Publications by authors named "Hidetoshi Hayashi"

186 Publications

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M-positive lung cancer after osimertinib.

Int J Clin Oncol 2021 Jun 11. Epub 2021 Jun 11.

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC).

Methods: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance.

Results: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib.

Conclusions: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
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http://dx.doi.org/10.1007/s10147-021-01947-3DOI Listing
June 2021

Gefitinib With Concurrent Thoracic Radiotherapy in Unresectable Locally Advanced NSCLC With EGFR Mutation; West Japan Oncology Group 6911L.

J Thorac Oncol 2021 Jun 9. Epub 2021 Jun 9.

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

Introduction: About 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted.

Methods: Chemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366).

Results: Between August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45-74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%-). The overall response rate was 81.5% (95% CI: 63.3%-91.3%), median PFS was 18.6 months (95% CI: 12.0-24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo-not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each).

Conclusions: This prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.
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http://dx.doi.org/10.1016/j.jtho.2021.05.019DOI Listing
June 2021

Clinical implications of bronchoscopy for immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer.

BMC Pulm Med 2021 May 8;21(1):155. Epub 2021 May 8.

Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan.

Background: The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition.

Patients And Methods: Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed.

Results: Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes.

Conclusion: A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.
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http://dx.doi.org/10.1186/s12890-021-01523-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106835PMC
May 2021

Periplocin and cardiac glycosides suppress the unfolded protein response.

Sci Rep 2021 May 4;11(1):9528. Epub 2021 May 4.

Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan.

The unfolded protein response (UPR) controls protein homeostasis through transcriptional and translational regulation. However, dysregulated UPR signaling has been associated with the pathogenesis of many human diseases. Therefore, the compounds modulating UPR may provide molecular insights for these pathologies in the context of UPR. Here, we screened small-molecule compounds that suppress UPR, using a library of Myanmar wild plant extracts. The screening system to track X-box binding protein 1 (XBP1) splicing activity revealed that the ethanol extract of the Periploca calophylla stem inhibited the inositol-requiring enzyme 1 (IRE1)-XBP1 pathway. We isolated and identified periplocin as a potent inhibitor of the IRE1-XBP1 axis. Periplocin also suppressed other UPR axes, protein kinase R-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Examining the structure-activity relationship of periplocin revealed that cardiac glycosides also inhibited UPR. Moreover, periplocin suppressed the constitutive activation of XBP1 and exerted cytotoxic effects in the human multiple myeloma cell lines, AMO1 and RPMI8226. These results reveal a novel suppressive effect of periplocin or the other cardiac glycosides on UPR regulation, suggesting that these compounds will contribute to our understanding of the pathological or physiological importance of UPR.
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http://dx.doi.org/10.1038/s41598-021-89074-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097017PMC
May 2021

Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease.

Sci Rep 2021 Apr 29;11(1):9242. Epub 2021 Apr 29.

Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8 T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4 T cells, CD8 T cells, CD20 B cells, and FOXP3 Tregs. Overall, the activation of CD8 T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
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http://dx.doi.org/10.1038/s41598-021-88824-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085223PMC
April 2021

First-line durvalumab plus platinum-etoposide in extensive-stage small-cell lung cancer: CASPIAN Japan subgroup analysis.

Int J Clin Oncol 2021 Jun 7;26(6):1073-1082. Epub 2021 Apr 7.

Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.

Background: In the phase 3 CASPIAN study (NCT03043872), first-line durvalumab plus etoposide and cisplatin or carboplatin (EP) significantly improved OS versus EP alone in patients with extensive-stage (ES)-SCLC (HR 0.73 [95% CI 0.59-0.91; p = 0.0047]). Here we report results for a preplanned subgroup analysis of patients recruited in Japan.

Methods: Treatment-naïve patients with ES-SCLC received either 4 cycles of durvalumab 1500 mg plus EP q3w followed by maintenance durvalumab 1500 mg q4w until disease progression or up to 6 cycles of EP q3w. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability.

Results: In the Japan subgroup, 18 patients were randomized to durvalumab plus EP and 16 patients to EP. At the interim analysis with a median follow-up of 12.5 months in the subgroup, OS numerically favored durvalumab plus EP versus EP (HR 0.77 [95% CI 0.26‒2.26]; median not reached vs 15.2 months). PFS was similar for durvalumab plus EP versus EP (HR 0.90 [95% CI 0.43‒1.89]). Confirmed ORR was 89% with durvalumab plus EP versus 69% with EP. Adverse events (AEs) of CTCAE grade 3 or 4 were reported in 78% versus 94% of patients in the durvalumab plus EP versus EP arms. There were no AEs leading to treatment discontinuation or death in the Japan subgroup.

