World’s First Demonstration on Efficacy of Drug for Lung Cancer Genetic Mutation Diagnosed with Blood sample using cobas EGFR mutation test v2.Alleviating burden on patients through diagnosis with blood tests

Assistant Professor Takayuki Takahama, Professor Kazuhiko Nakagawa and Professor Kazuto Nishio from the Faculty of Medicine at Kindai University (Osakasayama City in Osaka Prefecture, Japan) joined by researchers participating in a clinical study group (West Japan Oncology Group, WJOG) conducted an investigator initiated clinical study on the gene mutation of EGFR*1, which is considered to function as a switch for lung cancer cell growth. The efficacy was demonstrated for the first time in the world, by prescribing osimertinib, a molecular target drug, to patients who tested positive for genetic mutation with a blood test.
It has been considered necessary in the past to conduct a test for mutation of the EGFR gene, by collecting tissues from a part of the tumor, using an endoscope or the like. The findings of this study, however, present the potential to alleviate the burden to patients of such testing.
Findings of this study are scheduled to be presented at the Annual Meeting of the Japanese Society of Medical Oncology, to be held at Kobe International Exhibition Hall on July 19 (Thursday), 2018.
*1 Epidermal Growth Factor Receptor: A protein that transmits signals to promote cell growth.

[Key aspects of this study]
- World’s first research findings that demonstrate efficacy and safety of a drug which is administered based on genetic screening results.
- Efficacy demonstrated by a response rate of 55.1%, which represents the ratio of people whose tumor shrunk.
- Potential for partial transition to blood test from endoscopic biopsy, which places a heavy burden on patients.

[Overview of the study]
Lung cancer is a disease which causes a significant number of fatalities in Japan; about 70,000 people are dying from this disease annually. There are many treatments available, such as surgery or radiation therapy, but intervention with pharmacotherapy, which spreads medication throughout the entire body, is essential when cancer has metastasized and spread to other parts of the body, or where the tumor has grown large due to progression to an advanced stage.
The cancer cell continues to grow out of control when the EGFR gene mutates. In such cases, treatment involving the administration of the inhibitor tyrosine kinase is effective. The efficacy of the drug may plateau, however, since resistance to the inhibitor is gained about one year after the administration is commenced. About half of such instances are caused by the mutation of the EGFR T790M gene, for which osimertinib is effective.
At the present time, a part of the tumor tissue has to be collected using an endoscope or the like in order to verify mutation of the EGFR T790M gene, while blood tests are limited to cases where testing with an endoscope or similar is deemed difficult. This is because until now, no study had been conducted that demonstrates the efficacy of osimertinib for patients that test positive for genetic mutation by blood tests.
Takahama and his associates conducted an investigator initiated trial that involved oral administration of osimertinib to patients who tested positive to genetic mutation by blood test, and demonstrated the effectiveness of the treatment with the sweep efficiency of 55.1%, which represents the proportion of people whose tumor shrunk. There is a potential for a review on the value of blood testing in the future, through which the burden on patients can be alleviated.
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Osaka Science and University Press Club (Osaka Kagaku Daigaku Kishakurabu), Kanan Press Club (Kanan Kishakurabu) and Higashiosaka City Government Press Club (Higashiosaka Shisei Kishakurabu).

[Academic conference presentation and details on paper]
Name of academic conference: The 16th Annual Meeting of the Japanese Society of Medical Oncology
Date and time: July 19 (Thursday), 2018 14:00 to 16:00
This study is scheduled to be presented after 14:30 for a duration of about ten minutes.
Venue: Portopia Hall, 1st Floor South Building, Kobe Portopia Hotel
(Near Shimin Hiroba Station of Port Liner Monorail Line, 6-9-1 Minatojima Nakamachi, Chuo-ku, Kobe)
Reception: “General information and Press Reception” on 1st floor at Hall No. 1 Building, Kobe International Exhibition Hall.

* Access to the Japanese Society of Medical Oncology is also available. Parties wishing to conduct individual interviews at the venue are directed to inquire in advance using the contact details below.
(Presentations are given in English. No simultaneous interpretation is available.)

This annual meeting is sponsored by the Japanese Society of Medical Oncology and is the pinnacle of academic meetings in the field of clinical oncology in Japan.
The abstract is scheduled to be featured on the Annals of Oncology.

Title of presentation: Phase II study to Assess the Efficacy of Osimertinib in Patients with Plasma T790M Positive Advanced NSCLC (WJOG 8815L/LPS).
Authors: Takayuki Takahama, Koichi Azuma, Mototsugu Shimokawa, Terufumi Kato, Haruko Daga, Isamu Okamoto, Hiroaki Akamatsu, Toshiaki Takahashi, Tatsuo Ohira, Toshihide Yokoyama, Katsuya Hirano, Yoshimasa Shiraishi, Daisuke Himeji, Nobuyuki Yamamoto, Kazuto Nishio and Kazuhiko Nakagawa.

