|Isamu Okamoto||Last modified date：2021.10.26|
Lecturer / Research Institute for Disease of the Chest, Graduate School of Medical Sciences, Kyushu University
Kyushu University Hospital
Kyushu University Hospital
Reseacher Profiling Tool Kyushu University Pure
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
- Randomized controlled phase III trials to establish standard treatment for combined immunotherapy for treatment-naive advanced non-small cell lung cancer
keyword : Non-small-cell lung cancer, Combined immunotherapy, Randomized controlled phase III trials
- APPLE (WJOG11218L): a multicenter, open-label, randomized phase III study of atezolizumab and platinum-pemetrexed with or without bevacizumab for patients with advanced nonsquamous non–small cell lung cancer
keyword : bevacizumab, atezolizumab, advanced nonsquamous non–small cell lung cancer, progression-free survival, superiority
- J-SONIC: A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non-Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis
keyword : non-small cell lung cancer, Phase III study, idiopathic pulmonary fibrosis
- 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
- Phase 3 trial comparing nab-paclitaxel with docetaxel for previously treated advanced non–small cell lung cancer
keyword : Advanced non-small-cell lung cancer, Nab-paclitaxel, randomized phase 3 trial
- Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death in many countries. More than half of patients with NSCLC are diagnosed as advanced clinical stages, and there is an urgent need to develop more effective systemic drug therapies to improve their survival. In cases with driver genetic alterations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), the survival has been dramatically improved by the introduction of molecularly targeted agents. On the other hand, the prognosis for cases without driver-oncogene remains relatively poor.
Phase III studies in chemotherapy-naïve patients with advanced NSCLC including Keynote 189 and Keynote 407 have revealed that the combination of platinum-based therapy with pembrolizumab, an immune checkpoint inhibitor that targets programmed cell death–1 (PD-1), confers longer survival compared with platinum-based therapy alone, regardless of the level of PD-L1 expression in the tumor, with these findings having established such combinations as a new standard treatment. Moreover, the results of the CheckMate 9LA study were reported at ASCO 2020. Platinum combination chemotherapy with nivolumab (anti-PD-1 antibody) plus ipilimumab (anti- cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody) also significantly prolonged survival over platinum combination chemotherapy. Long-term survival, which is called the tail-plataeu, was expected in the combination group of chemotherapy with nivolumab plus ipilimumab.
We have now designed a randomized controlled phase III trial to confirm that chemotherapy with nivolumab plus ipilimumab is superior to chemotherapy with pembrolizumab for treatment-naïve patients with driver oncogene negative or unknown advanced NSCLC. This study will be conducted at 55 oncology facilities nationwide by the Japanese Clinical Oncology Group (JCOG), which has completed many phase III studies and contributed to the establishment of standard treatment. There are no randomized controlled phase III trials comparing chemotherapy with anti-PD-1 antibody with chemotherapy with anti-PD-1 antibody plus anti-CTLA-4 antibody as this study. If the primary endpoint of this study is achieved, chemotherapy with nivolumab plus ipilimumab will be established as a more powerful standard treatment and will be widely used in daily clinical practice. In addition, as an ancillary research, feces will be collected before the start of treatment and metagenomic analysis of the intestinal flora will be performed in this study. Thereby, the relationship between the intestinal flora and the therapeutic effect and adverse events will be examined. We hope that this will allow us to choose which combination immunotherapy is suitable for individual NSCLC patients.
- 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 III 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–naïve 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 (APP) or atezolizumab, pemetrexed-carboplatin, and bevacizumab (APPB). Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable side effects during treatment with at least one approved tyrosine kinase inhibitor. After four 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 III 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–naïve patients with advanced nonsquamous NSCLC.
- 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.
- Background: Nanoparticle albumin-bound (nab) paclitaxel is a promising new therapeutic agent for all histologic types
of nonesmall-cell lung cancer (NSCLC). We recently performed a phase 2 study of weekly nab-paclitaxel in patients
with previously treated advanced NSCLC, finding promising activity and acceptable toxicity for this regimen. We have
now designed a randomized phase 3 intergroup study (J-AXEL, UMIN000017487) to examine the clinical benefit and
safety of nab-paclitaxel compared to docetaxel in patients with previously treated advanced NSCLC. Patients and
Methods: Patients are randomized to receive either docetaxel (60 mg/m2 on day 1 every 3 weeks, control arm) or nabpaclitaxel
(100 mg/m2 on days 1, 8, and 15 every 3 weeks, experimental arm), with each drug being administered until
disease progression or unacceptable toxicity. The study will evaluate the noninferiority of nab-paclitaxel relative to
docetaxel for the primary end point of overall survival. Conclusion: If the primary objective is achieved, this study will
provide evidence for a new alternative treatment option for patients with previously treated advanced 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