|Isamu Okamoto||Last modified date：2019.06.25|
Lecturer / Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyushu University
Kyushu University Hospital
Kyushu University Hospital
Doctor of Medicine
Country of degree conferring institution (Overseas)
Field of Specialization
Respiratory disease, Thoracic Oncology, Medical Oncology
Total Priod of education and research career in the foreign country
Research InterestsMembership in Academic Society
- Establishment of new standard treatment for elderly patients with advanced non-squamous non-small cell lung cancer.
keyword : elderly patients, phase III study, non-squamous non-small cell lung cancer.
- A study on development of standard therapy for advanced non-small cell lung cancer with idiopathic pulmonary fibrosis
keyword : non-small cell lung cancer, Phase III study, idiopathic pulmonary fibrosis
- Combination cancer immunotherapy of the PD-1-blockade antibody and a mitochondrial activation chemical
keyword : 1 ( Immune metabolism ) 2 ( Bezafibrate ) 3 ( anti-PD-1 antibody ) 4 ( Mitochondria ) 5 ( PGC-1 ) 6 ( Killer T cells ) 7 ( Energy metabolism ) 8 ( Clinical investigator-initiated clinical trial ) 9 ( Cancer immunotherapy ) 10 ( Combination therapy )
- A study of HER2 targeted therapy for patients with non small cell lung cancer positive for HER2 gene mutations based on the analysis of comprehensive genomic profiling assay with next generation sequencing
keyword : HER2 targeted therapy, non small cell lung cancer, next generation sequencing
- PD-L1 expression in non-small-cell lung cancer haboring driver oncogene alterations
keyword : Non-small-cell lung cancer, EGFR mutations, ALK rearrangements, Immune check point, PD-L1
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by worsening dyspnea and progressive loss of lung function. Acute exacerbation of IPF is associated with high morbidity and mortality. It is the leading cause of death (40%) in patients with this condition, followed by chronic respiratory failure (24%) and lung cancer (11%). Several studies have provided evidence of an association between lung cancer and IPF, with the prevalence of lung cancer in IPF patients ranging from 9.8% to 38%. Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. The recent identification of driver oncogenes such as EGFR, ALK, ROS1 and BRAF has led to the development of targeted agents, which have proved superior to chemotherapy for first-line management of advanced NSCLC with these genetic alterations. However, treatment with such agents must be limited to patients with the corresponding molecular targets, with the standard first-line treatment of most cases of advanced NSCLC remaining platinum-based combination chemotherapy. Cytotoxic chemotherapy induces acute exacerbation of IPF that can be lethal in some patients, with the incidence of chemotherapy-induced acute exacerbation of interstitial pneumonia reported at w5% to 30%.
Nintedanib was investigated in 2 replicate, randomized phase III trials (INPULSIS-I/II). The integrated analysis revealed a significant benefit for nintedanib versus placebo in the interval to the first acute exacerbation.
Although the efficacy of nintedanib for IPF has been demonstrated, it is unclear whether this drug reduces the risk of chemotherapy-induced acute exacerbation of IPF. Given that patients with interstitial pneumonia have been excluded from most prospective clinical trials of NSCLC, data on the safety and efficacy of chemotherapy for such patients are lacking. A phase II trial of carboplatin plus weekly-paclitaxel was performed for patients with advanced NSCLC and interstitial pneumonia. Of the 18 patients enrolled in the trial, one (5.6%) with IPF experienced acute exacerbation. Although the sample size was small, that trial is one of the few prospective studies of for NSCLC with interstitial pneumonia. On the basis of these findings, the combination of carboplatin and paclitaxel is frequently given to such patients in clinical practice.
With this background, we designed a randomized study to evaluate the efficacy and safety of nintedanib combined with carboplatin plus nab-paclitaxel compared with carboplatin plus nabpaclitaxel alone for chemotherapy-naive patients with advanced NSCLC and IPF.
- “Cancer genomic medicine” for development of an innovative medicines based on the analysis of information about genomics and clinical records is now ongoing in Japan. It is expected that introduction of the comprehensive genomic analysis and screening of cancer-related gene are going to be carried on a full-scale operation in the near future. Although HER2 gene mutations are one of the driver mutations and have been identified in 2-4% of non-small cell lung cancer (NSCLC), no effective targeted therapy has been developed for NSCLC with such mutations. Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate of trastuzumab and derivative of maytansine (DM1), which has been approved for metastatic breast cancer positive for overexpression of HER2 protein but not for NSCLC. It has recently been reported that T-DM1 demonstrated a marked ORR of 44% (8 of 18 patients) in a phase II study abroad. Moreover, the ORR was 55% (6 of 11 patients) when focused on the exon 20 insertion mutation including exon 20 A775_G776insYVMA, which accounts for most (50-96%) of HER2 mutations. Several retrospective studies have shown that ORR in treatment with combination therapy of trastuzumab and chemotherapy for patients with NSCLC positive for HER2 exon 20 insertion mutations was 50-60%. Together with the basic studies demonstrating that HER2 exon 20 insertion mutations have functions as a driver mutation, such mutations should be a good target for treatment with an anti-HER antibody. We have planned to conduct a phase II study to evaluate the efficacy of T-DM1 for NSCLC positive for HER2 exon 20 insertion mutations (target sample size: 20), with ORR being a primary endpoint and with progression free survival, overall survival and safety being secondary endpoints. NSCLC with such mutations will be screened based on a next generation sequencing based comprehensive genomic profiling assay of FoundationOne CDxTM, LC-SCRUM-Japan or NCC Oncopanel. The purpose of our study is to have T-DM1 approved in expanded use forNSCLC positive for HER2 exon 20 insertion mutations, which confer an appropriate molecular targeted therapy to patients harboring such disease who have only received a treatment based on cytotoxic drugs. Approval of FoundationOne CDxTM as a companion diagnostic for T-DM1 is also the
aim of this study. Our study is expected to prolong the overall survival and to improve the QOL for these patients, which will make a pronounced contribution to the national welfare.