[Background of the case]
The most dominant type of lung cancer is adenocarcinoma or glandular cancer. The administration of the EGFR tyrosine kinase, which is an inhibitor, is considered effective for patients with the EGFR genetic mutation found in tumors. The efficacy, however, diminishes over about a year in most cases, and the tumor starts to show resistance (refered to as “acquired resistance”). The majority of such cases are caused by the genetic mutation of EGFR T790M.
The application of osimertinib has been approved in Japan for patients who test positive for EGFR T790M genetic mutation - which is resistant to the tyrosine kinase inhibitor, and also for those unable to have surgery, or who have recurring non-small cell lung cancer, since the efficacy and safety of osimertinib has been demonstrated through an international joint clinical trial conducted on lung cancer patients that tested positive for EGFR T790M genetic mutation.
Presently in order to determine that the EGFR T790M genetic mutation is the cause of resistance, bronchoscopy or similar methods are required to collect cancer tissues. The approval for the use of blood tests is permitted only for patients for whom bronchoscopy is difficult for that reason.
This is because there have been no study cases done to indicate the efficacy of osimertinib for patients with EGFR T790M genetic mutation confirmed by a blood test alone, while the only available study results came from a study that targeted patients who had positive results for EGFR T790M genetic mutation from both a biopsy and blood test. The blood test intended for detection of the EGFR T790M genetic mutation has been approved for conditions where “testing of lung cancer tissue as a sample is difficult to conduct” and “only once per patient”.
Tests involving blood tests, however, are essentially minimally intrusive (lower burden on patients), with such benefits as samples being collected repeatedly, and the time required until test results become available is shortened. Since the EGFR T790M genetic mutation is not always detected in the course of treatments, situations where restrictions are placed on sample collection are not desirable.
This finding by a prospective study, for the first time in the world demonstrated the efficacy and safety of the drug through genetic diagnosis by blood testing. This will be essential in making genetic diagnosis using blood available as one option of diagnosis and treatment available in clinical fields in the future.

[Details of study]
1. Background
The EGFR T790M genetic mutation test using blood (liquid biopsy*1) is a test that can be conducted as a part of routine medical care these days. There has been no test done to establish a relationship between the results derived by liquid biopsy and the efficacy of osimertinib, and as such, the implementation of liquid biopsy is limited to cases where histology is not possible. This trial was a single arm phase II trial to verify efficacy of osimertinib with patients that tested positive for T890 genetic mutation with liquid biopsy.
*1 Liquid biopsy
A general term used for genetic testing and other applications, using liquid specimen (blood, urine, saliva, etc.). Advantages include the ease of sample collection and minimal intrusion, allowing for repeated collections.
2. Method
Patients who tested positive for EGFR genetic mutation, who have had treatment involving one or more regimen of EGFR-TKI (EGFR tyrosine kinase inhibitor), for whom disease progression was confirmed with the performance status*2 of 0 or 1 were screened. Cases of patients who were confirmed to have tested positive for plasma T790M were considered to qualify for the trial. Registered patients were orally administered 80 mg daily dose of osimertinib. The primary evaluation item was the sweep efficiency of patients for whom plasma T790M genetic mutation was verified using the cobas® EGFR Mutation Test v2.
*2 Performance-status: Indicator that represents the degree of the limitation on the daily lives of cancer patients.

0: Daily activities possible without any problem.
1: Physically strenuous activities are restricted, but walking, light work or working while seated are possible.
3. Result
Screening was conducted on 276 patients between June 2016 and December 2017. 73 patients tested positive for plasma T790M genetic mutation, of which 53 qualified for the clinical trial, who were administered osimertinib. The overall response rate was 55.1% (95% confidence interval: 40.2 and 69.3), resulting in this trial achieving primary outcomes. The toxicity of osimertinib was the same as other test data and manageable.
4. Conclusion
This trial indicated beneficial effects of osimertinib for lung cancer of patients, who tested positive for serum EGFR T790M genetic mutation by using the cobas method, for the first time with a prospective study. This finding is believed to offer essential information on potentials of liquid biopsy for diagnosis of lung cancer.

[Future outlook]
The findings of this study are scheduled to be featured as an article in a clinical academic journal after the presentation at the Annual Meeting of the Japanese Society of Medical Oncology. It is our hope that the finding of this study will be utilized for genetic diagnoses with liquid biopsy in the future, alleviate the burden experienced by patients, and advance individualized health care.

[Profile of researchers]
Takayuki Takahama
Affiliation:Clinical Internal Medicine (Medical Oncology)
Post:Assistant Professor
Academic degree: Doctor (Medicine)
Medical specialist: Respiratory specialist accredited by the Japanese Respiratory Society
Specialization:Genetic diagnosis of solid carcinoma, study of biomarker using blood, diagnosis and pharmacotherapy of solid carcinoma.
Academic societies: Japanese Society of Medical Oncology, Japanese Respiratory Society, Japanese Cancer Association, Japanese Association for Molecular Therapy of Cancer, Japan Lung Cancer Society, the Japanese Society of Internal Medicine, American Society of Clinical Oncology, among others.

Kazuhiko Nakagawa
Affiliation:Clinical Internal Medicine (Medical Oncology)
Post:Professor
Academic degree:Doctor (Medicine)
Specialization:Diagnosis and pharmacotherapy of solid carcinoma
Academic societies:Japanese Society of Medical Oncology, Chairperson of West Japan Oncology Group(WJOG), Japan Lung Cancer Society, Japanese Cancer Association, Japanese Association for Molecular Therapy of Cancer, American Society of Clinical Oncology (ASCO), The International Association for the Study of Lung Cancer (IASLC), among others.

Kazuto Nishio
Affiliation:Department of Genome Biology
Post:Professor
Academic degree:Doctor (Medicine)
Specialization:Tumor biology and biomarker studies using blood.
Academic societies:Japanese Society of Medical Oncology, West Japan Oncology Group (WJOG), Japanese Cancer Association,
Japanese Association for Molecular Therapy of Cancer, Japan Lung Cancer Society, American Society of Clinical Oncology(ASCO), American Association of Cancer Research, among others.