Conclusion: First-line durvalumab plus EP was effective and well tolerated in Japanese patients with ES-SCLC. Despite the small size of the Japan subgroup, results were generally consistent with the global study population.
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http://dx.doi.org/10.1007/s10147-021-01899-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134304PMC
June 2021

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

Eur J Cancer 2021 Mar 22;145:183-193. Epub 2021 Jan 22.

Respiratory Division, Department of Internal Medicine, Itami City Hospital, 1-100 Koyaike, Itami City, Hyogo, 664-8540, Japan.

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited.

Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group.

Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001).

Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
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http://dx.doi.org/10.1016/j.ejca.2020.12.026DOI Listing
March 2021

Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial.

JAMA Oncol 2021 Mar;7(3):386-394

Internal Medicine III, Wakayama Medical University, Wakayama, Japan.

Importance: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically.

Objective: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation.

Design, Setting, And Participants: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio.

Interventions: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety.

Results: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%).

Conclusions And Relevance: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation.

Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000023761.
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http://dx.doi.org/10.1001/jamaoncol.2020.6758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791398PMC
March 2021

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

Oncologist 2021 04 6;26(4):e588-e596. Epub 2021 Jan 6.

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

Background: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors.

Materials And Methods: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan.

Results: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy.

Conclusion: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs.

Implications For Practice: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
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http://dx.doi.org/10.1002/onco.13639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018334PMC
April 2021

Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts.

Br J Cancer 2021 Mar 10;124(5):914-924. Epub 2020 Dec 10.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects.

Methods: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB).

Results: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8 T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8 T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice.

Conclusions: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8 T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
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http://dx.doi.org/10.1038/s41416-020-01201-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921555PMC
March 2021

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

JAMA Oncol 2020 Dec;6(12):1931-1938

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

Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.

Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.

Design, Setting, And Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.

Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations.

Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations.

Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.

Conclusions And Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.

Trial Registration: UMIN Identifier: UMIN000016794.
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http://dx.doi.org/10.1001/jamaoncol.2020.4643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563669PMC
December 2020

Safety and efficacy of cetuximab-containing chemotherapy after immune checkpoint inhibitors for patients with squamous cell carcinoma of the head and neck: a single-center retrospective study.

Anticancer Drugs 2021 01;32(1):95-101

Department of Medical Oncology.

Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.
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http://dx.doi.org/10.1097/CAD.0000000000001006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748051PMC
January 2021

Phase I/II Study of Cisplatin plus Nab-Paclitaxel with Concurrent Thoracic Radiotherapy for Patients with Locally Advanced Non-Small Cell Lung Cancer.

Oncologist 2021 01 28;26(1):19-e52. Epub 2020 Sep 28.

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

Lessons Learned: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted.

Background: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen.

Methods: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD.

Results: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively.

Conclusion: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m and cisplatin at 75 mg/m every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
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http://dx.doi.org/10.1002/ONCO.13524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794196PMC
January 2021

Anti-Inflammatory Activity of Kurarinone Involves Induction of HO-1 via the KEAP1/Nrf2 Pathway.

Antioxidants (Basel) 2020 Sep 9;9(9). Epub 2020 Sep 9.

Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.

Kurarinone, a flavonoid isolated from the roots of , was suggested to exert potent antioxidant and immunosuppressive effects. However, the underlying mechanisms remain unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the antioxidant defense system with anti-inflammatory activity. In the present study, we demonstrated that kurarinone activated Nrf2 and increased the expression of antioxidant enzymes, including heme oxygenase-1 (HO-1). Mechanistically, kurarinone downregulated the expression of kelch-like ECH-associated protein 1 (KEAP1), subsequently leading to the activation of Nrf2. Kurarinone also inhibited the expression of the inflammatory cytokine, interleukin (IL)-1β, and inducible nitric oxide synthase (iNos) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The overexpression of HO-1 suppressed the LPS-induced production of inflammatory mediators in RAW264.7 cells, and the immunosuppressive effects of kurarinone were partially inhibited by a treatment with Tin Protomorphyrin IX (TinPPIX), an inhibitor of HO-1. These results indicate that kurarinone activates the KEAP1/Nrf2 pathway to induce HO-1 expression, thereby exerting immunosuppressive effects.
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http://dx.doi.org/10.3390/antiox9090842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554885PMC
September 2020

A Case of Pulmonary Tumor Thrombotic Microangiopathy Suggested by the Presence of Tumor Cells in Peripheral Blood.

Case Rep Oncol 2020 May-Aug;13(2):843-848. Epub 2020 Jul 14.

