent of Mutation Status.

Cancer Res 2019 04 8;79(7):1658-1670. Epub 2019 Feb 8.

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

Mutations in the gene are detectable in approximately 40% of -rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both -mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with -rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT and . These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. SIGNIFICANCE: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2052DOI Listing
April 2019

Phase 1 Study of Cabozantinib in Japanese Patients With Expansion Cohorts in Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2019 05 31;20(3):e317-e328. Epub 2018 Dec 31.

St Luke's International Hospital, Tokyo, Japan.

Background: Cabozantinib inhibits tyrosine kinases including MET, AXL, VEGFR2, RET, KIT, and ROS1 and has demonstrated antitumor activity in multiple tumor types. The primary objective of this phase 1 study (NCT01553656) was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of cabozantinib in Japanese patients.

Patients And Methods: Patients with advanced solid tumors were enrolled at 2 sites in Japan. After determining the MTD and RP2D, an expansion in non-small-cell lung cancer (NSCLC) consisting of 3 molecularly defined cohorts (EGFR mutation; KRAS mutation; ALK, RET, or ROS1 fusion) was initiated. The study was registered with ClinicalTrials.gov (NCT01553656).

Results: Forty-three Japanese patients were enrolled (dose escalation, n = 23; NSCLC expansion, n = 20). The MTD of cabozantinib capsules was 60 mg daily, and the RP2D of cabozantinib tablets was 60 mg daily. Dose-limiting toxicities were hypertension, proteinuria, and venous embolism. Safety and pharmacokinetics in Japanese patients were consistent with those in non-Japanese patients. Common adverse events included palmar-plantar erythrodysesthesia, hypertension, and diarrhea. Reduction in tumor lesion size was observed in multiple tumor types in the dose-escalation cohorts, with partial responses observed in 4 of 9 patients with NSCLC (EGFR mutation, n = 1; ALK fusion, n = 2; and RET fusion, n = 1). In the NSCLC expansion, 4 patients with EGFR-mutant NSCLC had partial responses; the remaining 16 (EGFR mutation, n = 11; KRAS mutation, n = 2; ALK fusion, n = 1; and RET fusion, n = 2) had stable disease as best response.

Conclusion: Cabozantinib had a manageable safety profile in Japanese patients with solid tumors. Responses were observed in diverse molecular subtypes of NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2018.12.018DOI Listing
May 2019

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors.

Mol Cancer Ther 2019 03 24;18(3):531-540. Epub 2019 Jan 24.

Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3+3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m/day for QD, and 210.7 mg/m/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor.This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0831DOI Listing
March 2019

Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance.

EBioMedicine 2019 Mar 17;41:105-119. Epub 2019 Jan 17.

Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Electronic address:

Background: Alectinib has shown a greater efficacy to ALK-rearranged non-small-cell lung cancers in first-line setting; however, most patients relapse due to acquired resistance, such as secondary mutations in ALK including I1171N and G1202R. Although ceritinib or lorlatinib was shown to be effective to these resistant mutants, further resistance often emerges due to ALK-compound mutations in relapse patients following the use of ceritinib or lorlatinib. However, the drug for overcoming resistance has not been established yet.

Methods: We established lorlatinib-resistant cells harboring ALK-I1171N or -G1202R compound mutations by performing ENU mutagenesis screening or using an in vivo mouse model. We performed drug screening to overcome the lorlatinib-resistant ALK-compound mutations. To evaluate these resistances in silico, we developed a modified computational molecular dynamic simulation (MP-CAFEE).

Findings: We identified 14 lorlatinib-resistant ALK-compound mutants, including several mutants that were recently discovered in lorlatinib-resistant patients. Some of these compound mutants were found to be sensitive to early generation ALK-TKIs and several BCR-ABL inhibitors. Using our original computational simulation, we succeeded in demonstrating a clear linear correlation between binding free energy and in vitro experimental IC value of several ALK-TKIs to single- or compound-mutated EML4-ALK expressing Ba/F3 cells and in recapitulating the tendency of the binding affinity reduction by double mutations found in this study. Computational simulation revealed that ALK-L1256F single mutant conferred resistance to lorlatinib but increased the sensitivity to alectinib.

Interpretation: We discovered lorlatinib-resistant multiple ALK-compound mutations and an L1256F single mutation as well as the potential therapeutic strategies for these ALK mutations. Our original computational simulation to calculate the binding affinity may be applicable for predicting resistant mutations and for overcoming drug resistance in silico. FUND: This work was mainly supported by MEXT/JSPS KAKENHI Grants and AMED Grants.
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http://dx.doi.org/10.1016/j.ebiom.2019.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441848PMC
March 2019

Exploration of germline variants responsible for adverse events of crizotinib in anaplastic lymphoma kinase-positive non-small cell lung cancer by target-gene panel sequencing.

Lung Cancer 2019 02 4;128:20-25. Epub 2018 Dec 4.

Departments of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Objectives: Crizotinib is a standard treatment for advanced anaplastic lymphoma kinase (ALK)- or ROS1-fusion-gene-positive non-small cell lung cancer; however, serious adverse events (AEs), including elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and interstitial lung disease (ILD), develop occasionally. Here, we evaluated relationships between clinically significant crizotinib-associated AEs and germline variations.

Materials And Methods: DNA obtained from 75 patients allowed selection of 147 genes according to function, exon identification and sequencing, and determination of germline single nucleotide variants (SNVs). Correlations between clinically significant AEs and presence of germline variants were estimated by Fisher's exact test.

Results: We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of ILD. These AEs were observed in 26 patients (35%), with elevated AST/ALT (15%) the most common, followed by neutropenia (5%), ILD (4%), and thromboembolic events (4%). Nonsynonymous SNVs in epoxide hydrolase 1 (EPHX1) [odds ratio (OR): 3.86; p = 0.0009) and transcription factor 7-like 2 (TCF7L2) (OR: 2.51; p = 0.025) were associated with the presence of clinically significant AEs.

Conclusion: Nonsynonymous EPHX1 and TCF7L2 SNVs might be associated with clinically significant crizotinib-associated AEs. These data indicated that target-gene sequencing could be feasible for predicting anticancer-agent toxicity, and that germline multi-gene information might be useful for predicting patient-specific AEs to promote precision medicine.
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http://dx.doi.org/10.1016/j.lungcan.2018.12.002DOI Listing
February 2019
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