Strengthening Genetic Screening Platform in APAC for Lung Cancer Precision Medicine: An Interview with Dr. Koichi Goto

Lung cancer is the most common cancer worldwide and an estimated 2.2 million people were diagnosed with lung cancer in 2020. With the aim of delivering precision therapeutic drugs to lung cancer patients in the Asia-Pacific Region and promoting new clinical trials, LC-SCRUM-Asia, an industry-academia collaborative project investigating genomic alterations in lung cancer, was launched in Japan in 2013. As of February 2023, over 18,000 lung cancer patients have been enrolled in about 200 hospitals in Japan and multiple sites in several Asian countries. 

GeneOnline is honored to have Dr. Koichi Goto, the founder of the LC-SCRUM project, for an interview. Dr. Goto is currently the Chief of the Department of Thoracic Oncology at the National Cancer Center Hospital East, with research expertise in rare genetic mutations associated with lung cancer and lung cancer genomic screening. During the interview, he covered the origin, development and clinical importance of the LC-SCRUM project. He also mentioned the possible impact this large-scale genomic screening project would have on patient care and national health in Asian countries.

Related article: AstraZeneca Taps China’s AmoyDx for Companion Diagnostics 

Oncogenic Drivers for NSCLC and Their Importance

Overall, there are 2 main types of lung cancer: small cell lung cancer (SCLC, accounting for about 15% of cases) and non-small cell lung cancer (NSCLC, accounting for about 85% of cases). In particular, a rapidly increasing number of oncogenic drivers such as EGFR, ALK, KRAS, RET, HER2, BRAF and ROS1 have been identified in NSCLC in recent years. Mutations of these genes are not only associated with the initiation and maintenance of the cancer, but also determining factors on treatment options available and patients’ therapeutic outcomes. 

However, except for EGFR and KRAS mutations, which are more frequently found in NSCLC, each of other oncogenic driver mutations only account for a small portion of the total cases (less than 5%). Nevertheless, as Dr. Goto mentioned, the number of patients with one or more of these rare mutations constitutes roughly 15-20% of total NSCLC cases. With this in mind, he stressed that it is important to identify patients with rare driver alterations to enable more precise treatments and to support the development of novel targeted therapies.

Origin of the LC-SCRUM Project and its Major Achievements

As Dr. Goto recalled in the interview, a RET rearrangement , which is present in 1–2% of lung adenocarcinomas (a subtype of NSCLC), was identified and published in the journal Nature Medicine in 2012. The mutation was so rare that it was extremely difficult to find enough patients to conduct clinical trials and gather scientifically meaningful results for the development of drugs targeting such genomic alterations . 

In 2013, Dr. Goto initiated a large-scale lung cancer genomic screening platform (LC-SCRUM) in Japan, collaborating with multiple hospitals and research institutions around Japan to identify NSCLC patients with rare oncogenes, with the aim of collecting enough patients to conduct clinical trials for potential drugs. 

One example mentioned by Dr. Goto was Vandetanib, a multikinase inhibitor that is used for treating thyroid cancer. Although the drug originally could not win approval to treat lung cancer in general, it might have the potential to treat NSCLC patients with the rare RET rearrangements since RET-tyrosine kinase inhibition is one of its treatment targets. 

In January 2017, a Phase 2 LURET study was published in The Lancet Respiratory Medicine. This open-label trial aimed to assess the efficacy and safety of Vandetanib in treating patients with advanced RET-rearranged NSCLC. With the aid of LC-SCRUM-Asia, RET-positive patients were screened from about 200 participating institutions for clinical trial enrollment. Results of this trial showed that Vandetanib demonstrated clinical anti-tumor activity and a manageable safety profile in patients with advanced RET-rearranged NSCLC. In other words, RET rearrangement would be a new molecular subgroup of NSCLC suitable for targeted therapy. 

According to Dr. Goto, another targetable gene alteration in NSCLC efficiently screened by LC-SCRUM-Asia is ROS1 fusion. This nationwide screening system successfully identified sufficient ROS-1fusion-positive NSCLC patients for a Phase 2 trial assessing treatment effectiveness and safety of oral crizotinib. Published in the Journal of Clinical Oncology in March 2018, the study demonstrated clinically meaningful benefits and durable responses with crizotinib in East Asian patients with ROS1 fusion-positive advanced NSCLC.