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

Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by tumor cell microemboli with occlusive fibrointimal remodeling in small pulmonary vessels. Platelet-derived growth factor (PDGF) has been implicated in the development of PTTM, and fibroblast growth factor (FGF) promotes PDGF signaling via PDGF receptor β. We here describe a cancer patient who presented with dyspnea of uncertain etiology and whose condition worsened rapidly. A 68-year-old man with hypopharyngeal squamous cell carcinoma (cT4aN2bM0, stage IVA) was treated with surgery followed by radiation. Two years later, a lung metastatic lesion was surgically removed on the basis of suspected primary lung cancer. The patient was thereafter monitored without chemotherapy. Two months later, he had third-degree burns and received conservative therapy including debridement and application of trafermin (FGF2) spray. Two weeks later, he was hospitalized with complaints of fever and dyspnea. Pneumonia and pulmonary embolism were ruled out by chest computed tomography with pulmonary arterio-graphy, whereas intravascular lymphoma was excluded by laboratory testing. Malignant cells were detected in his peripheral blood on hospital day 8, and their number increased gradually thereafter. His respiratory symptoms worsened, and the patient died on hospital day 10. We concluded that the cause of death was PTTM, with the clinical course suggesting a possible relation to trafermin. This suggestion was supported by the detection of FGF receptor 2 overexpression in the primary tumor by immunostaining.
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http://dx.doi.org/10.1159/000508362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443647PMC
July 2020

Lorlatinib in previously treated anaplastic lymphoma kinase-rearranged non-small cell lung cancer: Japanese subgroup analysis of a global study.

Cancer Sci 2020 Oct 11;111(10):3726-3738. Epub 2020 Sep 11.

The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC-ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged/ROS1-rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. The ORR and the IC-ORR for Japanese patients in EXP2-5 were 54.8% (95% confidence interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single-dose and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
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http://dx.doi.org/10.1111/cas.14576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540988PMC
October 2020

Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2020 09 10;21(5):472-476. Epub 2020 Apr 10.

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

Background: First-line treatment of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor-mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC.

Patients And Methods: Cytotoxic chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival.

Conclusion: This is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC.
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http://dx.doi.org/10.1016/j.cllc.2020.03.010DOI Listing
September 2020

Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?

BMC Med 2020 04 21;18(1):111. Epub 2020 Apr 21.

Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osakasayama, Osaka, 589-8511, Japan.

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http://dx.doi.org/10.1186/s12916-020-01583-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171785PMC
April 2020

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer.

Invest New Drugs 2020 10 3;38(5):1588-1597. Epub 2020 Apr 3.

Medical Oncology Department, Vall d´Hebron University Hospital/Vall d´Hebron Institute of Oncology, Passeig de la Vall d'Hebron 119-129, Barcelona, 08035, Spain.

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m) or S-1 (30 mg/m). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.
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http://dx.doi.org/10.1007/s10637-020-00930-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497678PMC
October 2020

Severe Immune-Related Hepatitis Treated With Plasma Exchange.

J Thorac Oncol 2020 03;15(3):e39-e42

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

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http://dx.doi.org/10.1016/j.jtho.2019.11.014DOI Listing
March 2020

Propensity score-weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non-small cell lung cancer (WJOG10217L).

J Immunother Cancer 2020 02;8(1)

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

Background: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone.

Methods: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors.

Results: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, or genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively.

Conclusions: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
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http://dx.doi.org/10.1136/jitc-2019-000350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057433PMC
February 2020

Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in Mutation-Positive Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 04 14;26(8):2037-2046. Epub 2020 Jan 14.

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

Purpose: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear.

Experimental Design: We retrospectively identified 138 patients with -mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing.

Results: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI ( = 0.0010). Whereas CD8 and FOXP3 TIL densities were significantly lower after EGFR-TKI treatment than before, CD8 TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months.

Conclusions: EGFR-TKI treatment was associated with changes in the TME of -mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2027DOI Listing
April 2020

Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence.

Cells 2020 01 9;9(1). Epub 2020 Jan 9.

Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.

Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.
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http://dx.doi.org/10.3390/cells9010171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016652PMC
January 2020

Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration.

Nat Med 2020 01 13;26(1):47-51. Epub 2020 Jan 13.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs). These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition. Crizotinib is a multikinase inhibitor with potent activity against MET. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.
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http://dx.doi.org/10.1038/s41591-019-0716-8DOI Listing
January 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

Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors.

