Editor’s Note: The 27th National Conference on Clinical Oncology and the 2024 CSCO Annual Meeting, co-hosted by the Chinese Society of Clinical Oncology (CSCO) and the Beijing Xisike Clinical Oncology Research Foundation, was held from September 25 to 29, 2024, in Xiamen. During the conference, several forums on lung cancer covered cutting-edge research and developments in the field. During the event, Oncology Frontier invited Dr. Yilong Wu from Guangdong Provincial People’s Hospital to share his insights on making targeted therapy decisions for patients with EGFR-mutant non-small cell lung cancer (NSCLC).

1. Oncology Frontier: EGFR mutations are one of the most common driver mutations in NSCLC patients. Could you share your insights on personalized treatment strategies and how to choose between combination therapy and monotherapy for advanced EGFR-positive NSCLC patients?

Dr. Yilong Wu: EGFR mutations marked the beginning of precision medicine in NSCLC, and it has now been 20 years since these mutations were first targeted in clinical treatment. Over the past two decades, treatment strategies for EGFR mutations have evolved significantly in three key ways. First, we’ve moved from using first-generation targeted therapies to third-generation ones. Second, we’ve advanced from monotherapy to combination therapy. Third, we’ve expanded from single-target treatments to multi-target combination approaches.

As a result, treating patients with EGFR mutations has become increasingly complex, and clinical decisions must be made based on each patient’s specific circumstances rather than following a one-size-fits-all approach. Currently, third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib and China’s own amivantinib and furmonertinib, are the main drugs used in clinical practice. These third-generation EGFR TKIs have extended progression-free survival (PFS) to around 20 months, which is a significant achievement and has made them the mainstream treatment for EGFR-mutant NSCLC.

However, as our understanding of the biology of EGFR mutations deepens, we’ve discovered that some patients exhibit hyperactivity in this pathway, such as EGFR amplification or mutations in other EGFR sites. In these cases, third-generation EGFR TKIs may not be the best option, and we may consider using second-generation EGFR TKIs. Moreover, there are specific clinical situations, such as brain metastasis, that need to be addressed. Third-generation EGFR TKIs have excellent blood-brain barrier penetration, making them the preferred choice for brain metastasis. However, recent studies have shown that combining osimertinib with chemotherapy in patients with brain metastasis can offer greater survival benefits. Therefore, for NSCLC patients with brain metastasis, we recommend combining osimertinib with chemotherapy.

We also encounter patients with co-mutations, such as MET amplification, HER2 mutations, or ALK fusion, and in these cases, dual-targeted therapy is often employed. Given the wide range of options available, treatment decisions must be tailored to each patient’s specific situation to ensure the best therapeutic outcome.

2. Oncology Frontier: Combination therapy often increases the risk of adverse reactions compared to monotherapy. Could you share your approach to managing adverse reactions in NSCLC patients with EGFR mutations undergoing combination therapy?

Dr. Yilong Wu: It’s well known that all drugs come with side effects. Therefore, when making treatment decisions and throughout the treatment process, we must balance several factors. The first is efficacy—this includes both the effectiveness of the treatment and the duration of therapy. The second is toxicity, especially if the toxicity leads to treatment interruptions, which can negatively impact the overall treatment efficacy. It’s essential to balance efficacy and toxicity and prioritize using less toxic drugs when possible. This is one reason why combination therapy, despite offering longer survival benefits, is often questioned due to its higher toxicity.

The third factor to consider is cost. More drugs aren’t always better, and more expensive treatments aren’t necessarily more effective. Excessively high costs can be financially challenging for patients. The fourth factor, which is often overlooked, is the patient’s preference, including both the patient’s and their family’s wishes. Patients face not only medical issues but also many social and familial challenges during treatment. Therefore, the patient’s choice is always the best choice.

It’s crucial for physicians to inform patients of the best treatment options and outline the second-best and third-best alternatives. Once patients are presented with these options and understand the best course of action, they can make the decision that best fits their circumstances. At every critical juncture during treatment, we need to balance these four factors. As physicians, we must respect these factors and, above all, follow the patient’s wishes. However, it’s also our responsibility to clearly point out which treatment is the best and which is the second-best, providing clear guidance and advice to the patient.

3. Oncology Frontier: Some patients with advanced NSCLC may present with multiple mutations, such as MET amplification or HER2 mutations. How do you make targeted therapy decisions for such advanced NSCLC cases?

Dr. Yilong Wu: Gene mutations are complex. If a patient has co-mutations involving two driver genes, such as MET amplification, it can present in two distinct ways. In most cases, MET amplification occurs after resistance to targeted therapy has developed. In this situation, we often continue using the original targeted therapy while adding a MET inhibitor. For instance, our team recently reported that combining the MET inhibitor tepotinib with osimertinib resulted in an objective response rate of 45%–50% and significantly prolonged PFS. These findings were published in Lancet Oncology, and many similar studies are currently underway.

Another scenario is when MET amplification is detected before treatment begins. In such cases, when MET amplification coexists with EGFR mutations, combination therapy should be initiated from the start, rather than using monotherapy first and adding a second drug later. In clinical practice, different approaches should be taken depending on the specific situation.

It’s also important to note the need for accurate MET amplification detection. Fluorescence in situ hybridization (FISH) is the gold standard for detecting MET amplification, as it provides the most reliable results. There is some uncertainty regarding the reliability of MET amplification detection using next-generation sequencing (NGS), as its consistency is not always ideal. With NGS, we only consider MET amplification to be present if the copy number exceeds 5, at which point combination therapy becomes necessary.

Dr. Yilong Wu

Guangdong Provincial People’s Hospital Professor of Oncology, Doctoral Supervisor Recipient of the IASLC Outstanding Scientist Award Vice President of the Chinese Medical Doctor Association President of the Guangdong Medical Doctor Association (GDMDA) Chief Expert at Guangdong Provincial People’s Hospital (GDPH) Honorary Director of the Guangdong Lung Cancer Institute (GLCI) Chairman of the China Thoracic Oncology Group (CTONG) 2018–2023 Highly Cited Scientist in the field of Clinical Medicine Former President of the Chinese Society of Clinical Oncology (CSCO), now Chairman of the Advisory Board