- An immune checkpoint inhibitor, anti-PD-1 antibody has revolutionized the cancer immunothrapy. However, over a half proportion of cancer patients are still less responsive. In order to improve the response rate of the patients, developing combination therapy is an urgent task.
Although recent reports have suggested the importance of energy metabolism in immune responses, it is totally unknown how energy metabolism can affect the anti-tumor immunity. Using a mouse cancer immunothrapy model with PD-1 blockade, we demonstrated that the mitochondria in periheral T cells are activated during the tumor regression. Through the screening of mitochndrial activation chemicals using the PD-1 blockade therapy model, we found peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1), which is a common downstream signal molecule of energy sensors mTOR and AMPK, is effective as a targeting partner for the combination therapy. PGC-1 is an transcriptional coactivator that binds to several transcriptions and improves mitochndrial biosynthesis, fatty acid β-oxidation and oxidative phosphorylation. Subsequent screening of chemicals revealed that Bezafibrate, which is an activator of one of the PGC-1α associated transcriptional factors, peroxisome proliferator-activated receptor (PPAR), augments anti-tumor efficacy and improves survival rates. While Bezafibrate is used as an anti-hyperlipidemia in the clinic, it is the first time to demonstrate the role of Bezafibrate to activate mitochondria and killer T cell function (Chamoto et al, PNAS, 114: E761-E770, 2017).
Based on these basic studies, we have planned to conduct the Phase I clinical investigator-initiated IND clinical trial of Bezafibrate combination therapy with Nivolumab in patients with previously treated advanced non-small cell lung cancer in Japan, pursuing future Phase III trial with a pharmaceutical company. The primary objective of this trial is to investigate safety and tolerability of this combination therapy. The secondary objective is to explore the efficacy of Bezafibrate on “immune metabolism” during the combination therapy and to obtain the Proof of Concept for the next Phase II clinical trial. Our highly functioning project team consists of investigators at Kyushu University that is designated as Translational and Clinical Research Core Center, Kyoto University basic researchers who spcialized in anti-PD-1 antibody therapy and designed this combination therapy, and clinical trial specialists at Translational Research Informatics Center that is a main hub of translational research in Japan, and will strongly promote this clinical development project.
- Randomized phase III study comparing carboplatin plus pemetrexed followed by pemetrexed versus docetaxel in elderly patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC) (JCOG1210/WJOG7813L).
The aim of this phase III randomized trial is to determine the efficacy of pemetrexed and carboplatin followed by pemetrexed for elderly pts with advanced non-squamous NSCLC.
Cytotoxic chemotherapy-naïve, PS 0-1 pts aged 75 years or older with advanced stage non-squamous NSCLC were randomly assigned to receive either docetaxel 60 mg/m2 on day 1, every 3 weeks [DOC] or pemetrexed 500 mg/m2 and carboplatin AUC 5 mg/ml/min on day 1 every 3 weeks [CBDCA/PEM]. After 4 cycles of CBDCA/PEM, maintenance therapy with pemetrexed 500 mg/m2, every 3 weeks is given until evidence of disease progression or development of unacceptable toxicities. The primary endpoint was to compare overall survival (OS) to demonstrate noninferiority for CBDCA/PEM relative to DOC (upper CI limit for HR < 1.154).
Between August 2013 to February 2017, 433 pts with a median age of 78 years (range, 75 to 88 years) were randomly assigned to the DOC group (n=217) or the CBDCA/PEM group (n=216). The median survival time was 15.5 months for the DOC group and 18.7 months for the CBDCA/PEM group. The stratified hazard ratio (HR) for OS in the CBDCA/PEM group compared with the DOC group was 0.850 (95% confidence interval (CI), 0.684 to 1.056), demonstrating the noninferiority of CBDCA/PEM (P<0.01). Progression-free survival was significantly better in the CBDCA/PEM group than in the DOC group (HR, 0.734; 95% CI, 0.604 to 0.891). The response rate was 28.2% in the DOC group and 36.8% in the CBDCA/PEM group (P=0.07). The incidence of neutropenia or febrile neutropenia of grade 3 or 4 was significantly lower in the CBDCA/PEM group, whereas grade 3 or 4 thrombocytopenia or anemia was more common in the CBDCA/PEM group. Four treatment-related deaths (two in each treatment group) occurred. In QOL(FACT-LCS), there was no significant difference between the treatment groups.
Pemetrexed/carboplatin followed by pemetrexed maintenance is a valid therapeutic option for the first-line treatment of elderly pts with advanced non-squamous NSCLC.
- The Japanese Association for Molecular Target Therapy of Cancer
- Japan Society of Clinical Oncology
- Japanese Society of Medical Oncology
- The Japan Lung Cancer Society
- The Japanese Cancer Association
- The Japanese Respiratory Society
- The Japanese Society of Internal Medicine
- Research Fellowship for Japanese Biomedical and Benavioval at NIH