Sci Rep 2019 12 20;9(1):19501. Epub 2019 Dec 20.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, 589-8511, Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1-generation and 29 with 2-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274-7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865-4.318) but not against 2-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
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http://dx.doi.org/10.1038/s41598-019-55939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925200PMC
December 2019

Impact of coexisting gene mutations in EGFR-mutated non-small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs.

Lung Cancer 2020 01 3;139:28-34. Epub 2019 Nov 3.

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

Objectives: The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment.

Materials And Methods: A total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software.

Results: Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P =  0.049).

Conclusions: Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.
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http://dx.doi.org/10.1016/j.lungcan.2019.10.028DOI Listing
January 2020

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation.

J Clin Invest 2020 01;130(1):374-388

Department of Medical Oncology.

Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3-targeting (HER3-targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
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http://dx.doi.org/10.1172/JCI126598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934205PMC
January 2020

Aberrant HER3 ligand heregulin-expressing head and neck squamous cell carcinoma is resistant to anti-EGFR antibody cetuximab, but not second-generation EGFR-TKI.

Oncogenesis 2019 Sep 30;8(10):54. Epub 2019 Sep 30.

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

The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is standard therapy for head and neck squamous cell carcinoma (HNSCC). However, most HNSCC tumors are resistant to it and require alternative treatments. Here, we explored the mechanism of cetuximab resistance and evaluated its clinical relevance in HNSCC. An unbiased comprehensive transcriptome analysis was performed on cetuximab-resistant HNSCC FaDuCR cells. The causative resistance genome was knocked down with siRNA, cell signaling was immunologically analyzed, and drug efficacy was evaluated in vitro and in vivo. The mRNA in situ hybridization (ISH) of the causative genome was performed using 28 excised HNSCC tumors and its relationship with cetuximab efficacy was analyzed. FaDuCR cells were resistant to cetuximab, whereas parental FaDu cells were susceptible to it. FaDuCR cells expressed consistently higher levels of phosphorylated Akt than FaDu cells despite cetuximab exposure. A comprehensive transcriptome analysis revealed that the HER3-ligand heregulin was upregulated in FaDuCR cells compared to FaDu cells. Heregulin knockdown in FaDuCR cells repressed HER3 and Akt phosphorylation and recovered cetuximab anticancer efficacy. In contrast, pan-HER family tyrosine kinase inhibitors such as afatinib decreased HER3 and Akt phosphorylation in FaDuCR cells and inhibited FaDuCR tumor growth. Two of the 28 HNSCC tumor samples presented aberrant heregulin expression comparable to that of FaDuCR cells and were resistant to cetuximab therapy. In HNSCC, heregulin-mediated HER3-Akt activation causes resistance to cetuximab but not to second-generation EGFR-tyrosine kinase inhibitors. Subpopulations with aberrant heregulin-expressing HNSCC might be resistant to cetuximab.
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http://dx.doi.org/10.1038/s41389-019-0164-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769016PMC
September 2019

Combination therapy with PD-1 or PD-L1 inhibitors for cancer.

Int J Clin Oncol 2020 May 23;25(5):818-830. Epub 2019 Sep 23.

Department of Medical Oncology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Immune checkpoint inhibitors (ICIs)-such as antibodies to programmed cell death-1 (PD-1), to its ligand PD-L1, or to cytotoxic T lymphocyte-associated protein-4 (CTLA-4)-are an evolving treatment option for several types of cancer, but only a limited number of patients benefit from such therapy. Preclinical studies have suggested that the combination of PD-1 or PD-L1 inhibitors with either cytotoxic chemotherapy or antibodies to CTLA-4 is a promising treatment strategy for advanced cancer. Indeed, combinations of cytotoxic chemotherapy and PD-1/PD-L1 inhibitors have been approved and are now used in clinical practice for the treatment of advanced non-small cell lung cancer and small cell lung cancer on the basis of positive results of large-scale clinical trials. In addition, the combination of antibodies to CTLA-4 (ipilimumab) and to PD-1 (nivolumab) has been found to confer a survival benefit in patients with melanoma or renal cell carcinoma. Several ongoing clinical trials are also investigating ICI combination therapy in comparison with standard therapy for other tumor types. The identification of patients likely to achieve a sufficient benefit from PD-1/PD-L1 inhibitor monotherapy remains a challenge; however, with the establishment of novel complementary biomarkers being needed. Preclinical and clinical investigations of immune-related adverse events of ICI combination therapy are also warranted to establish management strategies. In this review, we summarize the current landscape of combination therapy with PD-1/PD-L1 inhibitors plus either cytotoxic chemotherapy or CTLA-4 inhibitors to clarify the benefits of and outstanding clinical issues related to such treatment.
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http://dx.doi.org/10.1007/s10147-019-01548-1DOI Listing
May 2020