Thanks to the progress of LC-SCRUM, NSCLC patients with rare driver oncogenes can be matched to participate in appropriate clinical trials. Molecular agents targeting rare oncogenic drivers have also been able to proceed because sufficient patients have been recruited, thus allowing these drugs to have the necessary clinical data to apply for approval. Over the past few years, several targeted drugs for lung cancer with rare oncogenic drivers have earned approval from the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.

Advancing LC-SCRUM by Amoy’s PLC PCR Panel

During the first two years of the LC-SCRUM-Asia, traditional singleplex PCR analysis was adopted for the project, focusing on one target gene (e.g., RET, ALK and ROS1) at a time. In 2015, Oncomine, a next-generation sequencing (NGS) and genomic profiling system was introduced, allowing identification of multiple oncogenic drivers in a single test. Starting from 2019, the Pan Lung Cancer (PLC) PCR Panel developed by Amoy Diagnostics was adopted. It is a 9-in-1 specialized panel for detecting 9 targetable oncogenic driver alterations in lung cancer, allowing efficient identification of patients that may benefit from targeted therapies. 

According to Dr. Goto, one of the biggest advantages of AmoyDx PLC PCR Panel is that it can significantly shorten the turnaround time when compared to NGS panels, from 14 days to approximately 3 days. He stressed that the dramatic reduction in turnaround time would allow early identification of NSCLC patients with rare oncogenic driver mutations, thereby making it possible to offer precision medicine targeting the genes in question as early as possible. This would be beneficial to the patient, as in the past with singleplex detection or NGS panel alone, patients usually had to wait two weeks or more for results before mutated genes could be identified and precision therapy could begin. However, with the AmoyDx PLC PCR Panel, doctors would be able to identify the mutated genes much faster and could already use precision medicine at the first line of treatment. This would make it a promising genetic alteration search tool in advanced-stage lung cancer cases, where treatment decisions must be made as quickly as possible.

While the AmoyDx PLC PCR Panel has made a significant contribution to the advancement of lung cancer precision medicine, Dr. Goto pointed out that NGS technology and the PLC PCR Panel can actually play different roles in lung cancer genomic screening. Through NGS panels, doctors or researchers can screen for dozens to hundreds of known genomic alterations  at a time, allowing them to better understand the combination of mutations in patients and explore the effects of using different drugs to target individual mutations. However, he added that from the clinical perspective, there are currently only 9 druggable oncogenes  with corresponding targeted drugs, and even if hundreds of mutations could be screened with NGS, most of the remaining results would be wasted for the treatment. Furthermore, even if there might be drugs targeting other rarer mutations, the number of patients would be too small to convince pharmaceutical companies to invest or sponsor in clinical trials. 

In recent years, AmoyDx PLC PCR Panel has received multiple approvals from the Ministry of Health, Labour and Welfare (MHLW) in Japan as companion diagnostics to direct the use of drugs targeting various oncogenic driver mutations in NSCLC. Examples include tepotinib for MET gene exon 14 skipping alterations, selpercatinib for RET fusion, and sotorasib for KRAS G12C mutation. 

Expanding Scale of LC-SCRUM Makes Way to Affordable Lung Cancer Precision Medicine

In November 2018, the National Cancer Center of Japan kicked off a partnership with Chang Gung Memorial Hospital in Taiwan, expanding the lung cancer genomic screening network of LC-SCRUM outside Japan. Since then, the project has been upgraded to an international genomic screening platform. From 2022, LC-SCRUM-Asia has expanded its network to Southeast Asian countries such as Thailand and Malaysia, making it possible for international clinical trials to be conducted in Southeast Asian countries. With the sponsorship from government agencies or pharmaceutical companies, patients no longer have to pay for these genomic screening tests.

Towards the end of the interview, Dr. Goto also mentioned his vision for the future of the LC-SCRUM-Asia program. As LC-SCRUM-Asia is gradually expanding, with more than 18,000 lung cancer patients having undergone genetic screening as of earlier this year, he expressed his hope that the program will continue to promote the development of precision medicine for lung cancer in Japan and across Asia, “finding the right drug for the right patient,” extending the overall survival of patients and improving their quality of life. 

In addition, in terms of medical insurance, lung cancer genomic screening is now covered by Japanese medical insurance, including single gene testing and some NGS panels. The AmoyDx PLC PCR Panel was also included in 2021 as a reimbursed companion diagnostic for multiple anti-cancer agents. However, Taiwan and Southeast Asia are relatively unprepared for the development of supportive health insurance packages. Dr. Goto expected that the successful experience of Japan would set a good example for other countries in the Asia-Pacific region to accelerate the inclusion of health insurance coverage and make precision medicine more accessible.

Author

Richard Chau