Understanding Asia’s growing role in epidermal growth factor receptor (EGFR) research Our expertise

EGFR is a transmembrane protein that is present on the surface of both normal cells and cancer cells. In short, it binds to epidermal growth factors, which activate a cascade of cellular responses leading to cell proliferation.

Mutations that cause EGFR overexpression are the leading cause of lung adenocarcinoma, the most common form of lung cancer. It is also the most common genetic change for which there are treatments available that directly target the lung cancer cells.

EGFR mutations are commonly detected in lung cancer among non-smokers and are more prevalent in women patients than men. Since the approval of gefitinib, a tyrosine kinase inhibitor (TKI) drug that targets EGFR mutations, nearly half of the new medications approved for the treatment of lung cancer address this molecular profile.

For EGFR-targeting TKI drugs, first- and second-generation TKIs are chosen for patients depending on their specific mutation and profile. Third-generation TKIs target the T790M mutation, which is an acquired resistance in approximately 50 percent of patients using first- and second-generation TKI therapies.

TKI drugs approved in the global market have been traditionally made and marketed by US and EU pharmaceutical companies. In an analysis of approved drugs and investigative drugs pipelines, we see that by the turn of the decade, Asia has overtaken as the leader in EGFR-targeting TKIs. As third-generation TKIs shifted to the center of attention, fourth-generation TKIs (for third-generation TKI resistance) are also under research and development.

Up until last year, only osimertinib was available as a third-generation EGFR TKI. In March 2020, almonertinib was approved in China, while in January this year, lazertinib received approval in South Korea. And most recently in March this year, furmonertinib was approved in China. Among the more than ten other candidates under clinical development, which include rezivertinib, nazartinib and mobocertinib, over two-thirds are from Chinese or Korean pharmaceutical companies.

While we still have to see whether these made-in-Asia drugs make it to US FDA and EU approval, we are already seeing developments that would not have happened five or ten years ago. In particular, Almonertinib was one of three Phase 3 trial drugs in-licensed by EQRx, a US startup that has already raised USD 750 million in its first year. Lazertinib has also been bundled in a Phase 3 combination trial with a promising EGFR-targeting biologic.

For the most up-to-date analysis on this topic, I recommend the following two articles:

• Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020
• Beyond Osimertinib: The Development of Third-Generation EGFR Tyrosine Kinase Inhibitors For Advanced EGFRþ NSCLC

In the past decade, Asia has become a preferred hub for evaluating new first-in-human/first-in-class compounds. Pharmacogenomic criteria for cohort selection are increasingly common in clinical trials for new oncological drugs and Asia of course makes the most sense for evaluating safety and efficacy in Asian populations.

Organizations such as the Asian Oncology Early Phase 1 Consortium and Asian Thoracic Oncology Research Group (ATORG) have both played a role in promoting Asian oncology clinical trials. The ATORG has been championing its own multi-national, multi-center Phase 2 clinical study - ATORG3 - on first-line treatment with a second-generation EGFR TKI drug, recruiting in Hong Kong, South Korea, Malaysia, Singapore and Thailand.

Another such trial is FLAURA2, a Phase 3 clinical study of a third-generation EGFR TKI drug used first-line in combination with chemotherapy. If successful, this trial would have implications on the way EGFR drugs are chosen for the patient. This trial is active in Japan, Taiwan, South Korea, China, India, South Korea, Thailand, the Philippines and Vietnam.

This has been indicative of trust in Asian markets in performing clinical trials and an affirmation of the technical and clinical abilities of South East Asia. I expect this trend of pharmaceutical companies choosing South East Asian countries to persist as these countries continue to upgrade their clinical trial capabilities.

Most long-standing sequencing initiatives look at clusters of populations localized to where sequencing infrastructure is abundant. For example, Gurdasani et al. found that genome-wide association studies have been significantly biased, with Asian ancestries accounting for only eleven percent of those studied. But the wide genetic diversity within East, South and Southeast Asia necessitates a more complete picture, and both normal and cancerous cells should be sequenced to gain meaningful information.

Initiatives such as Singapore’s SG10k and Taiwan’s G2020 have been launched in 2019 to sequence 10,000 genomes apiece. The Thai government’s 2019 GTI project is more ambitious, aiming at 50,000 genomes sequenced. Indeed, countries like Malaysia, the Philippines and Vietnam have also been exploring their projects. These projects are ongoing despite the COVID-19 pandemic.

One Asian-wide consortium, the GenomeAsia 100k, led by Indian clinical genomics company MedGenome and Singapore’s Nanyang Technological University, completed its Phase I sequencing study of approximately 1,700 individuals in 2019. The study had discovered or confirmed many genetic variants novel to Asian populations.

For example, it had found that approximately 400 million people in Austronesian groups are at severely increased risks of developing adverse effects to the epilepsy medication carbamazepine. Another confirmation was that one genetic variant of a hemoglobin gene found exclusively in South Indians is responsible for β-thalassemia.

The study also found that several on-the-market DNA chips optimized for Caucasian genomes are ineffective for Asian population samples, and that chips designed for Asians would be more efficient and cost-effective.

You can read the Consortium study here: 

• The GenomeAsia 100K Project enables genetic discoveries across Asia